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WO2023160509A1 - Amidine derivative compound, and preparation method therefor and use thereof - Google Patents

Amidine derivative compound, and preparation method therefor and use thereof Download PDF

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Publication number
WO2023160509A1
WO2023160509A1 PCT/CN2023/077288 CN2023077288W WO2023160509A1 WO 2023160509 A1 WO2023160509 A1 WO 2023160509A1 CN 2023077288 W CN2023077288 W CN 2023077288W WO 2023160509 A1 WO2023160509 A1 WO 2023160509A1
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Prior art keywords
fluoro
hydrogen
trifluoromethyl
alkyl
alkoxy
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French (fr)
Chinese (zh)
Inventor
高召兵
杨春皓
谭村
郑月明
符琳书
许海燕
张小飞
陈笑艳
胡有洪
熊兵
贺茜
魏爱环
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Shanghai Institute of Materia Medica of CAS
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Shanghai Institute of Materia Medica of CAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/275—Nitriles; Isonitriles
    • A61K31/277—Nitriles; Isonitriles having a ring, e.g. verapamil
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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    • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
    • C07C257/20—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having nitrogen atoms of amidino groups acylated
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/12—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines
    • C07C259/18—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. N-hydroxyamidines having carbon atoms of hydroxamidine groups bound to carbon atoms of six-membered aromatic rings
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/06—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom
    • C07D213/16—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom containing only hydrogen and carbon atoms in addition to the ring nitrogen atom containing only one pyridine ring
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to the field of medical technology, in particular to a class of amidine derivative compounds, their preparation method and their use in the preparation of sodium channel Nav1.8 inhibitors and their preparation of medicines for treating and/or alleviating pain and pain-related diseases the use of.
  • Voltage-gated sodium channels mediate the selective transmembrane flow of sodium ions, and mediate the initiation, conduction, and activation of action potentials in excitable cells such as neurons. Play a key role in delivery (Catterall et al., Pharmacol Rev. 2005; 57(4):397-409.).
  • Nav channel is an important drug target, and Nav channel inhibitors are used for the treatment of pain, arrhythmia, epilepsy, anesthesia, pruritus and other diseases (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.).
  • Voltage-gated sodium channel 1.8 (hereinafter referred to as Nav1.8), as a subtype of voltage-gated sodium channel, 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), and inhibition of Nav1.8 may not produce adverse effects of the drug on the central nervous system (CNS). Because the Nav1.8 channel has a high activation and inactivation voltage, it is the main component of the rising branch of the action potential (other Nav channel subtypes are already in a non-functional inactivation state) (Goodwin et al., Nat Rev Neurosci.2021, 22(5):263-274.).
  • Nav1.8 channel The characteristics of slow inactivation and fast reactivation of Nav1.8 channel make it participate in the physiological and pathological processes of pain and other membrane potential depolarization and high-frequency discharge of neurons (Alsaloum et al., Nat Rev Neurol.2020,16(12):689 -705.). Human genetic studies have shown that Nav1.8 gene mutations lead to small fiber neuralgia and erythematous allodynia (Faber et al., Proc Natl Acad Sci U S A. 2012,109(47):19444-9; Kaluza et al., Pflugers Arch .2018, 470(12):1787-1801.).
  • gene knockout or knockdown of Nav1.8 channel gene can alleviate various inflammatory pain and neuralgia; and administration of Nav1.8 inhibitors such as A-803467 can effectively relieve pain response (Jarvis et al., Proc Natl Acad Sci U S A. 2007,104(20):8520-5.).
  • Diabetic neuralgia is one of the most common neuropathic pain diseases. About 60% to 70% of diabetic patients suffer from this disease, and more than 70% of patients have not received effective treatment (Jensen et al., Brain. 2021, 144(6) :1632-1645.). In the mouse model of diabetic neuralgia, methylglyoxal can directly enhance the function of Nav1.8 channel, and gene knockout or knockdown of Nav1.8 channel can effectively alleviate the neuralgia caused by methylglyoxal (Bierhaus et al., Nat Med.2012, 18(6):926-33.).
  • Nav1.8 channels have also been linked to diseases such as multiple sclerosis, cardiac arrhythmias, coughing, itching, and epilepsy.
  • Multiple sclerosis is an inflammatory demyelinating disease that originates in the central nervous system, and its exact pathogenesis remains to be elucidated.
  • the cerebellar Purkinje fibers of normal people do not express Nav1.8 channels.
  • the expression of Nav1.8 in the cerebellum of patients with multiple sclerosis is up-regulated, and the expression of the channel increases with the development of the disease.
  • Nucleic acid polymorphism SNP is also associated with 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. ).
  • Osteoarthritis is a degenerative bone joint disease characterized by cartilage wear and pain.
  • Phosphorylated cAMP response element binding protein (CREB) directly binds to the promoter of the gene encoding Nav1.8, promotes the transcription of Nav1.8 protein, and up-regulates the expression level of Nav1.8 channels (Zhu et al., Elife.2020, 9:e57656.) .
  • Nav1.8 channels have been shown to be expressed in cardiac nerves such as Purkinje fibers, and some studies suggest that Nav1.8 is also expressed in cardiomyocytes (Verkerk et al., Circ Res.2012, 111(3): 333-43.). Human genetic studies have found that mutations in the Nav1.8 gene are associated with Brugada syndrome (Hu et al., J Am Coll Cardiol. 2014, 64(1):66-79.). Inhibition of Nav1.8 channels can improve cardiac remodeling, and Nav1.8 channels are considered to be potential therapeutic targets for cardiovascular diseases such as arrhythmia, atrial fibrillation, and heart failure (Dybkova et al., Cardiovasc Res. 2018, 114(13): 1728 -1737.).
  • Nav1.8 channel is expressed in the cough-related vagus plexus, and the phosphorylation level and expression of Nav1.8 increase during pathological cough, showing that it is involved in the cough reflex (Muroi et al., Lung.2014, 192(1): 15-20 .).
  • Nav1.8 congenital mutations have been reported to cause epilepsy and convulsive disorders (Kambouris et al., Ann Clin Transl Neurol. 2016, 4(1):26-35.). Therefore, inhibitors of Nav1.8 channels are considered to be useful in the treatment, prevention or control of diseases associated with Nav1.8 channel involvement or dysfunction.
  • VX-150 a Nav1.8 sodium ion channel inhibitor containing a pyridone-like structure
  • SFN small fiber neuropathy
  • WO2021018165 and CN202010932125.3 also announced pyridone compounds for inhibiting Nav1.8 sodium ion channel; in addition, WO2014120815, WO2014120820, US201901667, WO2020092187, CN202010889003.0, WO2020092187, CN202110107114.6, etc. respectively disclose aryl formic acids, benzamides, and arylsulfonamides for inhibiting Nav1.8 sodium ion channels and other classes of compounds; in addition WO2020169042 discloses Nav1.8 sodium ion channel inhibitors containing pyridazinone compounds, but none of the above studies have been launched. Therefore, the development of new Nav1.8 inhibitors has very important scientific value and clinical significance for the treatment of diseases related to Nav1.8 expression disorders.
  • One of the objectives of the present invention is to provide an amidine derivative compound with Nav1.8 selective inhibitory activity.
  • the second object of the present invention is to provide a method for preparing amidine derivatives.
  • the third object of the present invention is to provide a pharmaceutical composition comprising the amidine derivative compound.
  • the fourth object of the present invention is to provide a use of the amidine derivative compound or pharmaceutical composition in the preparation of Nav1.8 inhibitors or drugs for treating and/or alleviating pain and pain-related diseases.
  • One aspect of the present invention provides a compound of formula I, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, its deuterated product or its pharmaceutical acceptable salt,
  • 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, and S; preferably, ring A is substituted Or unsubstituted phenyl; the substituted substituent is 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, preferably selected from F
  • R 3 is selected from hydrogen, -CN, -OH or C1 ⁇ C6 alkoxy
  • One of X 1 and X 2 is C, and the other is selected from N and CR g ;
  • R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl;
  • X 3 , X 4 and X 5 are each independently selected from N and CR a , and there is at most one N in X 3 , X 4 and X 5 ;
  • R7 is selected from hydrogen, halogen, C1 ⁇ C6 alkyl, halogenated C1 ⁇ C6 alkyl, C1 ⁇ C6 alkoxy, halogenated C1 ⁇ C6 alkoxy;
  • R g and R a are independently selected from hydrogen, halogen, C1 ⁇ C6 alkyl, halogenated C1 ⁇ C6 alkyl, C1 ⁇ C6 alkoxy, halogenated C1 ⁇ C6 alkoxy, C2 ⁇ C6 alkenyl, halogenated C2 ⁇ C6 alkenyl, C2 ⁇ C6 alkenyloxy, halogenated C2 ⁇ C6 alkenyloxy, C2 ⁇ C6 alkynyl, halogenated C1 ⁇ C6 alkynyl, C2 ⁇ C6 alkynyloxy, halogen Substitute C1 ⁇ C6 alkynyloxy, C3 ⁇ C6 cycloalkyl, C3 ⁇ C6 cycloalkoxy;
  • the two adjacent substituents in R 7 and R a together with the carbon atoms attached to them form a ring Or a substituted or unsubstituted benzene ring;
  • the substituted substituent is selected from halogen, C1 ⁇ C6 alkyl, C1 ⁇ C6 alkoxy, preferably selected from F, Cl, C1 ⁇ C3 alkyl, C1 ⁇ C3 alkoxy base;
  • Y 1 and Y 2 are each independently selected from O, CH 2 ;
  • R 8 is selected from hydrogen, halogen or C1-C3 alkyl.
  • At least one of R 1 , R 2 and R 3 is H, especially, all of R 1 , R 2 and R 3 are hydrogen.
  • the compound of formula I is selected from:
  • X 1 and 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 , Ring A, X 3 , X 4 , and X 5 are the same as those described above.
  • the compound of formula I is selected from the compound of formula IA and the compound of formula IA':
  • X 1 and 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 , and X 5 are as defined above;
  • X 6 , X 7 , X 8 are each independently selected from N and CR b , and there is at most one N in X 6 , X 7 and X 8 ;
  • R b , R 9 and R 10 are 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 Group, deuterated C3 ⁇ C8 cycloalkoxy, halogenated C3 ⁇ C8 cycloalkoxy; 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
  • the compound of formula I is a compound of formula IA:
  • X2 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;
  • X 3 and 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, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy group, preferably R in X3 is selected from trifluoromethyl or trifluoromethoxy, and R in X4 and X5 is hydrogen;
  • X 6 , X 7 , and X 8 are each independently selected from CR b , R b is the same or different, selected from hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogen Substitute C1 ⁇ C6 alkoxy, C3 ⁇ C8 cycloalkyl, preferably selected from hydrogen, F, Cl, Br, trifluoromethyl, methoxy or trifluoromethoxy;
  • R 9 is hydrogen;
  • R 10 is selected from hydrogen, trifluoromethyl, C3 ⁇ C6 cycloalkyl, deuterated C3 ⁇ C6 cycloalkyl;
  • R 7 is selected from halogen, C1 ⁇ C6 alkoxy, preferably selected from F, Cl, Br or methoxy;
  • R 4 , R 5 , and R 6 are each independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, preferably hydrogen;
  • R 1 and R 2 are each independently selected from hydrogen, C1-C6 alkyl, preferably hydrogen;
  • R 3 is selected from hydrogen, -CN, -OH or C1-C6 alkoxy, preferably -OH.
  • the compound of formula IA is selected from the following compounds of formula IA-1:
  • R 1 , R 2 , R 3 , R 4 , R 5 , X 5 , R 6 , R 7 , R 9 , R 10 , R a , R b , and R g are the same as above;
  • R 1 , R 2 and R 3 are hydrogen;
  • R 4 , R 5 , R 6 , R g are H, especially at least three are H, more especially all are H;
  • At least one of R 7 and R a is H, especially at least two of them are H;
  • R 9 , R 10 , R b are H, especially at least three are H.
  • 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;
  • 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 in X3 is selected from trifluoromethyl or trifluoromethoxy, and R in X4 and X5 is hydrogen;
  • R b is the same or different, 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;
  • R 9 is hydrogen;
  • R 10 is selected from hydrogen, trifluoromethyl, C3 ⁇ C6 cycloalkyl, deuterated C3 ⁇ C6 cycloalkyl;
  • R 7 is selected from halogen, C1 ⁇ C6 alkoxy, preferably selected from F, Cl, Br or methoxy;
  • R 4 , R 5 , and R 6 are each independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, preferably hydrogen;
  • R 1 and R 2 are each independently selected from hydrogen, C1-C6 alkyl, preferably hydrogen;
  • R 3 is selected from hydrogen, -CN, -OH or C1-C6 alkoxy, preferably -OH.
  • the compound of formula IA-1 is selected from the following compounds of formula IA-1A:
  • 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 in X 3 is selected from three Fluoromethyl or trifluoromethoxy, R in X 4 and X 5 is hydrogen;
  • R b is the same or different, 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;
  • R 9 is hydrogen;
  • R 10 is selected from hydrogen, trifluoromethyl, C3 ⁇ C6 cycloalkyl, deuterated C3 ⁇ C6 cycloalkyl;
  • R 7 is selected from halogen, C1-C6 alkoxy, preferably from F, Cl, Br or methoxy.
  • the compound of formula I is selected from the following compounds:
  • halogen may be fluorine, chlorine, bromine or iodine.
  • C1 ⁇ C6 alkyl refers to a chain alkyl group with 1 ⁇ 6 carbon atoms; its specific examples 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 similar groups, but not limited thereto ; The definition of "C1-C3 alkyl" and so on.
  • the "deuterated C1-C6 alkyl” means that one or more hydrogens of the above-defined C1-C6 alkyl are replaced by deuterium.
  • halogenated C1-C6 alkyl means that one or more hydrogens of the above-defined C1-C6 alkyl are replaced by halogen.
  • C2-C6 alkenyl refers to a straight-chain or branched group containing 2-6 carbon atoms and at least one carbon-carbon double bond; its specific examples may include vinyl, propenyl, 2-propene Base, (E)-2-butenyl, (Z)-2-butenyl, (E)-2-methyl-2-butenyl, (Z)-2-methyl-2-butene base, 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.
  • C2-C6 alkynyl group refers to a straight-chain or branched group containing 2-6 carbon atoms and at least one carbon-carbon double bond; its specific examples may include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl.
  • C1-C6 alkoxy group refers to the RO- group, wherein R is the above-mentioned C1-C6 alkyl group.
  • alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, Isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy, 3,3-dimethylbutoxy, 2-ethylbutoxy and the like.
  • the definition of "C1-C3 alkoxy" is analogous.
  • halogenated C1-C6 alkoxy group refers to a group obtained by replacing at least one hydrogen of the above-mentioned alkoxy group with a halogen; specific examples thereof include trifluoromethoxy group and the like.
  • the “deuterated C1-C6 alkoxy group” refers to the RO- group, wherein R is the deuterated C1-C6 alkyl group as described above.
  • C2-C6 alkenyloxy group refers to the RO- group, wherein R is the above-mentioned C2-C6 alkenyl group; specific examples of the alkenyloxy group include ethyleneoxy and propyleneoxy.
  • C2-C6 alkynyloxy group refers to the RO- group, wherein R is the above-mentioned C2-C6 alkynyl group; specific examples of the alkynyloxy group include ethynyloxy and propynyloxy.
  • C3-C8 cycloalkyl refers to a fully saturated cyclic hydrocarbon compound group containing 3-8 carbon atoms, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
  • deuterated C3-C8 cycloalkyl group refers to a group obtained by replacing one or more hydrogens of the C3-C8 cycloalkyl group defined above with deuterium.
  • halogenated C3-C8 cycloalkyl refers to a group obtained by replacing one or more hydrogens of the C3-C8 cycloalkyl as defined above with halogen.
  • C3-C8 cycloalkoxy group refers to the RO-group, wherein R is the above-mentioned C3-C8 cycloalkyl group.
  • deuterated C3-C8 cycloalkoxy group refers to a group obtained by replacing one or more hydrogens of the C3-C8 cycloalkoxy group defined above with deuterium.
  • halogenated C3-C8 cycloalkoxy group refers to a group obtained by replacing one or more hydrogens of the C3-C8 cycloalkoxy group defined above with halogen.
  • C6-C12 aryl refers to a monocyclic or polycyclic aryl group having 6 to 12 carbon atoms; specific examples thereof include phenyl, naphthyl.
  • 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 on the ring, and its specific examples include pyridine, pyridazine, pyrimidine, etc. .
  • salts are well known in the art and include salts derived from suitable inorganic/organic acids and bases.
  • suitable inorganic/organic acids and bases include inorganic acids (e.g., hydrochloric, hydrobromic, phosphoric, sulfuric, and perchloric) or organic acids (e.g., acetic, oxalic, maleic, tartaric, citric, acid, succinic acid, or malonic acid) or by using the Salts formed with amino groups by other methods used in the art (eg, ion exchange).
  • salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate , glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate Salt, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate salt, pectate, 3-phen
  • salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations using, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and Formed by counter ions such as aryl sulfonates.
  • deuterated substance refers to a structure in which one or more hydrogens ( 1 H) in the compound structure are replaced by deuterium ( 2 H).
  • the compounds involved in the present application and their pharmaceutically acceptable salts may have isomers or racemates, such as optical isomers (including diastereoisomers and enantiomers), atropisomers, Geometric isomers (cis-trans isomers), conformational isomers, tautomers, mixtures thereof, etc., but not limited thereto. These isomers are also included in the scope defined by the claims of the present invention.
  • Another aspect of the present invention provides the preparation method of the above-mentioned compound of formula I, the method is realized by the following reaction scheme:
  • compound II-A and alcohol Under acid catalysis, compound II-A and alcohol generate Pinner salt, and then add NR 1 R 2 R 3 to prepare compound IA.
  • R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 in compound II-A are the same as in compound IA. definition.
  • the preparation method of the compound of formula II-A is one of the following method one or method two:
  • a base such as potassium carbonate or cesium carbonate
  • Step 2 M1 is hydrolyzed into acid, and then reacted with SM3 to prepare II-A through amino acid condensation reaction;
  • the amino acid condensation reaction is one of the following schemes one to three:
  • the amine acid condensation is in the presence of a condensing agent, conventional condensing agents 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, or N,N-dimethylformamide, dimethyl sulfoxide, etc. at a temperature in the range of 0 to 100°C to obtain II-A.
  • a condensing agent conventional condensing agents such as HATU or HBTU
  • a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc.
  • a suitable solvent such as acetonitrile , tetrahydrofuran, or N,N-dimethylformamide, dimethyl sulfoxide, etc. at a temperature in
  • POCl 3 is slowly added dropwise to the pyridine system of M1 and SM3 to obtain II-A.
  • the certain temperature is -10°C to 30°C, preferably around 0°C.
  • M1 is first prepared into an acid chloride under the action of thionyl chloride or phosphorus trichloride, and then mixed with SM2 in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc. , to obtain II-A in a suitable solvent such as dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethylsulfoxide, and the like.
  • a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc.
  • a suitable solvent such as dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethylsulfoxide, and the like.
  • Step 1 Dehydration of SM1 and SM3 to prepare M2;
  • the amino acid dehydration reaction is one of the following schemes 1 to 3:
  • SM1 and SM3 were condensed with amino acids to obtain M2.
  • the amine acid condensation is in the presence of a condensing agent, conventional condensing agents 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 or N,N-dimethylformamide, dimethyl sulfoxide, etc. at a temperature in the range of 0 to 100°C to obtain M2.
  • a condensing agent conventional condensing agents such as HATU or HBTU
  • a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc.
  • a suitable solvent such as acetonitrile , tetrahydrofuran or N,N-dimethylformamide
  • POCl 3 is slowly added dropwise to the pyridine system of SM1 and SM3 to obtain M2, and the certain temperature is -10°C to 30°C, preferably around 0°C.
  • SM1 is prepared into an acid chloride under the action of thionyl chloride or phosphorus trichloride, followed by SM3 in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc.
  • M2 is obtained in appropriate solvents such as dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethylsulfoxide, and the like.
  • a base such as potassium carbonate or cesium carbonate
  • R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 in the II-A' compound are the same as I-A ' Compounds are defined accordingly.
  • the preparation method of the compound of formula II-A' is one of the following methods one and two:
  • a base such as potassium carbonate or cesium carbonate
  • the second step first hydrolyze M1 into an acid, and then prepare II-A' through amino acid condensation reaction with SM4;
  • the amino acid condensation reaction is one of the following schemes one to three:
  • the amine acid condensation is carried out in a suitable solvent such as acetonitrile 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. , tetrahydrofuran or N,N-dimethylformamide, dimethyl sulfoxide, etc. in the range of 0 to 100 ° C at a temperature within the range.
  • a condensing agent such as a conventional condensing agent such as HATU or HBTU
  • a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc.
  • tetrahydrofuran or N,N-dimethylformamide, dimethyl sulfoxide, etc. in the range of 0 to 100 ° C at
  • POCl 3 is slowly added dropwise to the pyridine system of M1 and SM4 to obtain II-A'.
  • the certain temperature is -10°C to 30°C, preferably around 0°C.
  • M1 is first prepared into an acid chloride under the action of thionyl chloride or phosphorus trichloride, and then with SM4 in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc. , to obtain II-A' in a suitable solvent such as dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethylsulfoxide, etc.
  • a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc.
  • a suitable solvent such as dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethylsulfoxide, etc.
  • the first step SM1 and SM4 prepare M4 through amino acid condensation reaction
  • the amino acid dehydration reaction is one of the following schemes 1 to 3:
  • Amino acid condensation reaction between SM1 and SM4 gives M4.
  • the amine acid condensation is carried out in a suitable solvent such as acetonitrile 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. , tetrahydrofuran, or N,N-dimethylformamide, dimethyl sulfoxide, etc. at a temperature within the range of 0 to 100°C.
  • a condensing agent such as a conventional condensing agent such as HATU or HBTU
  • a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc.
  • tetrahydrofuran or N,N-dimethylformamide, dimethyl sulfoxide
  • POCl 3 is slowly added dropwise to the pyridine system of SM1 and SM4 to obtain M4.
  • the certain temperature is -10°C to 30°C, preferably around 0°C.
  • SM1 into an acid chloride under the action of thionyl chloride or phosphorus trichloride, and then with SM4 in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc.
  • M4 was obtained in a suitable solvent such as dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethylsulfoxide, etc.
  • a base such as potassium carbonate or cesium carbonate
  • R 1 and R 2 are 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
  • R 1 and R 2 are H
  • R 3 is OH
  • X 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 5 , X 6 , X 7 The definition of X and X is the same as the corresponding definition in the IA compound
  • 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.;
  • 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.;
  • the salts of hydroxylamine include, but are not limited to, hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine phosphate, and the like.
  • R 1 and R 2 are H, R 3 is OH, R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 ,
  • the definition of X is the same as the corresponding definition in the I-A'compound;
  • II-A' compound is reacted with hydroxylamine or a salt of hydroxylamine in the presence of anhydrous solvent and base to obtain I-A' compound;
  • 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.;
  • the base is anhydrous organic base, including but not limited to anhydrous triethylamine, anhydrous N,N-dimethylethylamine, anhydrous 1,8-diazabicyclo[5.4.0]undecane -7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, triethylenediamine, sodium methoxide, potassium ethoxide, potassium tert-butoxide, etc.;
  • the salts of hydroxylamine include, but are not limited to, hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine phosphate, and the like.
  • compositions which comprises a compound selected from formula I, its tautomers, mesoforms, racemates, enantiomers, diastereoisomers and one or more of its pharmaceutically acceptable salts, and optional pharmaceutically acceptable auxiliary materials.
  • compositions include any and all solvents, diluents or other liquid excipients, dispersion or suspension aids, surfactants, isotonic agents, thickening agents or Emulsifiers, preservatives, solid binders, lubricants, etc.
  • the use of any commonly used carrier medium is encompassed within the scope of the present invention unless such commonly used carrier medium is incompatible with the compounds of this invention, for example produces any undesired biological effect or otherwise interacts in a deleterious manner with the pharmaceutically acceptable composition. interact with any other components.
  • materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphoric acid salt, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal Silicon dioxide, magnesium trisilicate), polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars (for example, lactose, glucose and sucrose), starch (such as corn starch and potato starch), cellulose and its derivatives (such as sodium methylcellulose, ethyl cellulose and cellulose acetate), tragacanth gum powder
  • Another aspect of the present invention provides the compound of formula I, its tautomer, mesomer, racemate, enantiomer, diastereoisomer or pharmaceutically acceptable salt thereof or the above-mentioned Use of the pharmaceutical composition in the preparation of Nav1.8 inhibitors.
  • Another aspect of the present invention provides a method for inhibiting Nav1.8 in an individual, comprising administering to the individual a compound selected from formula I, its tautomer, meso, racemate, and enantiomer , diastereoisomers and pharmaceutically acceptable salts thereof One or more of or the above-mentioned pharmaceutical composition.
  • Another aspect of the present invention provides the compound of formula I, its tautomer, mesomer, racemate, enantiomer, diastereoisomer or pharmaceutically acceptable salt thereof or the above-mentioned Application of the pharmaceutical composition in the preparation of medicines for treating and/or alleviating pain diseases and pain-related diseases.
  • Another aspect of the present invention provides a method for treating or alleviating pain diseases and pain-related diseases or symptoms, the method comprising administering a compound selected from formula I, its tautomer, meso One or more of body, racemate, enantiomer, diastereomer and pharmaceutically acceptable salt thereof, or the above pharmaceutical composition.
  • the pain disorders include but 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 pain), musculoskeletal pain (including but not limited to osteoarthritis pain, back pain, cold pain, burn pain or tooth pain), post-operative pain (including but not limited to post-bunionectomy pain, abdominoplasty pain, etc.) and internal pain, functional pain, pain associated with musculoskeletal injury, pelvic pain, abdominal pain, chest pain, lumbosacral neuralgia, preoperative pain, intraoperative pain, postoperative pain, bowel 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 from chemotherapy or drug therapy, diabetic neuropathy pain,
  • the pain-related diseases include arthritis, pruritus, acute or chronic pruritus, asthma, multiple sclerosis, cardiac arrhythmia, atrial fibrillation, heart failure, Brugada syndrome, kidney stones, epilepsy, convulsions, Xia-Ma- Figure III Syndrome, incontinence, etc.
  • the present invention provides an amidine derivative compound which is different from the currently existing Nav1.8 selective inhibitors, has good Nav1.8 selective inhibitory activity, good pharmacokinetic properties, and good druggability , as a Nav1.8 inhibitor can be used to treat or alleviate pain or pain-related diseases, and has important clinical application value.
  • the raw materials, reagents, and methods used in the examples are conventional raw materials, reagents, and methods in the art.
  • Thin layer analysis (TLC) plate model is HSGF-254 (thickness 0.15-0.2mm, produced by Yantai Chemical Experimental Factory); column chromatography silica gel is 200-300 mesh commercial silica gel produced by Qingdao Ocean Chemical Factory; 1 H-NMR, 13 C-NMR using Bruker AM-300, Varian Mercury-500 nuclear magnetic resonance instrument records, internal standard is tetramethylsilane (TMS); chemical shift is (ppm, ⁇ :), proton coupling is marked as singlet (s), doublet (d), Triplet (t), quartet (q), multiplet (m), broad peak (br); low-resolution mass spectra were recorded using Finning/MAT-95 instruments or Agilent 6110 mass spectrometers.
  • TMS tetramethylsilane
  • HEPES 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid or N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid);
  • EGTA Ethylene glycol bis(2-aminoethyl ether) tetraacetic acid
  • the hydrogen chloride-ethyl acetate system, the hydrogen chloride-dioxane system, the hydrochloric acid-ethyl acetate system, and the hydrochloric acid-dioxane system all refer to the hydrogen chloride organic solution without water.
  • the first step the synthesis of 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzonitrile (1-a)
  • the second step the synthesis of 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoic acid (1-b)
  • N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-1) (200.0mg, 0.482mmol), triethylamine (0.4mL, 2.90mmol) and hydroxylamine hydrochloride (67.0mg, 0.965mmol) were added to 95% ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate.
  • the crude intermediate was dissolved in anhydrous methanol (20.0 mL), and cyclopropylamine (27.2 mg, 0.4 mmol) and triethylamine (0.17 mL, 1.2 mmol) were added to react under reflux. After the reaction was complete, it was concentrated to obtain the crude product I-6.
  • the first step methyl 4-chloro-6-methylnicotinate (8-SM1) (1.2g, 6.5mmol), 4-fluoro-2-methylphenol (897.0mg, 7.11mmol), cesium carbonate ( 4.2g, 12.9mmol), cuprous iodide (12.3mg, 0.065mmol) was added to toluene (10.0mL), and the reaction was refluxed at 100°C.
  • the second step Dissolve 2-(4-fluoro-2-methylphenoxy)-6-methylnicotinic acid methyl ester (8-a) (1.38g, 5.0mmol) in sodium hydroxide solution (10N, 5.0 mL), methanol (8.0 mL) was added, and the reaction was refluxed until the reaction of the raw materials was complete. Concentrate to remove methanol, add water, adjust the pH to about 2-3 with 2N dilute hydrochloric acid, a large amount of white solid precipitates, let it stand, and filter to obtain 2-(4-fluoro-2-methylphenoxy)-6-methylnicotinic acid ( 8-b) (1.2 g, yield 91.5%).
  • the third step 2-(4-fluoro-2-methylphenoxy)-6-methylnicotinic acid (8-b) (1.2g, 4.57mmol), m-aminobenzonitrile (567.0mg, 4.8 mmol) was dissolved in pyridine (12.0mL), and phosphorus oxychloride (0.9mL, 9.2mol) was slowly added dropwise at 0°C, and the temperature was controlled below 10°C. 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 a crude product.
  • N-(3-benzonitrile)-2-(4-fluoro-2-methylphenoxy)-6-methylnicotinamide (II-A-2) (200.0mg, 0.553 mmol), absolute ethanol (2.0 mL) and hydrochloric acid-ethyl acetate (10N, 6.0 mL) were added to the sealed tube, and the tube was locked to react at room temperature. After the reaction was complete, the reaction system was evaporated to dryness, anhydrous methanol (3.0 mL), ammonia-methanol solution (7N, 5.0 mL), 2 eq ammonium chloride were added, and the reaction was refluxed at 65°C.
  • the first step Dissolve 2-fluoro-4-trifluoromethylbenzoic acid (9-SM1) (2.08g, 10.0mmol), m-aminobenzonitrile (1.2g, 10.0mmol) in pyridine (16.0mL) , slowly add phosphorus oxychloride (1.9mL, 20.0mmol) dropwise at 0°C, and control the temperature below 10°C. Adjust the pH to about 2-3 with hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and evaporate to dryness to obtain a crude product.
  • the second step (9-a) (308.0mg, 1.0mmol), 4-trifluoromethoxyphenol (195.0mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were added to N,N-di Methylformamide (7.0 mL) was reacted 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 a crude product.
  • N-(3-cyanophenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (II-A-3 ) (149.0mg, 0.32mmol) was added to absolute ethanol (2.0mL) and hydrochloric acid-ethyl acetate system (10N, 0.6mL), and the reaction was sealed at room temperature. After the reaction was complete, the reaction system was evaporated to dryness, anhydrous methanol (3.0 mL), ammonia-methanol system (7N, 5.0 mL), ammonium chloride (68.6.0 mg, 1.3 mmol) were added, and the reaction was refluxed at 65° C. for 3 h.
  • the first step 9-a (308.0mg, 1.0mmol) obtained in Example 9, 4-trifluorocresol (178.0mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were added to N,N- Dimethylformamide (7.0 mL) was reacted 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 a crude product.
  • N-(3-cyanophenyl)-4-(trifluoromethyl)-2-(4-(trifluoromethyl)phenoxy)benzamide (II-A-4) (149.0mg, 0.32mmol) and absolute ethanol (2.0mL) were added to hydrochloric acid-ethyl acetate system (10N, 0.6mL), and the reaction was sealed 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), ammonium chloride (68.6 mg, 1.3 mmol) were added, and the reaction was refluxed at 65°C.
  • the first step 9-a (308.0mg, 1.0mmol), 4-fluoro-2-methoxyphenol (156.2mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) obtained in Example 9 were dissolved in In N,N-dimethylformamide (7.0 mL), 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 a crude product.
  • N-(3-cyanophenyl)-2-(4-fluoro-2-methoxyphenoxy)-4-(trifluoromethyl)benzamide (II-A-5 ) (180.0mg, 0.42mmol), absolute ethanol (2mL) and hydrochloric acid-ethyl acetate system (10N, 8.0mL) were added to the locked tube, and the tube was locked to react 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), ammonium chloride (89.4 mg, 1.68 mmol) were added, and the reaction was carried out under reflux until the raw materials were completely reacted.
  • the first step 9-a (308.0mg, 1.0mmol), 3-fluoro4-methoxyphenol (156.3mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) obtained in Example 9 were added to N , in N-dimethylformamide (7.0 mL), 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 a crude product.
  • N-(3-cyanophenyl)-2-(3-fluoro-4-methoxyphenoxy)-4-(trifluoromethyl)benzamide (II-A-6 ) (175.0mg, 0.42mmol), absolute ethanol (2.0mL) and hydrochloric acid-ethyl acetate system (10N, 10.0mL) were added to the locked tube, and the tube was locked to react at room temperature. After the reaction was complete, the reaction system was evaporated to dryness to obtain an intermediate, which was dissolved by adding anhydrous methanol (3.0 mL), ammonia-methanol solution (5 mL), ammonium chloride (87.0 mg, 1.67 mmol), and reacted under reflux until the raw materials were completely reacted.
  • anhydrous methanol (3.0 mL)
  • ammonia-methanol solution 5 mL
  • ammonium chloride 87.0 mg, 1.67 mmol
  • N-(2-chloro-5-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II- A-7) 134.0mg, 0.3mmol
  • absolute ethanol 0.17mL
  • hydrochloric acid-ethyl acetate system 10N, 7.0mL
  • N-(2-methyl-5-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II -A-8) (214.0mg, 0.5mmol), absolute ethanol (1.5mL) and hydrochloric acid-ethyl acetate system (10N, 7.0mL) were added to the locked tube, and the tube was locked to react at room temperature. After the reaction is complete, the intermediate is formed and the reaction system is evaporated to dryness. Add anhydrous methanol (3.0 mL), ammonia-methanol solution (5.0 mL), ammonium chloride (53.0 mg, 1 mmol), and react at reflux until the intermediate is completely reacted. .
  • the second step N-(2-methyl-5-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II -A-9) (214.0mg, 0.5mmol), absolute ethanol (1.5mL) and hydrochloric acid-ethyl acetate system (10N, 5.0mL) were added to the locked tube, and the tube was locked to react at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, ammonia-methanol solution (7N, 5.0 mL), ammonium chloride (53.0 mg, 1 mmol) was added, and the reaction was carried out under reflux until the intermediate was completely reacted.
  • the first step 2-fluoro-4-chlorobenzoic acid (16-SM1) (1.0g, 5.73mmol), m-aminobenzonitrile (710.6mg, 6.02mmol) were dissolved in pyridine (9.0mL), at 0 Slowly add phosphorus oxychloride (1.0mL, 11.5mmol) dropwise at °C, control the temperature below 10°C, continue the reaction until the raw materials are completely reacted, then pour the reaction system into ice water, and use 2N Adjust the pH value to about 2-3 with hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and evaporate to dryness to obtain a crude product.
  • the second step 16-a (275.0mg, 1.0mmol), 4-fluoro-2-methylphenol (138.0mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were dissolved in N,N-dimethyl In methyl formamide (7.0 mL), 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 a crude product.
  • the third step 4-chloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (II-A-10) (197.0mg, 0.5 mmol), absolute ethanol (0.2mL) and hydrochloric acid-ethyl acetate system (10N, 5.0mL) were added to the sealed tube, and the tube was locked to react at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, then ammonia-methanol solution (7N, 5.0 mL) and ammonium chloride (53.0 mg, 1 mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted.
  • the first step 2-fluoro-5-trifluoromethylbenzoic acid (17-SM1) (1.0g, 4.81mmol), m-aminobenzonitrile (694.0mg, 5.05mmol) were dissolved in pyridine (7mL), Phosphorus oxychloride (0.9mL, 9.6mmol) was slowly added dropwise at 0°C, and the temperature was controlled at Below 10°C, the dropwise addition is completed, 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, evaporate Dried rough.
  • the second step 17-a (275.0mg, 1.0mmol), 4-fluoro-2-methylphenol (138.0mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were dissolved in N,N-dimethyl In methyl formamide (7.0 mL), 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 a crude product.
  • the third step N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamide (II-A-11) (197.0mg, 0.5mmol), absolute ethanol (0.2mL) and hydrochloric acid-ethyl acetate system (10N, 5.0mL) were added to the locked tube, and the tube was locked to react at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, then ammonia-methanol solution (7N, 5.0 mL) and ammonium chloride (53.0 mg, 1 mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted.
  • the first step 2-fluoro-5-chlorobenzoic acid (18-SM1) (1.0g, 5.73mmol), m-aminobenzonitrile (710.6mg, 6.02mmol) were dissolved in pyridine (9.0mL), at 0 Slowly add phosphorus oxychloride (1.0mL, 11.5mmol) dropwise at °C, control the temperature below 10°C, continue the reaction until the raw materials are completely reacted, then pour the reaction system into ice water, and use 2N Adjust the pH value to about 2-3 with hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate and precipitate a solid to obtain compound (18-a) (360.0 mg, yield 24.4%).
  • the second step 18-a (275.0mg, 1.0mmol), 4-fluoro-2-methylphenol (138.0mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were added to N,N-dimethyl In methyl formamide (7.0 mL), 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 a crude product.
  • the third step 5-chloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (II-A-12) (97.0mg, 0.25 mmol), absolute ethanol (0.1 mL) and hydrochloric acid-ethyl acetate system (10N, 5.0 mL) were added to the sealed tube, and the tube was sealed to react at room temperature. After the reaction was complete and the intermediate was formed, the reaction system was evaporated to dryness, then ammonia-methanol solution (7N, 5.0mL) and ammonium chloride (30.0mg, 1.0mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted.
  • the first step Dissolve 2-fluoro-4,5-dichlorobenzoic acid (19-SM1) (2.0g, 9.6mmol), m-aminobenzonitrile (1.2g, 10.0mmol) in pyridine (15.0mL) , slowly add phosphorus oxychloride (1.8mL, 19.2mmol) dropwise at 0°C, and control the temperature below 10°C. Adjust the pH value to about 2-3 with hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to precipitate a solid to obtain compound (19-a) (1.6 g, yield 54.1%).
  • the second step 19-a (309.0mg, 1.0mmol), 4-fluorophenol (123.0mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were added to N,N-dimethylformamide (10.0 mL), react at 80°C until the raw materials are completely reacted.
  • the third step 4,5-dichloro-N-(3-cyanophenyl)-2-(4-fluorophenoxy)benzamide (II-A-13) (202.0mg, 0.49mmol) , absolute ethanol (1.0 mL) and hydrochloric acid-ethyl acetate system (10N, 5.0 mL) were added to the sealed tube, and the tube was locked to react at room temperature. After the reaction was complete and the intermediate was formed, the reaction system was evaporated to dryness, then ammonia-methanol solution (7N, 5.0mL) and ammonium chloride (52.4mg, 1mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted.
  • the first step 19-a (309.0mg, 1.0mmol) obtained in Example 19, 4-fluoro-2-methoxyphenol (156.3mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were dissolved in In N,N-dimethylformamide (5.0 mL), react at 80°C until the starting material is completely reacted.
  • the second step 4,5-dichloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide (II-A-14) ( 200.0mg, 0.49mmol), absolute ethanol (1.0mL) and hydrochloric acid-ethyl acetate system (10N, 5.0mL) were added to the locked tube, and the tube was locked to react at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, then ammonia-methanol solution (7N, 5.0 mL) and ammonium chloride (50.0 mg, 1 mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted. Cooling, concentrated directly to the crude product.
  • the first step 16-a (275.0mg, 1.0mmol) obtained in Example 16, 4-fluoro-2-methoxyphenol (156.3mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were added to In N,N-dimethylformamide (7.0 mL), 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 a crude product.
  • the second step 4-chloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide (II-A-15) (200.0mg, 0.47mmol), absolute ethanol (1.0mL) and hydrochloric acid-ethyl acetate system (10N, 10.0mL) were added to the sealed tube, and the tube was locked to react at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, ammonia-methanol solution (7N, 10.0 mL), ammonium chloride (55.0 mg, 1 mmol) was added, and the reaction was carried out under reflux until the intermediate was completely reacted. Subsequent direct concentration gave the crude product.
  • the second step 4,5-dichloro-N-(3-cyanophenyl)-2-(4-fluoro-3-methoxyphenoxy)benzamide (II-A-16) ( 100.0mg, 0.23mmol), absolute ethanol (0.1mL) and hydrochloric acid-dioxane system (4N, 10.0mL) were added to the locked tube, and the tube was locked to react at room temperature. After the reaction was complete to generate the intermediate, the reaction system was concentrated, then ammonia-methanol solution (4N, 10.0mL) and ammonium chloride (24.0mg, 0.46mmol) were added, and reacted under reflux until the intermediate was completely reacted. Subsequent direct concentration gave the crude product.
  • the first step 2-fluoro-4-trifluoromethylbenzoic acid (9-SM1) (1.0g, 4.8mmol) in Example 9, 3-amino-4-methylbenzonitrile (667.0mg, 5.05mmol) was dissolved in pyridine (10.0mL), and phosphorus oxychloride (0.9mL, 9.6mmol) was slowly added dropwise at 0°C, and the temperature was controlled below 10°C.
  • N-(5-cyano-2-methylphenyl)-2-fluoro-4-(trifluoromethyl)benzamide (23-a) 322.0mg, 1.0mmol
  • 4 -Fluorophenol (123.3 mg, 1.1 mmol
  • cesium carbonate 651.0 mg, 2.0 mmol
  • 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 a crude product.
  • the third step N-(5-cyano-2-methylphenyl)-2-(4-fluorophenoxy)-4-(trifluoromethyl)benzamide (II-A-23) (200.0mg, 0.48mmol) and absolute ethanol (0.3mL) were added to hydrochloric acid-dioxane system (4N, 12.0mL) into the sealed tube, and reacted at room temperature. After the reaction was complete, the reaction system was concentrated to dryness to obtain the intermediate, and then ammonia-methanol solution (4N, 10.0 mL) and ammonium chloride (51.6 mg, 0.46 mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted. Concentration gave the crude product.
  • the first step 18-a (275.0mg, 1.0mmol) obtained in Example 18, 4-fluoro-2-methoxyphenol (156.0mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were added to In N,N-dimethylformamide (7.0 mL), react at 80°C until the starting material is completely reacted. Use 2N dilute hydrochloric acid to adjust the pH to about 2 ⁇ 3, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate get crude.
  • the second step 5-chloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide (II-A-18) (50.0mg, 0.13mmol) and absolute ethanol (0.1mL) were added to hydrochloric acid-dioxane system (4N, 10mL), and the reaction was sealed at room temperature. After the reaction was complete, the reaction system was concentrated to obtain an intermediate, then ammonia-methanol solution (4N, 5mL) and ammonium chloride (22.0mg, 0.26mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted. Concentrated crude.
  • the first step 4-bromo-2-fluorobenzonitrile (19-SM1) (4.0g, 20.0mmol), 4-fluoro-2-methylphenol (2.52g, 20.0mmol) and cesium carbonate (13.0g , 40.0mmol) was added into N,N-dimethylformamide (60.0mL) at 80°C until the main raw material was completely reacted. Ethyl acetate and water were added to carry out stirring and liquid separation. The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated to give the crude product.
  • Step 4 Under nitrogen protection, mix 19-c (850.0mg, 2.0mmol), trimethylsilylacetylene (294.5mg, 3.0mmol), cuprous iodide (76.0mg, 0.02mmol), tetrakistriphenylphosphine Palladium (206.0mg, 0.2mmol) and triethylamine (0.56mL, 4.0mmol) were added to toluene (10mL) and reacted under reflux until the main raw material was completely reacted. After cooling, the reaction system was poured into ice water and washed with ethyl acetate. Ester extraction, drying, and concentration gave the crude product.
  • Step 5 Add 19-d (331.0mg, 0.75mmol) to formic acid (10mL) to react at 80°C and concentrate to obtain a crude product.
  • N-(3-cyanophenyl)-4-ethynyl-2-(4-fluoro-2-methylphenoxy)benzamide (II-A-19) (65.0mg, 0.175mmol) and absolute ethanol (0.1mL) were added to hydrochloric acid-ethyl acetate system (10N, 10.0mL), and the reaction was sealed at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, ammonia-methanol solution (4N, 8.0mL) and ammonium chloride (18.7mg, 0.34mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted. Subsequent direct concentration gave the crude product.
  • the first step under nitrogen protection, 19-c (425.0mg, 1.0mmol) obtained in Example 25, 4-methyl-1-pentyne (353mg, 3.0mmol), cuprous iodide (38.0mg, 0.01 mmol), tetrakistriphenylphosphine palladium (103mg, 0.1mmol) and triethylamine (0.28mL, 2.0mmol) were added in toluene (10.0mL) and reacted under reflux until the main raw material was completely reacted, cooled, and the reaction system was poured Pour into ice water, extract with ethyl acetate, dry and concentrate to obtain the crude product.
  • the second step N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(4-methyl-1-4-methyl-1-pentane Alkynyl)benzamide (II-A-20) (140mg, 0.34mmol) and absolute ethanol (0.1mL) were added to hydrochloric acid/ethyl acetate (10N, 16.0mL), and the reaction was sealed at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, ammonia-methanol solution (7N, 3.0mL) and ammonium chloride (35.0mg, 0.68mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted.
  • Step 1 Dissolve 2,6-dichloro-5-fluoronicotinic acid (27-SM1) (1.05g, 5.0mmol), m-aminobenzonitrile (587mg, 5.0mmol) in pyridine (4.0mL), Phosphorus oxychloride (0.9mL, 2.0mmol) was slowly added dropwise at 0°C, and the temperature was controlled below 10°C. After the dropwise addition was completed, the reaction was continued until the raw materials were completely reacted, and then the reaction system was poured into ice water and washed with 2N salt Adjust the pH value to about 2-3 with acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and evaporate to dryness to obtain a crude product.
  • the second step 27-a (310.0mg, 1.0mmol), 4-fluoro-2-methylphenol (126.0mg, 1.1mmol), cuprous iodide (2.0mg, 0.01mmol) and cesium carbonate (651.0mg , 2.0mmol) was added to toluene (7.0mL) and reacted 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 a crude product.
  • Step 1 Dissolve 2-fluorobenzoic acid (28-SM1) (1.4g, 10.0mmol), m-aminobenzonitrile (1.2g, 10.0mmol) in pyridine (8.0mL), drop slowly at 0°C Add phosphorus oxychloride (1.9mL, 20.0mmol), control the temperature below 10°C, dropwise, continue the reaction until the reaction of the raw materials is complete, then pour the reaction system into ice water, adjust with 2N hydrochloric acid When the pH value was about 2-3, it was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product.
  • the second step under the protection of nitrogen, 28-a (480.0mg, 2.0mmol), 4-fluoro-2-methylphenol (252.0mg, 2.0mmol) and cesium carbonate (1.3mg, 4.0mmol) and iodide Copper (38.0mg, 0.2mmol) was added to toluene (20.0mL) and reacted at 90°C. After the reaction is complete, pour it 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 a crude product.
  • the third step N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (II-A-22) (250.0mg, 0.72mmol) and no Water ethanol (0.4mL) was added to hydrochloric acid-ethyl acetate system (10N, 14.0mL), and the reaction was sealed at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, ammonia-methanol solution (7N, 5.0 mL), ammonium chloride (77.0 mg, 1.4 mmol) was added, and the reaction was carried out under reflux until the intermediate was completely reacted. Subsequent direct concentration gave the crude product.
  • the first step 5-chloro-2-fluoro-6-methylnicotinic acid ethyl ester (29-SM1) (434.0mg, 2.0mmol), 4-fluoro-2-methylphenol (252.0mg, 2.0mmol) , cesium carbonate (1.3g, 4.0mmol), cuprous iodide (38.0mg, 0.2mmol) was added to toluene (20.0 mL), the reaction was refluxed 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 a crude product.
  • the second step Dissolve ethyl 5-chloro-2-(4-fluoro-2-methylphenoxy)-6-methylnicotinate (29-a) (323.0mg, 1.0mmol) in sodium hydroxide To the solution (10N, 5.0 mL), methanol (8.0 mL) was added, and the reaction was refluxed at 80° C. for 1 h. Concentrate to remove methanol, add water, adjust the pH value to about 2-3 with 2N dilute hydrochloric acid, a large amount of white solid precipitates, let stand, filter, and dry to obtain 5-chloro-2-(4-fluoro-2-methylphenoxy )-6-methylnicotinic acid (29-b) 290.0mg to the next step directly;
  • the third step N-(3-cyanophenyl)-5-fluoro-(4-fluoro-2-methylphenoxy)-6-methylnicotinamide (II-A-23) (100.0mg , 0.25mmol) and absolute ethanol (0.2mL) were added to hydrochloric acid-ethyl acetate system (10N, 10.0mL), and the reaction was sealed at room temperature. The reaction system was concentrated after the intermediate was completely generated in the reaction. Then ammonia-methanol solution (7N, 5.0mL) and ammonium chloride (27.0mg, 0.5mmol) were added, and the mixture was refluxed until the intermediate was completely reacted. Subsequent direct concentration gave the crude product.
  • the first step Dissolve 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (30-SM1) (628.0mg, 2.2mmol), m-aminobenzonitrile (272.0mg, 2.3mmol) in In pyridine (3.5mL), slowly add phosphorus oxychloride (0.4mL, 4.4mmol) dropwise at 0°C, control the temperature below 10°C, after the dropwise addition is complete, continue the reaction until the raw materials are completely reacted, then pour the reaction system into 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 a crude product.
  • 6-SM1 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid
  • m-aminobenzonitrile 272.0mg, 2.3mmol
  • pyridine 3.5mL
  • the second step 30-a (200.0mg, 0.52mmol), 4-fluoro-2-methylphenol (1-SM2) (78.2mg, 0.62mmol), cesium carbonate (336.0mg, 2.0mmol), iodide Cuprous (9.0mg, 0.05mmol) was added into toluene (10.0mL), and the reaction was refluxed 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 a crude product.
  • N-(3-cyanophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (II- A-24) (90.0mg, 0.21mmol) and absolute ethanol (0.1mL) were added to hydrochloric acid-ethyl acetate system (10N, 10.0mL), and the reaction was blocked at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, then ammonia-methanol solution (7N, 8.0mL) and ammonium chloride (23.0mg, 1.4mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted. Subsequent direct concentration gave the crude product.
  • Step 1 Dissolve 2-chloronicotinic acid (31-SM1) (3.0g, 19.04mmol), m-aminobenzonitrile (2.25g, 19.04mmol) in pyridine (20.0mL), drop slowly at 0°C Add phosphorus oxychloride (3.55mL, 38.08mmol), control the temperature below 10°C, and continue the reaction until the raw materials are completely reacted, then pour the reaction system into ice water, and adjust the pH value to 2 with 2N dilute hydrochloric acid. ⁇ 3 or so, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product.
  • the second step 2-chloro-N-(3-benzonitrile)nicotinamide (31-a) (250.0mg, 0.97mmol), 4-fluoro-2-methylphenol (122.4mg, 0.97mmol), Cesium carbonate (632.2mg, 1.94mmol) and cuprous iodide (1.85mg, 0.0097mmol) were added to toluene (6.0mL) and refluxed 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 a crude product.
  • the third step N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-nicotinamide (II-A-25) (100.0mg, 0.2mmol) and no Water ethanol (0.2 mL) was added to hydrochloric acid-ethyl acetate system (10N, 10.0 mL), and the reaction was sealed at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, ammonia-methanol solution (7N, 5.0mL) and ammonium chloride (21mg, 0.4mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted. Subsequent direct concentration gave the crude product.
  • N-(3-aminocarboximidoylphenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I -3) (215mg, 0.5mmol) was dissolved in tetrahydrofuran (10.0mL), cooled to about 0°C and added sodium hydroxide (10N, 74.76mmL), then slowly added methyl chloroformate (56.5mg, 0.6mmol) at room temperature React until the raw material is completely reacted. Then extract with ethyl acetate. The organic phase was dried and concentrated to give the crude product.
  • N-(3-aminocarboximidoylphenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I -3) (215.0mg, 0.5mmol) was dissolved in tetrahydrofuran (10.0mL), cooled to about 0°C and added sodium hydroxide (10N, 74.8mmL), then slowly added ethyl chloroformate (64.8mg, 0.6mmol) at room temperature Lower the reaction until the raw material is completely reacted. Then extracted with ethyl acetate, the organic phase was dried and concentrated to obtain the crude product.
  • Step 1 Dissolve 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (34-SM1) (485.0mg, 2.0mmol), m-aminobenzonitrile (268.3mg, 20mmol) in pyridine (6.0mL), slowly drop phosphorus oxychloride (0.38mL, 4.0mmol) at 0°C, control the temperature below 10°C, after the dropwise addition is complete, continue the reaction until the raw materials are completely reacted, then pour the reaction system into In ice water, use 2N hydrochloric acid to adjust the pH value to about 2 ⁇ 3, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate and precipitate the solid to obtain off-white 5-chloro-N-(3-cyanophenyl)-2- Fluoro-4-(trifluoromethyl)benzamide (34-a) (469.0 mg, yield 58.3%).
  • the second step 5-chloro-N-(3-cyanophenyl)-2-fluoro-4-(trifluoromethyl)benzamide (34-a) (342.0mg, 1.0mmol), 4- Fluoro-2-methylphenol (140.0 mg, 1.1 mmol) and cesium carbonate (651.0 mg, 2.0 mmol) were added to N,N-dimethylformamide (7.0 mL), and reacted 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 a crude product.
  • the third step 5-chloro-N-(3-cyanophenyl)-2-(4-fluoro-3-methoxyphenoxy)-4-(trifluoromethyl)benzamide (II -A-26) (224.0mg, 0.5mmol), absolute ethanol (0.2mL) were added to hydrochloric acid-ethyl acetate system (10N, 10.0mL), and the reaction was sealed at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, ammonia-methanol solution (4N, 10mL) and ammonium chloride (54.0mg, 1mmol) were added, and the mixture was refluxed until the intermediate was completely reacted, then concentrated to obtain the crude product.
  • N-(3-aminocarboximidoylphenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I -3) (43.0mg, 0.01mmol) was dissolved in acetonitrile (5.0mL), then formic acid (13.8mg, 0.03mmol) and zinc powder (1.3mg, 0.2eq) were added and the reaction was refluxed until completely clarified. Then extracted with ethyl acetate, the organic phase was dried and concentrated to obtain the crude product.
  • the first step 2-bromo-4-fluorophenol (1.33g, 6.96mmol), potassium phosphate (5.12g, 24.4mmol), tricyclohexylphosphine (218.2mg, 0.696mmol), cyclopropylboronic acid (897.0mg , 10.4mmol), added toluene (30.0mL), water (1.5mL) mixture, argon replacement 3 times. Palladium acetate (78.1mg, 0.35mmol) was added, argon was replaced three times, and the reaction was refluxed at 100°C for 16h.
  • N-(3-benzonitrile)-2-fluoro-4-(trifluoromethyl)benzamide (9-a) (1.0g, 3.24mmol), 2-cyclopropyl-4- Fluorophenol (38-a) (518.4mg, 3.41mmol) and cesium carbonate (2.11g, 6.49mmol) were added to N,N-dimethylformamide (10.0mL) and reacted at 100°C.
  • 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 a crude product.
  • the third step N-(3-benzonitrile)-2-(2-cyclopropyl-4-fluorophenoxy)-4-(trifluoromethyl)benzamide (II-A-27)( 200.0mg, 0.454mmol), absolute ethanol (2.6mL) was added to hydrochloric acid-ethyl acetate system (10N, 7.0mL), and the reaction was sealed at room temperature. After the reaction is complete, the intermediate is concentrated to the next step. Add anhydrous methanol (4.0mL), ammonia-methanol solution (5.0mL), 2eq ammonium chloride to the intermediate, and react under reflux until the intermediate is completely reacted.
  • the first step 2-bromo-4,5-dimethoxybenzoic acid (3.0g, 11.5mmol), m-aminobenzonitrile (1.43g, 12.1mmol) were dissolved in pyridine (8.0mL), at 0 Slowly add phosphorus oxychloride (2.14mL, 23mmol) dropwise at °C, control the temperature below 10°C, continue the reaction until the raw materials are completely reacted, then pour the reaction system into ice water, and use 2N Adjust the pH value to about 2-3 with hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain 2-bromo-N-(3-cyanophenyl)-4,5-dimethoxybenzamide (39-a) 3.2g of crude product, directly to the next step.
  • MS (ESI) m/z [M+H] + 362.9
  • the second step 2-bromo-N-(3-cyanophenyl)-4,5-dimethoxybenzamide (39-a) (3.0g, 8.31mmol), 4-fluoro-2- Methylphenol (1.1g, 8.72mmol), cesium carbonate (5.4g, 16.6mmol), cuprous iodide (15.8mg, 0.083mmol) were dissolved in N,N-dimethylformamide (10mL), at 80 Reaction at °C. After the reaction, 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 a crude product.
  • the third step N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4,5-dimethoxybenzamide (II-A-28) (200.0mg, 0.492mmol), absolute ethanol (2.0mL) were added to hydrochloric acid-ethyl acetate system (10N, 6.0mL), and the reaction was sealed at room temperature. After the reaction of the raw materials was complete, the reaction system was evaporated to dryness to obtain the crude intermediate, and then anhydrous methanol (3.0 mL), ammonia-methanol solution (5.0 mL), and 2 eq ammonium chloride were added to react under reflux until the conversion of the intermediate was complete.
  • the first step under the drying system, the 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoic acid (1-b) (314.0mg, 1.0 mmol), m-aminobenzonitrile (0.4g, 3.34mmol) was added to anhydrous pyridine (4.0mL) to dissolve, cooled to about 0°C, slowly added dropwise phosphorus oxychloride (0.5mL, 5mmol), and the temperature was controlled at Below 10°C, the dropwise addition is completed, 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, and then extract with dichloromethane.
  • N-(4-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-B-1) 250.0mg, 0.6mmol
  • absolute ethanol 0.1mL
  • hydrogen chloride-ethyl acetate system 10N, 20.0mL
  • Pinner's salt intermediate (92.0 mg, 0.2 mol) and ammonium chloride (20.8 mg, 0.4 mmol) were added into ammonia-methanol system (12 mL) to react under reflux, and concentrated to obtain a crude product.
  • the first step 2-bromo-4-methoxybenzoic acid (41-SM1) (300.0mg, 1.30mmol), m-aminobenzonitrile (153.4mg, 1.30mmol) were dissolved in pyridine (4.0mL), Phosphorus oxychloride (0.242mL, 2.60mmol) was slowly added dropwise at 0°C, and the temperature was controlled below 10°C. After the dropwise addition was completed, the reaction was continued until the reaction of the raw materials was complete, and then the reaction system was poured into ice water and diluted with 2N Adjust the pH value to about 2-3 with hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain a crude product.
  • pyridine 4.0mL
  • Phosphorus oxychloride 0.242mL, 2.60mmol
  • the second step 2-bromo-N-(3-benzonitrile)-4-methoxybenzamide (41-a) (250.0mg, 0.755mmmol), 4-fluoro-2-methylphenol (95.2 mg, 0.755mmol), cesium carbonate (491.9mg, 1.51mmol), cuprous iodide (1.4mg, 0.00755mmol) were dissolved in toluene (7.35mL), 100 °C reflux reaction. 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 a crude product.
  • N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-methoxybenzamide (II-A-29) (100mg, 0.27mmol) was added into absolute ethanol (0.1mL) and hydrochloric acid-ethyl acetate (6mL), and the reaction was sealed at room temperature. After the reaction was complete, the reaction system was evaporated to dryness, anhydrous methanol (3mL), ammonia-methanol solution (5mL), 2eq ammonium chloride were added, and the reaction was refluxed at 65°C. After the reaction was complete, it was concentrated to obtain a crude product.
  • N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-30) (216mg, 0.5mmol), absolute ethanol (0.3mL) were added to hydrochloric acid-ethyl acetate system (10N, 10.0mL), and the reaction was sealed at room temperature. After the reaction of the raw materials was complete, the reaction system was evaporated to dryness to obtain Pinner's salt, then anhydrous methanol (3.0 mL), ammonia-methanol solution (7N, 5.0 mL), and 2 eq ammonium chloride were added, and the mixture was refluxed until the intermediate was completely reacted.
  • N-(3-benzonitrile)-2-fluoro-4-(trifluoromethyl)benzamide (9-a) (1.0g, 3.24mmol), 2-chloro-4-fluorophenol (523mg, 3.57mmol) and cesium carbonate (2.11g, 6.49mmol) were added to N,N-dimethylformamide (10.0mL) and reacted at 60°C.
  • the second step 2-(2-chloro-4-fluorophenoxy)-N-(3-benzonitrile)-4-(trifluoromethyl)benzamide (II-A-31) (170mg, 0.391mmol), absolute ethanol (2.0mL) was added to hydrochloric acid-ethyl acetate system (10N, 6.0mL), and the reaction was sealed at room temperature. After the reaction was complete, the reaction system was concentrated to obtain Pinner's salt, then anhydrous methanol (3.0 mL), ammonia-methanol solution (7N, 5.0 mL), and 2 eq ammonium chloride were added, and the mixture was refluxed until the Pinner's salt was completely reacted.
  • the first step Dissolve 2-fluoro-4,5-dichlorobenzoic acid (1.0g, 4.8mmol), 5-amino-2-fluorobenzonitrile (684.0mg, 5.0mmol) in pyridine (15.0mL) , slowly add phosphorus oxychloride (1.8mL, 19.2mmol) dropwise at 0°C, and control the temperature below 10°C.
  • the second step 4,5-dichloro-N-(3-cyano-4-fluorophenyl)-2-fluorobenzamide (45-a) (327.0mg, 1.0mmol), 4-fluoro- 2-Methylphenol (132mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were added into N,N-dimethylformamide (5.0mL), and reacted at 80°C until the raw materials were completely reacted.
  • the third step 4,5-dichloro-N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (II-A- 32) (200mg, 0.46mmol), absolute ethanol (0.25mL) was added to hydrochloric acid-ethyl acetate system (10N, 10.0mL), and the reaction was sealed at room temperature. After the reaction was complete, the reaction system was evaporated to dryness to obtain Pinner's salt, then anhydrous methanol (3.0 mL), ammonia-methanol solution (7N, 13 mL), and 2 eq ammonium chloride were added, and the mixture was refluxed until the Pinner salt was completely reacted.
  • the first step 6-bromobenzo[d][1,3]dioxolane-5-carboxylic acid (46-SM1) (735.mg, 3.0mmol), m-aminobenzonitrile (372mg, 3.2 mmol) was dissolved in pyridine (10.0mL), and phosphorus oxychloride (0.6mL, 2.0mmol) was slowly added dropwise at 0°C, and the temperature was controlled below 10°C.
  • the reaction system was poured into ice water, the pH value was adjusted to about 2-3 with 2N hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a crude product.
  • the second step 46-a (200.0mg, 0.58mmol), 4-fluoro-2-methylphenol (87.8mg, 0.7mmol), cuprous iodide (11.0mg, 0.06mmol) and cesium carbonate (377.6mg , 1.2mmol) was added to toluene (10.0mL) and reacted 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 a crude product.
  • N-(3-cyanophenyl)-6-(4-fluoro-2-methylphenoxy)benzo[d][1,3]dioxazole-5-carboxamide ( II-A-34) (50.0mg, 0.13mmol) and absolute ethanol (0.2mL) were added to hydrochloric acid-ethyl acetate system (10N, 10.0mL), and the reaction was sealed at room temperature. After the reaction was complete, evaporate the crude Pinner salt from the reaction system to dryness, then add ammonia-methanol solution (7N, 5.0 mL) and ammonium chloride (10.0 mg, 0.24 mmol), and react under reflux until the Pinner salt was completely reacted. then Concentrate directly to crude product.
  • the first step first 2-chloro-6-(trifluoromethyl)nicotinic acid methyl ester (478.0mg, 2.00mmol), 4-fluoro-2 methylphenol (251.9mg, 2.00mmol), cesium carbonate (1.3 g, 4.0mmol) and cuprous iodide (38.0mg, 0.2mmol) were added to toluene (20mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • Second step 2-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)nicotinic acid methyl ester (400.0mg, 1.21mmol) was added in 95% ethanol (20mL), Then add sodium hydroxide (5N, 2.43mL, 12.15mmol) 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 to 3 with hydrochloric acid to precipitate a large amount of white solid, filter, and dry to obtain 2-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)nicotinic acid (329.0 mg, yield 85.9%).
  • sodium hydroxide 5N, 2.43mL, 12.15mmol
  • the third step in a reaction flask equipped with a drying tube, first dissolve 2-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)nicotinic acid (325.0mg, 1.03mmol) In dichloromethane (20mL), add a catalytic amount of DMF and cool the reaction system to about 0°C, then slowly add oxalyl chloride (0.8mL, 10.31mmol) dropwise, and react at room temperature until the acid is completely converted For acid chloride.
  • N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)nicotinamide 100.0mg, 0.23mmol
  • triethylamine 140.1mg, 1.38mmol
  • hydroxylamine hydrochloride 32.1mg, 0.46mmol
  • the first step 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.00g, 6.97mmol), 4-fluoro-2-methylphenol (1-SM2) (1.05g, 8.36mmol), cesium carbonate (4.54g, 13.94mmol) and cuprous iodide (265.4mg, 1.39mmol), were added to toluene (50mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • the second step 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzoic acid (210.0mg, 1.00mmol) and 5-amino-2-fluoro Dissolve benzonitrile (143.6mg, 1.06mmol) in anhydrous pyridine (4mL, 49.71mmol), cool to about 0°C and slowly add phosphorus oxychloride (0.2mL, 2.01mmol) dropwise, control the temperature below 10°C, drop 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 a crude product.
  • the third step N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzyl Amide (250.0mg, 0.55mmol), absolute ethanol (0.16mL, 2.8mmol) and hydrogen chloride-ethyl acetate system (10N, 50.0mL) were added to a sealed reaction flask and reacted at room temperature until the raw material was completely converted into an intermediate Pinner salt, then concentrated to remove the solvent to give the crude product intermediate Pinner salt, then dissolved in absolute ethanol, then added triethylamine (1.54mL, 11.10mmol) and methoxylamine hydrochloride (463.6mg, 5.55mmol) in Reaction under reflux until Pinner salt conversion is complete, then add ammonia methanol system (7N, 4.2mL) to react under reflux to obtain the target product, then concentrate to obtain the crude product, then use petroleum ether:ethyl acetate
  • the first step first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (287.0mg, 1.0mmol), 2-(trifluoromethyl)phenol (194.5mg, 1.20mmol), carbonic acid Cesium (651.6mg, 2.00mmol) and cuprous iodide (38.1mg, 0.2mmol) were added into toluene (50.00mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • Petroleum ether: ethyl acetate 2:1 (v/v) for the crude product to pass through a silica gel column (200-300 mesh) to obtain 2-fluoro-3-(trifluoromethyl)-6-(2-(trifluoroethyl) )phenoxy)benzoic acid (110.0 mg, yield 27%).
  • the second step in the reaction flask equipped with a drying tube, first 2-fluoro-3-(trifluoromethyl)-6-(2-(trifluoroethyl)phenoxy)benzoic acid (95.0mg, 0.26mmol) was dissolved in dichloromethane (10mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then slowly added dropwise oxalyl chloride (327.5mg, 2.58mmol), and reacted at room temperature after the dropwise addition until the acid is completely converted to acid chloride.
  • the third step N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)-6-(2-(trifluoroethyl)phenoxy)benzyl Amide (70.0mg, 0.14mmol), triethylamine (145.65mg, 1.44mmol) and hydroxylamine hydrochloride (40.0mg, 0.58mmol) were added to absolute ethanol, and reacted under reflux until the raw materials were completely reacted. Concentrate, add water, and extract with ethyl acetate.
  • the first step first 2-chloro-5-(trifluoromethyl)nicotinic acid methyl ester (586.0mg, 2.45mmol), 4-fluoro-2-methylphenol (1-SM2) (308.8mg, 2.45mmol ), cesium carbonate (1.6g, 4.89mmol) and cuprous iodide (46.6mg, 0.24mmol) were added to toluene (20ml), replaced by nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • the second step 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)nicotinic acid methyl ester (500.0mg, 1.52mmol) was added in 95% ethanol (20mL), Then add sodium hydroxide (5N, 607.4mg, 15.2mmol) and react under reflux until the raw material is completely hydrolyzed into an acid, concentrate, add water, and then adjust the pH value to about 2 to 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).
  • the third step in a reaction flask equipped with a drying tube, first dissolve 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)nicotinic acid (315.0mg, 1.0mmol) In dichloromethane (10mL), add a catalytic amount of DMF and cool the reaction system to about 0°C, then slowly add oxalyl chloride (1.27g, 10.00mmol) dropwise, and react at room temperature until the acid is completely converted For acid chloride.
  • N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)nicotinamide (185.0mg, 0.43mmol), triethylamine (432.0mg, 4.27mmol) and hydroxylamine hydrochloride (118.7mg, 1.71mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate.
  • N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (112.0mg , 0.25mmol) [see step 2 of Example 48], triethylamine (151.0mg, 1.49mmol) and hydroxylamine hydrochloride (34.6mg, 0.50mmol) were added to absolute ethanol, and reacted under reflux until the raw materials were completely reacted. Concentrate, add water, and extract with ethyl acetate.
  • the first step first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (340.0mg, 1.2mmol), 2-methyl-4-(trifluoromethoxy)phenol (230.6mg , 1.2mmol), cesium carbonate (771.9mg, 2.4mmol) and cuprous iodide (45.1mg, 0.24mmol), were added to toluene (20mL), replaced by nitrogen, and then heated to 100 ° C until the reaction of the raw materials was complete. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • the second step in the reaction bottle equipped with a drying tube, first 2-fluoro-6-(2-methyl-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl) Benzoic acid (289.0mg, 0.73mmol) was dissolved in dichloromethane (10mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, and then oxalyl chloride (921.1mg, 7.26mmol) was slowly added dropwise. After completion, react at room temperature until all the acids are converted into acid chlorides.
  • the first step first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (345.0mg, 1.20mmol), 2-methoxy-4-(trifluoromethoxy)phenol (249.7 mg, 1.20mmol), cesium carbonate (783.3mg, 2.40mmol) and cuprous iodide (45.8mg, 0.24mmol), were added to toluene (20.0mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted .
  • the reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • the second step in a reaction flask equipped with a drying tube, first 2-fluoro-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl ) benzoic acid (324.0mg, 0.78mmol) was dissolved in dichloromethane (20mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then slowly added dropwise oxalyl chloride (0.6mL, 7.82mmol), dropwise After the addition was complete, it was reacted at room temperature until all the acids were converted to acid chlorides.
  • N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(2-methoxy-4-trifluoromethoxy)phenoxy)-3-(tri Fluoromethyl)benzamide (188.0mg, 0.35mmol)
  • triethylamine (107.2mg, 1.06mmol)
  • hydroxylamine hydrochloride 49.1mg, 0.70mmol
  • the first step first 6-bromo-2-fluoro-3-(trifluoromethyl))benzoic acid (287.0mg, 1.0mmol), 4-bromo-2-(trifluoromethyl)phenol (289.2mg, 1.20mmol), cesium carbonate (651.6mg, 2.00mmol) and cuprous iodide (38.1mg, 0.2mmol), were added to toluene (20mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • the second step in a reaction flask equipped with a drying tube, first 6-(4-bromo-2-(trifluoromethyl)phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (199.0mg, 0.46mmol) was dissolved in dichloromethane (10mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, and then oxalyl chloride (564.9mg, 4.45mmol) was slowly added dropwise. React at room temperature until all the acid is converted to acid chloride.
  • the third step 6-(4-bromo-2-(trifluoromethyl)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl Base) benzamide (130.0mg, 0.23mmol), triethylamine (69.8mg, 0.69mmol) and hydroxylamine hydrochloride (32.0mg, 0.46mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate.
  • the first step first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (287.0mg, 1.0mmol), 4-fluoro-2-methoxyphenol (170.6mg, 1.20mmol), Cesium carbonate (651.6mg, 2.00mmol) and cuprous iodide (38.1mg, 0.2mmol) were added into toluene (20.0mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • the second step in the reaction flask equipped with a drying tube, first 2-fluoro-6-(4-fluoro-2-methoxyphenoxy)-3-(trifluoromethyl)benzoic acid (172.0mg , 0.49mmol) was dissolved in dichloromethane (20mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then slowly added dropwise oxalyl chloride (626.9mg, 4.94mmol), and after the dropwise addition was completed, the React until all the acid is converted to acid chloride.
  • Formamide (100.0mg, 0.21mmol)
  • triethylamine (65.1mg, 0.63mmol)
  • hydroxylamine hydrochloride 29.8mg, 0.42mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete.
  • the first step earlier 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (340.0mg, 1.2mmol), 3-chloro-2-fluoro-5-(trifluoromethyl)phenol ( 250.0mg, 1.2mmol), cesium carbonate (772.0mg, 2.4mmol) and cuprous iodide (45.1mg, 0.24mmol), added to toluene (20mL), replaced by nitrogen, then heated to 100 ° C until the reaction of the raw materials was complete . The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • the second step in a reaction flask equipped with a drying tube, first 6-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-2-fluoro-3-(trifluoromethyl Base) benzoic acid (70.0mg, 0.17mmol) was dissolved in dichloromethane (10mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, and then oxalyl chloride (211.2mg, 1.66mmol) was slowly added dropwise, After the dropwise addition, react at room temperature until the acid is completely converted into acid chloride.
  • the third step 6-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3- (Trifluoromethyl)benzamide (50.0mg, 0.09mmol), triethylamine (28.2mg, 0.28mmol) and hydroxylamine hydrochloride (12.9mg, 0.18mmol) were added to absolute ethanol, and reacted under reflux until the raw material reacted completely. Concentrate, add water, and extract with ethyl acetate.
  • the first step first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (287.0mg, 1.0mmol), 4-(trifluoromethyl)phenol (194.5mg, 1.2mmol), carbonic acid Cesium (651.6mg, 2.0mmol) and cuprous iodide (38.1mg, 0.2mmol) were added to toluene (50mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • the second step in the reaction flask equipped with a drying tube, first 2-fluoro-3-(trifluoromethyl)-6-(4-(trifluoroethyl)phenoxy)benzoic acid (67.0mg, 0.18mmol) was dissolved in dichloromethane (10mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, and then oxalyl chloride (231.0mg, 1.82mmol) was slowly added dropwise, and reacted at room temperature after the dropwise addition until the acid is completely converted to acid chloride.
  • the third step N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)-6-(4-(trifluoromethyl)phenoxy)benzyl Amide (20.0mg, 0.041mmol), triethylamine (12.48mg, 0.12mmol) and hydroxylamine hydrochloride (5.7mg, 0.082mmol) were added to absolute ethanol, and reacted under reflux until the raw materials were completely reacted. Concentrate, add water, and extract with ethyl acetate.
  • the first step first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (287.0mg, 1.0mmol), 2,4-dimethylphenol (146.6mg, 1.2mmol), cesium carbonate (651.6mg, 2.00mmol) and cuprous iodide (38.1mg, 0.2mmol), were added to toluene (20.0mL), replaced with nitrogen, and then heated to 100°C to react until the reaction of the raw materials was complete. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • the second step in a reaction flask equipped with a drying tube, first add 6-(2,4-dimethylphenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (100.0mg, 0.3 mmol) was dissolved in dichloromethane (10mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then slowly added dropwise oxalyl chloride (386.6mg, 3.0mmol), and reacted at room temperature until full conversion of acid For acid chloride.
  • N-(3-cyano-4-fluorophenyl)-6-(2,4-dimethylphenoxy)-2-fluoro-3-(trifluoromethyl)benzamide (69.0mg, 0.15mmol)
  • triethylamine 46.9mg, 0.46mmol
  • hydroxylamine hydrochloride 21.5mg, 0.31mmol
  • the first step first 6-bromo-2-fluoro-3-(trifluoromethoxy)benzoic acid (250.0mg, 0.83mmol), 4-fluoro-2-methylphenol (156.1mg, 1.24mmol), Cesium carbonate (537.6mg, 1.65mmol) and cuprous iodide (157.1mg, 0.83mmol) were added to Nitrogen was replaced in toluene (20.0 mL), and then the temperature was raised to 100° C. to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • the second step in the reaction flask equipped with a drying tube, first 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethoxy)benzoic acid (140.0mg ,0.4mmol) was dissolved in dichloromethane (20mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then slowly added dropwise oxalyl chloride (510.3mg, 4.02mmol), and after the dropwise addition, the React until all the acid is converted to acid chloride.
  • Formamide 100.0mg, 0.22mmol
  • triethylamine 130.2mg, 1.29mmol
  • hydroxylamine hydrochloride 29.8mg, 0.43mmol
  • the first step in a reaction flask equipped with a drying tube, first dissolve 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (968.0mg, 4.0mmol) in dichloromethane (20mL) , after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then oxalyl chloride (3.8mL, 40.0mmol) was slowly added dropwise, and reacted at room temperature after the addition was completed until the acid was completely converted into acid chloride.
  • the second step first 5-chloro-N-(3-cyano-4-fluorophenyl)-2-fluoro-4-(trifluoromethyl)benzamide (360.00mg, 1.0mmol), 4- Fluorine-2-methylphenol (138.49mg, 1.10mmol), cesium carbonate (650.43mg, 2.00mmol) and cuprous iodide (38mg, 0.2mmol) were added in toluene (20mL), replaced by nitrogen, and then heated to 100 °C to react until the raw materials are completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • Petroleum ether: ethyl acetate 10:1 (v/v) was used to pass the crude product through a silica gel column (200-300 mesh) to obtain 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4 -Fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (218.0 mg, yield 68%).
  • the third step 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzene Amide (638.0mg, 1.37mmol), triethylamine (276.6mg, 2.73mmol) and hydroxylamine hydrochloride (189.9mg, 2.73mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate.
  • the first step Weigh 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzoic acid (150.0mg, 0.45mmol) prepared by Example 48 In a round bottom flask, add N,N-dimethylformamide (5mL) as a solvent, then add HATU (206.0mg, 0.54mmol), stir at room temperature for 15min, then add 3-cyano-4-chloroaniline ( 75.6mg, 0.50mmol) and N,N-diisopropylethylamine (129.25mg, 1.36mmol), and continued stirring at room temperature for 5h. The reaction was monitored by TLC.
  • N,N-dimethylformamide 5mL
  • HATU 206.0mg, 0.54mmol
  • 3-cyano-4-chloroaniline 75.6mg, 0.50mmol
  • N,N-diisopropylethylamine 129.25mg, 1.36mmol
  • the second step weigh N-(4-chloro-3-cyanophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzene
  • Formamide 140.0mg, 0.3mmol
  • hydroxylamine hydrochloride 104.3mg, 1.5mmol
  • triethylamine 151.8mg, 1.5mmol
  • the first step Weigh 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzoic acid (150.0mg, 0.45mmol) prepared by Example 48 In a round bottom flask, add N,N-dimethylformamide (5mL) as solvent, then add HATU (206.0mg, 0.54mmol), stir at room temperature for 15min, then add 5-amino-2-methylbenzyl Nitrile (65.6mg, 0.50mmol) and N,N-diisopropylethylamine (129.25mg, 1.36mmol), continued stirring at room temperature for 5h. The reaction was monitored by TLC.
  • the second step weigh N-(3-cyano-4-methylphenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl) Benzamide (133.8mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, 5mL of absolute ethanol was added, and then triethylamine (151.8mg, 1.5mmol) was added, under nitrogen atmosphere for 80 °C overnight.
  • the first step Weigh 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzoic acid (150.0mg, 0.45mmol) prepared by Example 48 In a round bottom flask, add dichloromethane (15mL) as a solvent, stir in an ice-water bath for 10min, then add oxalyl chloride (171.4mg, 1.35mmol) and a catalytic amount of N,N-dimethylformamide, dropwise Then react at room temperature until the acid is completely converted to acid chloride.
  • the second step weigh N-(2-cyanopyridin-4-yl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzene Add amide (130.0mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) in a sealed tube, add 5mL of absolute ethanol, then add triethylamine (151.8mg, 1.5mmol), and react at 80°C under nitrogen atmosphere overnight.
  • the first step Weigh 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzoic acid (150.0mg, 0.45mmol) prepared by Example 48 In a round bottom flask, add N,N-dimethylformamide (5mL) as solvent, then add HATU (206.0mg, 0.54mmol), stir at room temperature for 15min, then add 5-amino-2-methoxybenzene Formonitrile (73.6mg, 0.50mmol) and N,N-diisopropylethylamine (129.25mg, 1.36mmol) were stirred at room temperature for 5h. The reaction was monitored by TLC.
  • the second step weigh N-(3-cyano-4-methoxyphenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl ) benzamide (138.6mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, 5mL of absolute ethanol was added, then triethylamine (151.8mg, 1.5mmol) was added, under nitrogen atmosphere React overnight at 80°C.
  • the first step first 2,6-dichloro-5-fluoronicotinic acid (1.46g, 6.97mmol), 4-fluoro-2-methylphenol (1-SM2) (1.05g, 8.36mmol), cesium carbonate (4.54g, 13.94mmol) and cuprous iodide (265.43mg, 1.39mmol), were added to toluene (50mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • the second step Weigh 6-chloro-5-fluoro-2-(4-fluoro-2-methylphenoxy) nicotinic acid (135.0mg, 0.45mmol) into a round bottom flask, add N,N- Dimethylformamide (5mL) was used as solvent, then HATU (206.0mg, 0.54mmol) was added, stirred at room temperature for 15min, then 3-cyano-4-fluoroaniline (68mg, 0.50mmol) and N,N-di Isopropylethylamine (129.2mg, 1.36mmol), continued stirring at room temperature for 5h. The reaction was monitored by TLC.
  • the third step weigh 6-chloro-N-(3-cyano-4-fluorophenyl)-5-fluoro-2-(4-fluoro-2-methylphenoxy)nicotinamide (125.1mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, 5mL of absolute ethanol was added, and then triethylamine (151.8mg, 1.5mmol) was added, and reacted overnight at 80°C under a nitrogen atmosphere.
  • the first step first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.0g, 6.97mmol), 4-fluoro-3-(trifluoromethyl)phenol (1.5g, 8.36 mmol), cesium carbonate (4.54g, 13.94mmol) and cuprous iodide (265.4mg, 1.4mmol), were added to toluene (50mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. Pour the reaction system into ice water, Subsequent extraction with ethyl acetate, the organic phase was dried and concentrated to give the crude product.
  • the second step Weigh 2-fluoro-6-(4-fluoro-3-trifluoromethylphenoxy)-3-(trifluoromethyl)benzoic acid (173.7mg, 0.45mmol) and place it in a round bottom flask Add N,N-dimethylformamide (5mL) as solvent, then add HATU (206.0mg, 0.54mmol), stir at room temperature for 15min, then add 3-cyano-4-fluoroaniline (68.0mg, 0.50 mmol) and N,N-diisopropylethylamine (129.3mg, 1.36mmol), stirring was continued at room temperature for 5h.
  • the third step weigh N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-3-trifluoromethylphenoxy)-3-(trifluoromethyl ) benzamide (151.2mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, 5mL of absolute ethanol was added, then triethylamine (151.8mg, 1.5mmol) was added, under nitrogen atmosphere React overnight at 80°C.
  • the first step earlier 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.0g, 6.97mmol), 2,3-difluorophenol (1.09g, 8.36mmol), cesium carbonate ( 4.5g, 14.0mmol) and cuprous iodide (265.43mg, 1.4mmol), were added to toluene (50mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • the second step take 6-(2,3-difluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (151.2mg, 0.45mmol) and place it in a round bottom flask, add N , N-dimethylformamide (5mL) as solvent and HATU (206.0mg, 0.54mmol), stirred at room temperature for 15min, then added 3-cyano-4-fluoroaniline (68.0mg, 0.50mmol) and N, N-Diisopropylethylamine (129.25mg, 1.36mmol), continued stirring at room temperature for 5h.
  • N , N-dimethylformamide 5mL
  • HATU 206.0mg, 0.54mmol
  • the third step weigh N-(3-cyano-4-fluorophenyl)-6-(2,3-difluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzamide (136.2mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, 5mL of absolute ethanol was added, and then triethylamine (151.8mg, 1.5mmol) was added, and reacted overnight at 80°C under a nitrogen atmosphere .
  • the first step earlier 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.0g, 6.97mmol), 4-bromo-2-fluoro-6-(trifluoromethyl)phenol ( 2.2g, 8.36mmol), cesium carbonate (4.54g, 13.94mmol) and cuprous iodide (265.43mg, 1.39mmol), were added to toluene (50mL), replaced by nitrogen, and then heated to 100 ° C until the reaction of the raw materials was complete . The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • the second step weigh 6-(4-bromo-2-fluoro-6-(trifluoromethyl)phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (208.8mg, 0.45mmol ) in a round bottom flask, add N,N-dimethylformamide (5mL) as solvent, then add HATU (206mg, 0.54mmol), stir at room temperature for 15min, then add 3-cyano-4-fluoroaniline (68.0mg, 0.50mmol) and N,N-diisopropylethylamine (129.25mg, 1.36mmol), and continued stirring at room temperature for 5h.
  • the third step weigh 6-(4-bromo-2-fluoro-6-(trifluoromethyl)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3 -(Trifluoromethyl)benzamide (174.6mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, and 5mL of anhydrous ethyl alcohol was added Alcohol, then added triethylamine (151.8mg, 1.5mmol), and reacted overnight at 80°C under a nitrogen atmosphere.
  • the first step first 6-bromo-2,3,4-trifluorobenzoic acid (1.77g, 6.97mmol), 4-fluoro-2-methylphenol (1-SM2) (1.05g, 8.36mmol), Cesium carbonate (4.54g, 13.94mmol) and cuprous iodide (265.43mg, 1.39mmol) were added to toluene (50mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • Second step Weigh 2,3,4-trifluoro-6-(4-fluoro-2-methylphenoxy)benzoic acid (135.0mg, 0.45mmol) into a round bottom flask, add N,N -Dimethylformamide (5mL) was used as solvent, then HATU (206.0mg, 0.54mmol) was added, stirred at room temperature for 15min, then 3-cyano-4-fluoroaniline (68.0mg, 0.50mmol) and N,N -Diisopropylethylamine (129.3mg, 1.36mmol), stirring was continued at room temperature for 5h.
  • N,N -Dimethylformamide 5mL
  • HATU 206.0mg, 0.54mmol
  • the third step weigh N-(3-cyano-4-fluorophenyl)-2,3,4-trifluoro-6-(4-fluoro-2-methylphenoxy)benzamide (125.4 mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, added absolute ethanol (5mL), then added triethylamine (151.8mg, 1.5mmol), and reacted overnight at 80°C under a nitrogen atmosphere .
  • the first step first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.0g, 6.97mmol), 2-ethyl-4-fluorophenol (1.2g, 8.36mmol), carbonic acid Cesium (4.54g, 13.94mmol) and cuprous iodide (265.43mg, 1.39mmol) were added to toluene (50mL), replaced by nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • the second step take 6-(2-ethyl-4-fluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (155.7mg, 0.45mmol) and place it in a round bottom flask, Add N,N-dimethylformamide (5mL) as solvent, then add HATU (206mg, 0.54mmol), stir at room temperature for 15min, then add 3-cyano-4-fluoroaniline (68mg, 0.50mmol) and N , N-diisopropylethylamine (129.3mg, 1.36mmol), continued stirring at room temperature for 5h.
  • the third step weigh N-(3-cyano-4-fluorophenyl)-6-(2-ethyl-4-fluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzene
  • Formamide 139.2mg, 0.3mmol
  • hydroxylamine hydrochloride 104.3mg, 1.5mmol
  • absolute ethanol 5mL
  • triethylamine 151.8mg, 1.5mmol
  • the first step first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.0g, 6.97mmol), 2-cyclopropyl-4-fluorophenol (38-a) (1.27g , 8.36mmol), cesium carbonate (4.54g, 13.94mmol) and cuprous iodide (265.43mg, 1.39mmol) were added to toluene (50mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • the second step Weigh 6-(2-cyclopropyl-4-fluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (161.1mg, 0.45mmol) and place it in a round bottom flask , add N,N-dimethylformamide (5mL) as solvent, then add HATU (206mg, 0.54mmol), stir at room temperature for 15min, then add 3-cyano-4-fluoroaniline (68.0mg, 0.50mmol) And N,N-diisopropylethylamine (129.2mg, 1.36mmol), stirring was continued at room temperature for 5h.
  • the third step weigh N-(3-cyano-4-fluorophenyl)-6-(2-cyclopropyl-4-fluorophenoxy)-2-fluoro-3-(trifluoromethyl) Benzamide (142.8mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, and absolute ethanol (5mL) was added, followed by triethylamine (151.8mg, 1.5mmol). React overnight at 80°C.
  • the first step first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.00g, 6.97mmol), 3-fluoro-2-methoxy-4-(trifluoromethoxy ) phenol (1.89g, 8.36mmol), cesium carbonate (4.54g, 13.94mmol) and cuprous iodide (265.43mg, 1.39mmol) were added in toluene (50mL), replaced by nitrogen, and then heated to 100 ° C to react until the raw material The response is complete. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • the second step weigh 2-fluoro-6-(3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzoic acid (194.8mg , 0.45mmol) in a round bottom flask, add N,N-dimethylformamide (5mL) as solvent, then add HATU (206mg, 0.54mmol), stir at room temperature for 15min, then add 3-cyano-4 -Fluoroaniline (68mg, 0.50mmol) and N,N-diisopropylethylamine (129.25mg, 1.36mmol), continued stirring at room temperature for 5h.
  • the third step weigh N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy )-3-(trifluoromethyl)benzamide (165.0mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, added absolute ethanol (5mL), and then added triethylamine ( 151.8mg, 1.5mmol), react overnight at 80°C under nitrogen atmosphere.
  • the first step in the reaction bottle that drying tube is housed, the 2-(4-fluoro-2-methylphenoxy group)-4-(trifluoromethyl)benzoic acid (1-b that embodiment 1 obtains ) (628.0mg, 2.00mmol) was dissolved in dichloromethane (20mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, and then oxalyl chloride (1.7mL, 20.00mmol) was slowly added dropwise, and the addition was completed Then react at room temperature until the acid is completely converted to acid chloride.
  • N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide 43.00mg , 0.1mmol
  • triethylamine 20.13mg, 0.2mmol
  • hydroxylamine hydrochloride 13.82mg, 0.2mmol
  • the first step first methyl 4-bromo-2,6-difluorobenzoate (474.0mg, 1.89mmol), 4-fluoro-2-methylphenol (262.0mg, 2.08mmol), cesium carbonate (1.23g , 3.78mmol) was added into N,N-dimethylformamide (20.0mL), replaced with nitrogen, and then the temperature was raised to 100°C to react until the reaction of the raw materials was complete.
  • the reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • the second step in the reaction flask equipped with a drying tube, first dissolve 4-bromo-2-fluoro-6-(4-fluoro-2-methylphenoxy)benzoic acid (350.0mg, 1.0mmol) in In dichloromethane (20mL), add a catalytic amount of DMF and cool the reaction system to about 0°C, then slowly add oxalyl chloride (1.3g, 10.2mmol) dropwise, and react at room temperature until the acid is completely converted to acid chloride.
  • the third step 4-bromo-N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)benzamide (112.00mg, 0.24mmol), triethylamine (147.43mg, 1.5mmol) and hydroxylamine hydrochloride (33.75mg, 0.48mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate.
  • the first step in the reaction flask equipped with a drying tube, 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoic acid (471.0mg) prepared according to Example 48 , 1.5mmol) was dissolved in dichloromethane (20mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then slowly added dropwise oxalyl chloride (1.27mL, 14.99mmol), and after the dropwise addition, the React until all the acid is converted to acid chloride.
  • N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide 43.0mg , 0.1mmol
  • triethylamine 20.1mg, 0.2mmol
  • hydroxylamine hydrochloride 13.8mg, 0.2mmol
  • the first step first 6-bromo-2-fluoro-3-trifluoromethylbenzoic acid (1.0g, 3.5mmol), 4-chloro-2-trifluoromethylphenol (720.0mg, 3.7mmol), carbonic acid Cesium (2.3g, 7.0mmol) and cuprous iodide (130.0mg, 0.7mmol) were added into toluene (50mL), replaced with nitrogen, and then heated to 100°C to react until the reaction of the raw materials was complete. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • the second step in the reaction flask equipped with a drying tube, 6-(4-chloro-2-trifluoromethyl)phenoxy-2-fluoro-3-trifluoromethylbenzoic acid (776.0mg, 2.0mmol ) was dissolved in dichloromethane (20mL), and after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then slowly added dropwise oxalyl chloride (1.63mL, 20.0mmol), and reacted at room temperature until the acid All were converted to acid chlorides.
  • the third step 6-(4-chloro-2-trifluoromethyl)phenoxy-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-trifluoromethylbenzene Amide (300.0mg, 0.58mmol), triethylamine (0.24mL, 1.7mmol) and hydroxylamine hydrochloride (400.0mg, 12.0mmol) were added to absolute ethanol, and reacted under reflux until the raw materials were completely reacted. Concentrate, add water, and extract with ethyl acetate.
  • the first step first 6-bromo-2-fluoro-3-trifluoromethylbenzoic acid (1.2g, 4.2mmol), 4-fluoro-2-trifluoromethylphenol (790.0mg, 4.4mmol), carbonic acid Cesium (2.7g, 7.0mmol) and cuprous iodide (160.0mg, 0.2mmol) were added into toluene (50mL), replaced with nitrogen, and then heated to 100°C to react until the reaction of the raw materials was complete. Pour the reaction system into ice water, Subsequent extraction with ethyl acetate, the organic phase was dried and concentrated to give the crude product.
  • the second step in the reaction flask equipped with a drying tube, 6-(4-fluoro-2-trifluoromethyl)phenoxy-2-fluoro-3-trifluoromethylbenzoic acid (1.16g, 3.0mmol ) was dissolved in dichloromethane (20mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then slowly added dropwise oxalyl chloride (2.54mL, 30.0mmol), and reacted at room temperature until the acid All were converted to acid chlorides.
  • the third step 6-(4-fluoro-2-trifluoromethyl)phenoxy-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-trifluoromethylbenzene Amide (850.0mg, 1.7mmol), triethylamine (0.7mL, 5.0mmol) and hydroxylamine hydrochloride (234.0mg, 3.4mmol) were added to absolute ethanol, and reacted under reflux until the raw materials were completely reacted. Concentrate, add water, and extract with ethyl acetate.
  • the first step first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (600mg, 2.1mmol), 2-cyclopropyl-4-)trifluoromethoxy)phenol (501.6mg , 2.3mmol), cesium carbonate (1.36g, 4.2mmol) and cuprous iodide (39.6mg, 0.21mmol), were added to toluene (25mL), replaced with nitrogen, and heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, then the pH was adjusted to 2-3, extracted with ethyl acetate, the organic phase was dried and concentrated to obtain a crude product.
  • the second step 6-(2-cyclopropyl-4-(trifluoromethoxy)phenoxy)-2-fluoro-3-)trifluoromethyl)benzoic acid (550.0mg, 1.3mmol) was dissolved In thionyl chloride (20 mL), reflux at 80° C. for 2 h until the acid is completely converted to acid chloride.
  • reaction system was concentrated to remove excess thionyl chloride, then the residue was dissolved in dichloromethane (20mL), triethylamine (0.360mL, 2.60mmol) was added, followed by 5-amino-2-fluorobenzonitrile ( 176.0mg, 1.30mmol) was reacted at room temperature until the reaction was complete, water was added, extracted with ethyl acetate, the organic phase was dried and concentrated to obtain a crude product.
  • the third step 6-(2-cyclopropyl-4-(trifluoromethoxy)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-tri Fluoromethylbenzamide (100.0mg, 0.18mmol), triethylamine (0.08mL, 0.55mmol) and hydroxylamine hydrochloride (25.6mg, 0.37mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate.
  • the first step first 6-bromo-2-fluoro-3-trifluoromethylbenzoic acid (500.0mg, 1.74mmol), 2,4-ditrifluoromethylphenol (421.0mg, 1.83mmol), cesium carbonate (1.14g, 3.48mmol) and cuprous iodide (66.0mg, 0.35mmol), were added to toluene (20mL), replaced with nitrogen, and heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product.
  • Petroleum ether: ethyl acetate 10 ⁇ 2:1 (v/v) for the crude product to pass through a silica gel column (200 ⁇ 300 mesh) to obtain 6-(2,4-bis(trifluoromethyl)phenoxy)-2- Fluoro-3-(trifluoromethyl)benzoic acid (540.0 mg, yield 71.0%).
  • the second step in the reaction flask equipped with a drying tube, 6-(2,4-bis(trifluoromethyl)phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (400.0mg , 9.2mmol) was dissolved in dichloromethane (20mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then slowly added dropwise oxalyl chloride (0.78mL, 9.2mmol), and after the dropwise addition, the React until all acid is converted For acid chloride.
  • the reaction system was concentrated to remove excess oxalyl chloride and dichloromethane, then the residue was dissolved in dichloromethane and cooled to about 0°C, slowly added triethylamine (0.38mL, 2.7mmol), followed by 5-amino- 2-Fluorobenzonitrile (131.0 mg, 0.96 mmol) was reacted at room temperature until the reaction was complete, water was added, neutralized with dilute hydrochloric acid, static liquid separation was obtained to dichloromethane phase, concentrated crude product.
  • the third step 6-(2,4-bis(trifluoromethyl)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl ) benzamide (140.0mg, 0.25mmol), triethylamine (0.1mL, 0.75mmol) and hydroxylamine hydrochloride (25.7mg, 0.50mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate.
  • Detection method Whole-cell manual patch clamp technique to detect the effect of compounds on voltage-gated Nav1.8 channel current
  • Negative control electrophysiological extracellular fluid containing 0.5% DMSO
  • Test compound Weigh a certain mass of compound and dissolve it in DMSO to prepare a 20 mM DMSO stock solution. On the day of the test, the 20mM compound mother solution was gradiently diluted with the extracellular fluid to the final concentration to be detected to ensure that the DMSO content in the test drug solution did not exceed 0.5%. This concentration of DMSO had no effect on the detected Nav1.8 channel current.
  • the gradient dilution method is as follows: first absorb 5 ⁇ L DMSO mother solution and add it to 10mL extracellular fluid, dissolve evenly, and obtain a 10 ⁇ M compound solution; then absorb 1mL of 10 ⁇ M compound and add it to 9mL of cells In the external fluid, dissolve evenly to obtain a 1 ⁇ M compound solution; then pipette 1 mL of the 1 ⁇ M compound, add it to 9 mL of extracellular fluid, and dissolve evenly to obtain a 100 nM compound solution. All positive controls in this experiment used VX-150 as the positive control drug, and its half inhibitory concentration was 33.45 ⁇ 0.86nM, which was consistent with the results reported in the original literature. The negative control used in this experiment was the extracellular fluid containing 0.5% DMSO, and the current change value of the channel was ⁇ 5% after administration for 10 minutes.
  • Nav1.8 cell line HEK293 (Flp-In T-Rex-293) cells stably expressing human Nav1.8 sodium channel,
  • the encoding gene information is as follows: NM_001293306.2.
  • Axon patch 700B patch clamp amplifier (Molecular Devices Company) was used in the whole-cell voltage clamp recording experiment, the digital-to-analog converter was Digidata 1440A (Molecular Devices Company), and the glass microelectrodes were made of glass electrode blanks (World Precision Instruments Company) It is drawn by a drawing machine (P97, Sutter Company), and the resistance of the tip after filling the electrode inner liquid is about 1.5-2.5 M ⁇ . Insert the glass microelectrode into the amplifier probe to connect to the patch clamp amplifier.
  • the clamping voltage and data recording are controlled and recorded by the pClamp 10 software (Molecular Devices) through a computer, the sampling frequency is 20kHz, and the filtering frequency is 2kHz.
  • Electrophysiological stimulation protocol After obtaining whole-cell recordings (reaching high-impedance G ⁇ sealing conditions), wait for 4-5 minutes at a clamping voltage of -80mV until the electrode internal fluid and intracellular fluid are balanced, and then start electrophysiological stimulation Record.
  • Current stimulation and compound activity detection scheme cells were clamped at -80mV, given a depolarization voltage stimulation of +10mV for 20ms, then repolarized to -80mV, and the stimulation frequency was 0.5Hz. After confirming that the Nav1.8 sodium channel current is stable (about 1 minute), the administration process starts until the cell current no longer changes (compound inhibition reaches a steady state). At least 3 cells (n > 3) were tested for each concentration of compound. A single concentration of 100nM VX-150 was given as a positive control after all the tested compounds.
  • Inhibition rate (%) [1-the magnitude of the current after drug administration (I Drug )/the magnitude of the current before drug administration (I Control )] ⁇ 100.
  • Table 1 The compounds of the present invention are to the active IC of Nav1.8 channel 50 value (nM)
  • the compound of the present invention is to the percent blocking activity of Nav1.8 channel under the concentration of 1nM
  • the compound of the present invention is to the percent blocking activity of Nav1.8 channel at the concentration of 10nM
  • the compound of the present invention is to the percent blocking activity of Nav1.8 channel under the concentration of 30nM
  • Test method and condition Male SD rats, all animals were fasted overnight, and the compound to be tested was administered intravenously at 2 mg/kg or 1 mg/kg (intravenous vehicle was 5% DMSO/10% Solutol/10% EtOH/75 %Saline, the administration volume is 5 mL/kg) and intragastric administration of 10 mg/kg or 5 mg/kg (the administration vehicle is 0.5% CMC-Na, the administration volume is 10 mL/kg).
  • Sampling information 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 24 before administration and after administration respectively (intravenous administration group increased 5min sampling point); Take 0.2ml of blood from the posterior venous plexus, put it in an EDTA-K2 test tube, centrifuge at 11,000rpm for 5min, separate the plasma, and freeze it in a -20°C refrigerator.
  • Detection information LC/MS/MS method was used to determine the concentration of the original drug in the plasma of rats/mouses after intravenous administration of the compound to be tested and intragastric administration. Calculate the rat/mouse plasma pharmacokinetic parameters under the two administration modes, and calculate the bioavailability of each compound in rats. The results are shown in Table 6 and Table 7 below.

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Abstract

Provided in the present invention are an amidine derivative compound as represented by formula I, and a preparation method therefor and the use thereof. The amidine derivative 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 for treating or relieving pain-related diseases, and has important clinical application value.

Description

脒类衍生化合物及其制备方法和用途Amidine derivative compound and its preparation method and use

优先权信息priority information

本发明请求于2022年2月25日向中国国家知识产权局提交的、申请号为202210176519X、发明名称为“脒类衍生化合物及其制备方法和用途”的中国专利申请的优先权，并且其全部内容通过引用结合在本发明中。The present invention claims the priority of the Chinese patent application with the application number 202210176519X and the title of the invention "amidine derivative compounds and their preparation methods and uses" submitted to the State Intellectual Property Office of China on February 25, 2022, and its entire content Incorporated herein by reference.

技术领域technical field

本发明涉及医药技术领域，尤其是涉及一类脒类衍生化合物、其制备方法以及其用于制备钠通道Nav1.8抑制剂的用途和其制备治疗和/或减轻疼痛和疼痛相关疾病的药物中的用途。The present invention relates to the field of medical technology, in particular to a class of amidine derivative compounds, their preparation method and their use in the preparation of sodium channel Nav1.8 inhibitors and their preparation of medicines for treating and/or alleviating pain and pain-related diseases the use of.

背景技术Background technique

电压门控钠离子通道(voltage-gated sodium channels，以下称VGSC或Nav)介导钠离子选择性的跨膜流动，并在可兴奋细胞如神经元等中介导动作电位的起始、传导、传递中发挥关键作用(Catterall等,Pharmacol Rev.2005；57(4):397-409.)。Nav通道是重要的药物靶点，Nav通道抑制剂用于疼痛、心律失常、癫痫、麻醉、瘙痒等疾病的治疗(Black等，Neuron.2013；80(2):280-91；Catterall等,Annu Rev Pharmacol Toxicol.2014；54:317-38；Bennett等,Physiol Rev.2019；99(2):1079-1151.)。Voltage-gated sodium channels (VGSC or Nav) mediate the selective transmembrane flow of sodium ions, and mediate the initiation, conduction, and activation of action potentials in excitable cells such as neurons. Play a key role in delivery (Catterall et al., Pharmacol Rev. 2005; 57(4):397-409.). Nav channel is an important drug target, and Nav channel inhibitors are used for the treatment of pain, arrhythmia, epilepsy, anesthesia, pruritus and other diseases (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.).

电压门控钠离子通道1.8(以下简称Nav1.8)作为电压门控钠离子通道的一种亚型，在疼痛的病理生理学中发挥重要作用。它主要表达在背根神经节(DRG)中传递痛觉信号的神经元中，抑制Nav1.8可能不会产生药物对中枢神经系统(CNS)的不利影响。因为Nav1.8通道具有较高的激活和失活电压，使其成为动作电位上升支的主要成分(其它Nav通道亚型已处于无功能的失活态)(Goodwin等,Nat Rev Neurosci.2021,22(5):263-274.)。Nav1.8通道慢失活、快复活的特点，使其参与疼痛等膜电位去极化和神经元高频放电的生理和病理过程(Alsaloum等，Nat Rev Neurol.2020,16(12):689-705.)。人类遗传学研究表明，Nav1.8基因突变导致小纤维神经痛和红斑性致痛症(Faber等,Proc Natl Acad Sci U S A.2012,109(47):19444-9；Kaluza等,Pflugers Arch.2018,470(12):1787-1801.)。在啮齿类动物中，基因敲除或敲减Nav1.8通道基因可缓解多种炎性痛和神经痛；而给予Nav1.8抑制剂如A-803467可有效缓解疼痛反应(Jarvis等,Proc Natl Acad Sci U S A.2007,104(20):8520-5.)。Voltage-gated sodium channel 1.8 (hereinafter referred to as Nav1.8), as a subtype of voltage-gated sodium channel, 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), and inhibition of Nav1.8 may not produce adverse effects of the drug on the central nervous system (CNS). Because the Nav1.8 channel has a high activation and inactivation voltage, it is the main component of the rising branch of the action potential (other Nav channel subtypes are already in a non-functional inactivation state) (Goodwin et al., Nat Rev Neurosci.2021, 22(5):263-274.). The characteristics of slow inactivation and fast reactivation of Nav1.8 channel make it participate in the physiological and pathological processes of pain and other membrane potential depolarization and high-frequency discharge of neurons (Alsaloum et al., Nat Rev Neurol.2020,16(12):689 -705.). Human genetic studies have shown that Nav1.8 gene mutations lead to small fiber neuralgia and erythematous allodynia (Faber et al., Proc Natl Acad Sci U S A. 2012,109(47):19444-9; Kaluza et al., Pflugers Arch .2018, 470(12):1787-1801.). In rodents, gene knockout or knockdown of Nav1.8 channel gene can alleviate various inflammatory pain and neuralgia; and administration of Nav1.8 inhibitors such as A-803467 can effectively relieve pain response (Jarvis et al., Proc Natl Acad Sci U S A. 2007,104(20):8520-5.).

糖尿病神经痛是最为常见的神经病理性疼痛疾病之一，约60％～70％的糖尿病患者遭受此疾病的困扰，超过70％的患者未得到有效治疗(Jensen等,Brain.2021,144(6):1632-1645.)。在糖尿病神经痛小鼠模型中，丙酮醛可直接增强Nav1.8通道功能，基因敲除或敲减Nav1.8通道可有效缓解丙酮醛增加的神经痛(Bierhaus等,Nat Med.2012, 18(6):926-33.)。在STZ诱导的糖尿病神经痛大鼠模型中，腹腔或足底给予Nav1.8抑制剂A-803467可剂量依赖的缓解动物的疼痛行为反应(Mert等,J Am Assoc Lab Anim Sci.2012,51(5):579-85.)。Diabetic neuralgia is one of the most common neuropathic pain diseases. About 60% to 70% of diabetic patients suffer from this disease, and more than 70% of patients have not received effective treatment (Jensen et al., Brain. 2021, 144(6) :1632-1645.). In the mouse model of diabetic neuralgia, methylglyoxal can directly enhance the function of Nav1.8 channel, and gene knockout or knockdown of Nav1.8 channel can effectively alleviate the neuralgia caused by methylglyoxal (Bierhaus et al., Nat Med.2012, 18(6):926-33.). In the STZ-induced diabetic neuralgia rat model, intraperitoneal or plantar administration of Nav1.8 inhibitor A-803467 can dose-dependently relieve the animal's pain behavior response (Mert et al., J Am Assoc Lab Anim Sci.2012,51( 5): 579-85.).

除疼痛外，Nav1.8通道也与多发性硬化症、心律失常、咳嗽、瘙痒和癫痫等疾病有关。In addition to pain, Nav1.8 channels have also been linked to diseases such as multiple sclerosis, cardiac arrhythmias, coughing, itching, and epilepsy.

多发性硬化症(Multiple sclerosis,MS)是一种原发于中枢神经系统的炎症性脱髓鞘疾病，其确切的发病机制尚有待阐明。正常人的小脑浦肯野纤维不表达Nav1.8通道，多发性硬化症患者的小脑Nav1.8表达上调，且通道的表达量随病程的发展呈现依赖性增加，Nav1.8编码基因的单核苷酸多态性(SNP)也和MS发病程度相关(Craner等,J Neuropathol Exp Neurol.2003,62(9):968-75；Roostaei等,Neurology.2016,86(5):410-7.)。小脑浦肯野纤维敲入Nav1.8(过表达)的基因鼠(L7-1.8TG)表现多发性硬化行为，给予Nav1.8选择性抑制剂PF-01247324可以缓解L7-1.8TG转基因鼠的MS行为(Shields等,Ann Neurol.2012,71(2):186-94；Shields等,PLoS One.2015,10(3):e0119067.)。Multiple sclerosis (Multiple sclerosis, MS) is an inflammatory demyelinating disease that originates in the central nervous system, and its exact pathogenesis remains to be elucidated. The cerebellar Purkinje fibers of normal people do not express Nav1.8 channels. The expression of Nav1.8 in the cerebellum of patients with multiple sclerosis is up-regulated, and the expression of the channel increases with the development of the disease. Nucleic acid polymorphism (SNP) is also associated with 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. ). Cerebellar Purkinje fiber knock-in Nav1.8 (overexpression) mice (L7-1.8TG) exhibit multiple sclerosis behavior, and administration of Nav1.8 selective inhibitor PF-01247324 can alleviate MS in L7-1.8TG transgenic mice Behavior (Shields et al., Ann Neurol. 2012, 71(2):186-94; Shields et al., PLoS One. 2015, 10(3):e0119067.).

骨关节炎是退行性骨关节病，软骨磨损和疼痛是其主要特征。磷酸化的cAMP反应元件结合蛋白(CREB)直接结合Nav1.8编码基因的启动子，促进Nav1.8蛋白的转录，上调Nav1.8通道表达水平(Zhu等,Elife.2020,9:e57656.)。Osteoarthritis is a degenerative bone joint disease characterized by cartilage wear and pain. Phosphorylated cAMP response element binding protein (CREB) directly binds to the promoter of the gene encoding Nav1.8, promotes the transcription of Nav1.8 protein, and up-regulates the expression level of Nav1.8 channels (Zhu et al., Elife.2020, 9:e57656.) .

在心血管系统中，Nav1.8通道已被证明在心脏神经如浦肯野纤维中表达，也有部分研究认为Nav1.8在心肌细胞中也有表达(Verkerk等,Circ Res.2012,111(3):333-43.)。人类遗传学研究发现Nav1.8基因突变与Brugada综合征有关(Hu等,J Am Coll Cardiol.2014,64(1):66-79.)。抑制Nav1.8通道可改善心脏重构，Nav1.8通道被认为是心律失常、房颤、心衰等心血管疾病潜在的治疗靶点(Dybkova等,Cardiovasc Res.2018,114(13):1728-1737.)。In the cardiovascular system, Nav1.8 channels have been shown to be expressed in cardiac nerves such as Purkinje fibers, and some studies suggest that Nav1.8 is also expressed in cardiomyocytes (Verkerk et al., Circ Res.2012, 111(3): 333-43.). Human genetic studies have found that mutations in the Nav1.8 gene are associated with Brugada syndrome (Hu et al., J Am Coll Cardiol. 2014, 64(1):66-79.). Inhibition of Nav1.8 channels can improve cardiac remodeling, and Nav1.8 channels are considered to be potential therapeutic targets for cardiovascular diseases such as arrhythmia, atrial fibrillation, and heart failure (Dybkova et al., Cardiovasc Res. 2018, 114(13): 1728 -1737.).

Nav1.8通道在咳嗽相关的迷走神经丛中表达，病理性咳嗽过程中Nav1.8磷酸化水平和表达量升高，显示参与咳嗽反射(Muroi等,Lung.2014,192(1):15-20.)。Nav1.8 channel is expressed in the cough-related vagus plexus, and the phosphorylation level and expression of Nav1.8 increase during pathological cough, showing that it is involved in the cough reflex (Muroi et al., Lung.2014, 192(1): 15-20 .).

在哺乳动物的痒感受中，淋巴细胞、肥大细胞等释放的组胺等致痒因子可激活Nav1.8通道，敲除小鼠Nav1.8可有效缓解组胺和内皮素诱导的瘙痒行为(Riol-Blanco等,2014,510(7503):157-61.)。In the itch sensation of mammals, itching factors such as histamine released by lymphocytes and mast cells can activate Nav1.8 channels, and knocking out Nav1.8 in mice can effectively alleviate the itching behavior induced by histamine and endothelin (Riol -Blanco et al., 2014, 510(7503):157-61.).

此外，人类Nav1.8先天性突变被报道可引发癫痫、惊厥疾病(Kambouris等,Ann Clin Transl Neurol.2016,4(1):26-35.)。因此，Nav1.8通道的抑制剂被认为可用于治疗、预防或控制与Nav1.8通道参与或功能紊乱相关的疾病。In addition, human Nav1.8 congenital mutations have been reported to cause epilepsy and convulsive disorders (Kambouris et al., Ann Clin Transl Neurol. 2016, 4(1):26-35.). Therefore, inhibitors of Nav1.8 channels are considered to be useful in the treatment, prevention or control of diseases associated with Nav1.8 channel involvement or dysfunction.

由于Nav1.8主要分布在外周神经系统，所以选择性地抑制Nav1.8可以有效地减少副作用。在现有研究中，含有吡啶酮类结构的Nav1.8钠离子通道抑制剂VX-150，在治疗因为小纤维神经病变(SFN)导致的疼痛患者的2期临床试验达到主要终点，用于治疗中度至重度疼痛，被美国FDA授予突破性疗法的认定；此外WO2021018165和CN202010932125.3也公布了用于抑制Nav1.8钠离子通道吡啶酮化合物类；另外， WO2014120815、WO2014120820、US201901667、WO2020092187、CN202010889003.0、WO2020092187、CN202110107114.6等分别公开包含有用于抑制Nav1.8钠离子通道芳基甲酸类、苯甲酰胺类、芳基磺酰胺类等类别化合物；此外WO2020169042公开了含有哒嗪酮类化合物的Nav1.8钠离子通道抑制剂，以上研究均没有产品上市。因此，开发新的Nav1.8抑制剂对治疗Nav1.8表达失调相关的疾病有着非常重要的科学价值和临床意义。Since Nav1.8 is mainly distributed in the peripheral nervous system, selective inhibition of Nav1.8 can effectively reduce side effects. In the existing study, VX-150, a Nav1.8 sodium ion channel inhibitor containing a pyridone-like structure, met its primary endpoint in a phase 2 clinical trial in the treatment of patients with pain caused by small fiber neuropathy (SFN). Moderate to severe pain, granted breakthrough therapy designation by the US FDA; in addition, WO2021018165 and CN202010932125.3 also announced pyridone compounds for inhibiting Nav1.8 sodium ion channel; in addition, WO2014120815, WO2014120820, US201901667, WO2020092187, CN202010889003.0, WO2020092187, CN202110107114.6, etc. respectively disclose aryl formic acids, benzamides, and arylsulfonamides for inhibiting Nav1.8 sodium ion channels and other classes of compounds; in addition WO2020169042 discloses Nav1.8 sodium ion channel inhibitors containing pyridazinone compounds, but none of the above studies have been launched. Therefore, the development of new Nav1.8 inhibitors has very important scientific value and clinical significance for the treatment of diseases related to Nav1.8 expression disorders.

有鉴于此，特提出本发明。In view of this, the present invention is proposed.

发明内容Contents of the invention

本发明的目的之一在于提供一种脒类衍生化合物，具有Nav1.8选择性抑制活性。One of the objectives of the present invention is to provide an amidine derivative compound with Nav1.8 selective inhibitory activity.

本发明的目的之二在于提供一种脒类衍生化合物的制备方法。The second object of the present invention is to provide a method for preparing amidine derivatives.

本发明的目的之三在于提供一种包含所述脒类衍生化合物的药物组合物。The third object of the present invention is to provide a pharmaceutical composition comprising the amidine derivative compound.

本发明的目的之四在于提供一种所述脒类衍生化合物或药物组合物在制备Nav1.8抑制剂或用于治疗和/或减轻疼痛和疼痛相关疾病的药物中的用途。The fourth object of the present invention is to provide a use of the amidine derivative compound or pharmaceutical composition in the preparation of Nav1.8 inhibitors or drugs for treating and/or alleviating pain and pain-related diseases.

为了实现本发明的上述目的，特采用以下技术方案：In order to realize the above-mentioned purpose of the present invention, special adopt following technical scheme:

本发明一方面提供了一种式I化合物、，其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，其氘代物或其药学上可接受的盐，
One aspect of the present invention provides a compound of formula I, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, its deuterated product or its pharmaceutical acceptable salt,

其中：in:

A环为取代或未取代的C6～C12芳基、取代或未取代的含有选自N、O、S的1至4个杂原子的5～10元杂芳基；优选地，A环为取代或未取代的苯基；所述取代的取代基选自卤素、C1～C6烷基、氘代C1～C6烷基、卤代C1～C6烷基、C1～C6烷氧基、氘代C1～C6烷氧基、卤代C1～C6烷氧基、C3～C8环烷基、氘代C3～C8环烷基、卤代C3～C8环烷基、C3～C8环烷氧基、氘代C3～C8环烷氧基、卤代C3～C8环烷氧基，优选选自F、Cl、C1～C3烷基、氘代C1～C3烷基、卤代C1～C3烷基、C1～C3烷氧基、氘代C1～C3烷氧基、卤代C1～C3烷氧基、C3～C6环烷基、氘代C3～C6环烷基、卤代C3～C6环烷基、C3～C6环烷氧基、氘代C3～C6环烷氧基、卤代C3～C6环烷氧基； 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, and S; preferably, ring A is substituted Or unsubstituted phenyl; the substituted substituent is 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, preferably selected from F, Cl, C1~C3 alkyl, deuterated C1~C3 alkyl, halogenated C1~C3 alkyl, C1~C3 alkane Oxygen, deuterated C1～C3 alkoxy, halogenated C1～C3 alkoxy, C3～C6 cycloalkyl, deuterated C3～C6 cycloalkyl, halogenated C3～C6 cycloalkyl, C3～C6 ring Alkoxy, deuterated C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy;

R1和R2各自独立地选自氢、C1～C6烷基、C3～C6环烷基、C(＝O)R1a、C(＝O)OR2a，其中，R1a选自氢、C1～C6烷基、C3～C6环烷基、苯基，R2a选自C1～C6烷基、C3～C6环烷基、苯基；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, phenyl, R 2a is selected from C1～C6 alkyl, C3～C6 cycloalkyl, phenyl;

R3选自氢、-CN、-OH或C1～C6烷氧基；R 3 is selected from hydrogen, -CN, -OH or C1～C6 alkoxy;

X1和X2之一为C，另一个选自N和CRg；One of X 1 and X 2 is C, and the other is selected from N and CR g ;

R4、R5和R6各自独立地选自氢、卤素、C1～C3烷基、C1～C3烷氧基、C3～C6环烷基；R 4 , R 5 and R 6 are each independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, C3-C6 cycloalkyl;

X3、X4和X5各自独立地选自N和CRa，且X3、X4和X5中至多存在一个N；X 3 , X 4 and X 5 are each independently selected from N and CR a , and there is at most one N in X 3 , X 4 and X 5 ;

R7选自氢、卤素、C1～C6烷基、卤代C1～C6烷基、C1～C6烷氧基、卤代C1～C6烷氧基； R7 is selected from hydrogen, halogen, C1～C6 alkyl, halogenated C1～C6 alkyl, C1～C6 alkoxy, halogenated C1～C6 alkoxy;

Rg、Ra在每次出现时独立地选自氢、卤素、C1～C6烷基、卤代C1～C6烷基、C1～C6烷氧基、卤代C1～C6烷氧基、C2～C6烯基、卤代C2～C6烯基、C2～C6烯氧基、卤代C2～C6烯氧基、C2～C6炔基、卤代C1～C6炔基、C2～C6炔氧基、卤代C1～C6炔氧基、C3～C6环烷基、C3～C6环烷氧基；R g and R a are independently selected from hydrogen, halogen, C1~C6 alkyl, halogenated C1~C6 alkyl, C1~C6 alkoxy, halogenated C1~C6 alkoxy, C2~ C6 alkenyl, halogenated C2～C6 alkenyl, C2～C6 alkenyloxy, halogenated C2～C6 alkenyloxy, C2～C6 alkynyl, halogenated C1～C6 alkynyl, C2～C6 alkynyloxy, halogen Substitute C1~C6 alkynyloxy, C3~C6 cycloalkyl, C3~C6 cycloalkoxy;

或者，R7和Ra中相邻的两个取代基连同与其相连的碳原子共同构成环或取代或未取代的苯环；所述取代的取代基选自卤素、C1～C6烷基、C1～C6烷氧基，优选选自F、Cl、C1～C3烷基、C1～C3烷氧基；Alternatively, the two adjacent substituents in R 7 and R a together with the carbon atoms attached to them form a ring Or a substituted or unsubstituted benzene ring; the substituted substituent is selected from halogen, C1～C6 alkyl, C1～C6 alkoxy, preferably selected from F, Cl, C1～C3 alkyl, C1～C3 alkoxy base;

Y1和Y2各自独立地选自O、CH2；Y 1 and Y 2 are each independently selected from O, CH 2 ;

R8选自氢、卤素或C1～C3烷基。R 8 is selected from hydrogen, halogen or C1-C3 alkyl.

在一些优选实施方式中，R1、R2和R3至少一个为H，特别地，R1、R2和R3都为氢。In some preferred embodiments, at least one of R 1 , R 2 and R 3 is H, especially, all of R 1 , R 2 and R 3 are hydrogen.

在一些实施方式中，为 In some embodiments, for

在一些实施方式中，式I化合物选自：
In some embodiments, the compound of formula I is selected from:

其中，in,

X1、X2各自独立地选自N和CRg，X 1 and X 2 are each independently selected from N and CR g ,

R1、R2、R3、R4、R5、R6、R7、Rg、A环、X3、X4、X5的定义与前述相同。The definitions of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R g , Ring A, X 3 , X 4 , and X 5 are the same as those described above.

在一些实施方式中，式I化合物选自式I-A化合物和式I-A’化合物：
In some embodiments, the compound of formula I is selected from the compound of formula IA and the compound of formula IA':

其中，in,

X1、X2各自独立地选自N和CRg；X 1 and X 2 are each independently selected from N and CR g ;

R1、R2、R3、R4、R5、R6、R7、Rg、X3、X4、X5的定义与前述相同；R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R g , X 3 , X 4 , and X 5 are as defined above;

X6、X7、X8各自独立地选自N和CRb，且X6、X7和X8中至多存在一个N；X 6 , X 7 , X 8 are each independently selected from N and CR b , and there is at most one N in X 6 , X 7 and X 8 ;

Rb、R9和R10在每次出现时各自独立地选自氢、卤素、C1～C6烷基、氘代C1～C6烷基、卤代C1～C6烷基、C1～C6烷氧基、氘代C1～C6烷氧基、卤代C1～C6烷氧基、C3～C8环烷基、氘代C3～C8环烷基、卤代C3～C8环烷基、C3～C8环烷氧基、氘代C3～C8环烷氧基、卤代C3～C8环烷氧基；优选选自氢、F、Cl、C1～C3烷基、氘代C1～C3烷基、卤代C1～C3烷基、C1～C3烷氧基、氘代C1～C3烷氧基、卤代C1～C3烷氧基、C3～C6环烷基、氘代C3～C6环烷基、卤代C3～C6环烷基、C3～C6环烷氧基、氘代C3～C6环烷氧基、卤代C3～C6环烷氧基。R b , R 9 and R 10 are 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 Group, deuterated C3～C8 cycloalkoxy, halogenated C3～C8 cycloalkoxy; 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 ring Alkyl, C3-C6 cycloalkoxy, deuterated C3-C6 cycloalkoxy, halogenated C3-C6 cycloalkoxy.

在一些实施方式中，式I化合物为式I-A化合物：
In some embodiments, the compound of formula I is a compound of formula IA:

其中，X2选自N或CRg，优选为CRg，Rg选自氢、F、Cl、Br、C1～C6烷基或C1～C6烷氧基，优选为氢、F、Cl或Br，更优选为氢或F，特别是F；Among them, X2 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;

X3、X4各自独立地为CRa，X5选自N或CRa，Ra每次出现时相同或不同，选自氢、卤代C1～C6烷基、卤代C1～C6烷氧基，优选X3中的Ra选自三氟甲基或三氟甲氧基，X4和X5中的Ra为氢；X 3 and 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, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy group, preferably R in X3 is selected from trifluoromethyl or trifluoromethoxy, and R in X4 and X5 is hydrogen;

X6、X7、X8各自独立地选自CRb，Rb相同或不同，选自氢、卤素、C1～C6烷基、卤代C1～C6烷基、C1～C6烷氧基、卤代C1～C6烷氧基、C3～C8环烷基，优选选自氢、F、Cl、Br、三氟甲基、甲氧基或三氟甲氧基；X 6 , X 7 , and X 8 are each independently selected from CR b , R b is the same or different, selected from hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogen Substitute C1～C6 alkoxy, C3～C8 cycloalkyl, preferably selected from hydrogen, F, Cl, Br, trifluoromethyl, methoxy or trifluoromethoxy;

R9为氢；R10选自氢、三氟甲基、C3～C6环烷基、氘代C3～C6环烷基；R 9 is hydrogen; R 10 is selected from hydrogen, trifluoromethyl, C3～C6 cycloalkyl, deuterated C3～C6 cycloalkyl;

R7选自卤素、C1～C6烷氧基，优选选自F、Cl、Br或甲氧基；R 7 is selected from halogen, C1～C6 alkoxy, preferably selected from F, Cl, Br or methoxy;

R4、R5、R6各自独立地选自氢、卤素、C1～C3烷基、C1～C3烷氧基，优选为氢；R 4 , R 5 , and R 6 are each independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, preferably hydrogen;

R1和R2各自独立地选自氢、C1～C6烷基，优选为氢；R 1 and R 2 are each independently selected from hydrogen, C1-C6 alkyl, preferably hydrogen;

R3选自氢、-CN、-OH或C1～C6烷氧基，优选为-OH。R 3 is selected from hydrogen, -CN, -OH or C1-C6 alkoxy, preferably -OH.

在一些实施方式中，式I-A化合物选自如下式I-A-1化合物：
In some embodiments, the compound of formula IA is selected from the following compounds of formula IA-1:

其中，R1、R2、R3、R4、R5、X5、R6、R7、R9、R10、Ra、Rb、Rg的定义与前述相同；Wherein, the definitions of R 1 , R 2 , R 3 , R 4 , R 5 , X 5 , R 6 , R 7 , R 9 , R 10 , R a , R b , and R g are the same as above;

特别地，R1、R2和R3为氢；In particular, R 1 , R 2 and R 3 are hydrogen;

特别地，R4、R5、R6、Rg中至少两个为H，特别是至少三个为H，更特别是全部为H；In particular, at least two of R 4 , R 5 , R 6 , R g are H, especially at least three are H, more especially all are H;

特别地，R7、Ra中至少一个为H，特别是至少二个为H；In particular, at least one of R 7 and R a is H, especially at least two of them are H;

特别地，R9、R10、Rb中至少两个为H，特别是至少三个为H。In particular, at least two of R 9 , R 10 , R b are H, especially at least three are H.

在一些优选实施方式中，式I-A-1化合物中，In some preferred embodiments, in the compound of formula I-A-1,

Rg选自氢、F、Cl、Br、C1～C6烷基或C1～C6烷氧基，优选为氢、F、Cl或Br，更优选为氢或F，特别是F；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;

X5选自N或CRa，Ra每次出现时相同或不同，选自氢、卤代C1～C6烷基、卤代C1～C6 烷氧基，优选X3中的Ra选自三氟甲基或三氟甲氧基，X4和X5中的Ra为氢；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 in X3 is selected from trifluoromethyl or trifluoromethoxy, and R in X4 and X5 is hydrogen;

Rb相同或不同，选自氢、卤素、C1～C6烷基、卤代C1～C6烷基、C1～C6烷氧基、卤代C1～C6烷氧基、C3～C8环烷基，优选选自氢、F、Cl、Br、三氟甲基、甲氧基或三氟甲氧基；R b is the same or different, 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;

R9为氢；R10选自氢、三氟甲基、C3～C6环烷基、氘代C3～C6环烷基；R 9 is hydrogen; R 10 is selected from hydrogen, trifluoromethyl, C3～C6 cycloalkyl, deuterated C3～C6 cycloalkyl;

R7选自卤素、C1～C6烷氧基，优选选自F、Cl、Br或甲氧基；R 7 is selected from halogen, C1～C6 alkoxy, preferably selected from F, Cl, Br or methoxy;

R4、R5、R6各自独立地选自氢、卤素、C1～C3烷基、C1～C3烷氧基，优选为氢；R 4 , R 5 , and R 6 are each independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, preferably hydrogen;

R1和R2各自独立地选自氢、C1～C6烷基，优选为氢；R 1 and R 2 are each independently selected from hydrogen, C1-C6 alkyl, preferably hydrogen;

R3选自氢、-CN、-OH或C1～C6烷氧基，优选为-OH。R 3 is selected from hydrogen, -CN, -OH or C1-C6 alkoxy, preferably -OH.

在一些实施方式中，式I-A-1化合物选自如下式I-A-1A化合物：
In some embodiments, the compound of formula IA-1 is selected from the following compounds of formula IA-1A:

X5、R7、R9、R10、Ra、Rb的定义与前述相同。The definitions of X 5 , R 7 , R 9 , R 10 , R a , and R b are the same as described above.

在一些实施方式中，式I-A-1A化合物中，In some embodiments, in the compound of formula I-A-1A,

X5选自N或CRa，Ra每次出现时相同或不同，选自氢、卤代C1～C6烷基、卤代C1～C6烷氧基，优选X3中的Ra选自三氟甲基或三氟甲氧基，X4和X5中的Ra为氢；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 in X 3 is selected from three Fluoromethyl or trifluoromethoxy, R in X 4 and X 5 is hydrogen;

Rb相同或不同，选自氢、卤素、C1～C6烷基、卤代C1～C6烷基、C1～C6烷氧基、卤代C1～C6烷氧基、C3～C8环烷基，优选选自氢、F、Cl、Br、三氟甲基、甲氧基或三氟甲氧基；R b is the same or different, 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;

R9为氢；R10选自氢、三氟甲基、C3～C6环烷基、氘代C3～C6环烷基；R 9 is hydrogen; R 10 is selected from hydrogen, trifluoromethyl, C3～C6 cycloalkyl, deuterated C3～C6 cycloalkyl;

R7选自卤素、C1～C6烷氧基，优选选自F、Cl、Br或甲氧基。R 7 is selected from halogen, C1-C6 alkoxy, preferably from F, Cl, Br or methoxy.

本领域普通技术人员将理解，与为互变异构体，因此含有结构的本发明化合物也可以视为含有结构，两者是等价的。 在一些实施方式中，选自如下结构：
Those of ordinary skill in the art will understand that, and are tautomers and therefore contain The compounds of the present invention of structure can also be regarded as containing structure, both are equivalent. In some embodiments, Choose from the following structures:

在一些优选实施方式中，式I化合物选自下列化合物：






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






本发明中的术语定义如下：Terms in the present invention are defined as follows:

所述“卤素”可以为氟、氯、溴或碘。The "halogen" may be fluorine, chlorine, bromine or iodine.

所述“C1～C6烷基”是指具有1～6个碳原子的链状烷基；其具体实例可以包括甲基、乙基、丙基、正丙基、异丙基、丁基、正丁基、异丁基、叔丁基、1-甲基-丁基、1-乙基-丁基、戊基、正戊基、异戊基、新戊基、叔戊基、己基、正己基、1-甲基戊基、2-甲基戊基、4-甲基-2-戊基、3,3-二甲基丁基、2-乙基丁基以及类似基团，但不限于此；“C1-C3烷基”的定义以此类推。The "C1~C6 alkyl" refers to a chain alkyl group with 1~6 carbon atoms; its specific examples 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 similar groups, but not limited thereto ; The definition of "C1-C3 alkyl" and so on.

所述“氘代C1～C6烷基”是指如上所定义的C1～C6烷基的一个或多个氢被氘取代。The "deuterated C1-C6 alkyl" means that one or more hydrogens of the above-defined C1-C6 alkyl are replaced by deuterium.

所述“卤代C1～C6烷基”是指如上所定义的C1～C6烷基的一个或多个氢被卤素取代。The "halogenated C1-C6 alkyl" means that one or more hydrogens of the above-defined C1-C6 alkyl are replaced by halogen.

所述“C2～C6烯基”是指直链或支链的含有2～6个碳原子，至少有一个碳碳双键的基团；其具体实例可以包括乙烯基、丙烯基、2-丙烯基、(E)-2-丁烯基、(Z)-2-丁烯基、(E)-2-甲基-2-丁烯基、(Z)-2-甲基-2-丁烯基、2,3-二甲基-2-丁烯基、(Z)-2-戊烯基、(E)-1-戊烯基、(E)-2-戊烯基、(Z)-2-己烯基、(E)-1-己烯基、(Z)-1-己烯基、(E)-2-己烯基、(Z)-3-己烯基、(E)-3- 己烯基、(E)-1,3-己二烯基、4-甲基-3-戊烯基或降冰片烯。The "C2-C6 alkenyl" refers to a straight-chain or branched group containing 2-6 carbon atoms and at least one carbon-carbon double bond; its specific examples may include vinyl, propenyl, 2-propene Base, (E)-2-butenyl, (Z)-2-butenyl, (E)-2-methyl-2-butenyl, (Z)-2-methyl-2-butene base, 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.

所述“C2～C6炔基”是指直链或支链的含有2～6个碳原子，至少有一个碳碳双键的基团；其具体实例可以包括乙炔基、1-丙炔基、2-丙炔基、1-丁炔基、2-丁炔基、1-戊炔基、2-戊炔基、1-己炔基、2-己炔基、3-己炔基。The "C2-C6 alkynyl group" refers to a straight-chain or branched group containing 2-6 carbon atoms and at least one carbon-carbon double bond; its specific examples may include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl.

所述“C1～C6烷氧基”是指RO-基团，其中R为如上所述的C1-C6烷基。烷氧基的具体实例包括甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基、仲丁氧基、正戊氧基、异戊氧基、新戊氧基、正己氧基、异己氧基、3-甲基戊氧基、3,3-二甲基丁氧基、2-乙基丁氧基等。“C1-C3烷氧基”的定义以此类推。The "C1-C6 alkoxy group" refers to the RO- group, wherein R is the above-mentioned C1-C6 alkyl group. Specific examples of alkoxy include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, tert-butoxy, sec-butoxy, n-pentoxy, Isopentyloxy, neopentyloxy, n-hexyloxy, isohexyloxy, 3-methylpentyloxy, 3,3-dimethylbutoxy, 2-ethylbutoxy and the like. The definition of "C1-C3 alkoxy" is analogous.

所述“卤代C1～C6烷氧基”是指如上所述的烷氧基的至少一个氢被卤素取代得到的基团；其具体实例包括三氟甲氧基等。The "halogenated C1-C6 alkoxy group" refers to a group obtained by replacing at least one hydrogen of the above-mentioned alkoxy group with a halogen; specific examples thereof include trifluoromethoxy group and the like.

所述“氘代C1～C6烷氧基”是指RO-基团，其中R为如上所述的氘代C1-C6烷基。The "deuterated C1-C6 alkoxy group" refers to the RO- group, wherein R is the deuterated C1-C6 alkyl group as described above.

所述“C2～C6烯氧基”是指RO-基团，其中R为如上所述的C2～C6烯基；烯氧基的具体实例包括乙烯氧基、丙烯氧基。The "C2-C6 alkenyloxy group" refers to the RO- group, wherein R is the above-mentioned C2-C6 alkenyl group; specific examples of the alkenyloxy group include ethyleneoxy and propyleneoxy.

所述“C2～C6炔氧基”是指RO-基团，其中R为如上所述的C2～C6炔基；炔氧基的具体实例包括乙炔氧基、丙炔氧基。The "C2-C6 alkynyloxy group" refers to the RO- group, wherein R is the above-mentioned C2-C6 alkynyl group; specific examples of the alkynyloxy group include ethynyloxy and propynyloxy.

所述“C3～C8环烷基”是指包含3-8个碳原子的完全饱和的环状烃类化合物基团，其具体实例包括环丙基、环丁基、环戊基、环己基。The "C3-C8 cycloalkyl" refers to a fully saturated cyclic hydrocarbon compound group containing 3-8 carbon atoms, and specific examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

所述“氘代C3～C8环烷基”指的是如上所定义的C3～C8环烷基的一个或多个氢被氘取代所得到的基团。The "deuterated C3-C8 cycloalkyl group" refers to a group obtained by replacing one or more hydrogens of the C3-C8 cycloalkyl group defined above with deuterium.

所述“卤代C3～C8环烷基”指的是如上所定义的C3～C8环烷基的一个或多个氢被卤素取代所得到的基团。The "halogenated C3-C8 cycloalkyl" refers to a group obtained by replacing one or more hydrogens of the C3-C8 cycloalkyl as defined above with halogen.

所述“C3～C8环烷氧基”是指RO-基团，其中R为如上所述的C3～C8环烷基。The "C3-C8 cycloalkoxy group" refers to the RO-group, wherein R is the above-mentioned C3-C8 cycloalkyl group.

所述“氘代C3～C8环烷氧基”指的是如上所定义的C3～C8环烷氧基的一个或多个氢被氘取代所得到的基团。The "deuterated C3-C8 cycloalkoxy group" refers to a group obtained by replacing one or more hydrogens of the C3-C8 cycloalkoxy group defined above with deuterium.

所述“卤代C3～C8环烷氧基”指的是如上所定义的C3～C8环烷氧基的一个或多个氢被卤素取代所得到的基团。The "halogenated C3-C8 cycloalkoxy group" refers to a group obtained by replacing one or more hydrogens of the C3-C8 cycloalkoxy group defined above with halogen.

所述“C6～C12芳基”是指具有6至12个碳原子的单环或多环芳基；其具体实例包括苯基、萘基。The "C6-C12 aryl" refers to a monocyclic or polycyclic aryl group having 6 to 12 carbon atoms; specific examples thereof include phenyl, naphthyl.

所述“5～10元芳杂基”是指环上含有1至4个选自氮、氧、硫中的杂原子的5～10元芳香基团，其具体实例包括吡啶、哒嗪、嘧啶等。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 on the ring, and its specific examples include pyridine, pyridazine, pyrimidine, etc. .

所述“药学上可接受的盐”为本领域内所熟知，包括衍生自适宜无机/有机酸和碱的盐。药学上可接受的无毒酸加成盐的实例是无机酸(例如，盐酸、氢溴酸、磷酸、硫酸及高氯酸)或有机酸(例如，乙酸、草酸、马来酸、酒石酸、柠檬酸、琥珀酸或丙二酸)或通过使用本领 域内所用的其他方法(例如，离子交换)与氨基形成的盐。其他药学上可接受的盐包括己二酸盐、海藻酸盐、抗坏血酸盐、天冬氨酸盐、苯磺酸盐、苯甲酸盐、硫酸氢盐、硼酸盐、丁酸盐、樟脑酸盐、樟脑磺酸盐、柠檬酸盐、环戊烷丙酸盐、二葡糖酸盐、十二烷基硫酸盐、乙磺酸盐、甲酸盐、富马酸盐、葡庚糖酸盐、甘油磷酸盐、葡萄糖酸盐、半硫酸盐、庚酸盐、已酸盐、氢碘酸盐、2-羟基-乙磺酸盐、乳糖酸盐、乳酸盐、月桂酸盐、月桂基硫酸盐、苹果酸盐、马来酸盐、丙二酸盐、甲磺酸盐、2-萘磺酸盐、烟酸盐、硝酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、果胶酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、硬脂酸盐、琥珀酸盐、硫酸盐、酒石酸盐、硫氰酸盐、对甲苯磺酸盐、十一烷酸盐、戊酸盐等。若适当，其他药学上可接受的盐包括无毒铵、季铵及胺阳离子，其是使用例如卤离子、氢氧根、羧酸根、硫酸根、磷酸根、硝酸根、低级烷基磺酸根及芳基磺酸根等抗衡离子形成的。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, hydrobromic, phosphoric, sulfuric, and perchloric) or organic acids (e.g., acetic, oxalic, maleic, tartaric, citric, acid, succinic acid, or malonic acid) or by using the Salts formed with amino groups by other methods used in the art (eg, ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, besylate, benzoate, bisulfate, borate, butyrate, camphoric acid Salt, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, lauryl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate , glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate Salt, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate salt, pectate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate Salt, p-toluenesulfonate, undecanoate, pentanoate, etc. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium, and amine cations using, for example, halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkylsulfonates, and Formed by counter ions such as aryl sulfonates.

所述“氘代物”是指化合物结构中的一个或多个氢(1H)被氘(2H)取代所形成的结构。The "deuterated substance" refers to a structure in which one or more hydrogens ( 1 H) in the compound structure are replaced by deuterium ( 2 H).

本申请所涉及的化合物及其药学可接受的盐可具有异构体或消旋体，例如光学异构体(包括非对映异构体和对映异构体)、阻转异构体、几何异构体(顺反异构体)、构象异构体、互变异构体以及它们的混合物等，但不限于此。这些异构体也包含在本发明的权利要求所限定的范围中。The compounds involved in the present application and their pharmaceutically acceptable salts may have isomers or racemates, such as optical isomers (including diastereoisomers and enantiomers), atropisomers, Geometric isomers (cis-trans isomers), conformational isomers, tautomers, mixtures thereof, etc., but not limited thereto. These isomers are also included in the scope defined by the claims of the present invention.

本发明另一方面提供了上述式I化合物的制备方法，该方法通过以下反应路线实现：Another aspect of the present invention provides the preparation method of the above-mentioned compound of formula I, the method is realized by the following reaction scheme:

路线1：
Route 1:

II-A化合物与醇在酸催化下，生成Pinner盐，随后加入NR1R2R3制备I-A化合物。Under acid catalysis, compound II-A and alcohol generate Pinner salt, and then add NR 1 R 2 R 3 to prepare compound IA.

II-A化合物中R4、R5、R6、R7、R9、R10、X2、X3、X4、X5、X6、X7、X8的定义同I-A化合物中相应定义。The definitions of R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 in compound II-A are the same as in compound IA. definition.

在一些实施方式中，式II-A化合物制备方法为如下方法一或方法二之一：In some embodiments, the preparation method of the compound of formula II-A is one of the following method one or method two:

方法一：
method one:

第一步：SM1(其中LG为亲核反应离去基团，诸如卤素或S(O)2Me,Y为酯基或氰基)和SM2在碱诸如碳酸钾或碳酸铯的存在下，在适当溶剂诸如乙腈、四氢呋喃或N,N-二甲基甲酰胺、二甲基亚砜等中加热进行亲核取代反应得到相应的M1,所述反应通常在50℃至110℃范围内的温度下进行。The first step: SM1 (where LG is a nucleophilic reaction leaving group, such as halogen or S(O) 2 Me, Y is an ester group or cyano) and SM2 in the presence of a base such as potassium carbonate or cesium carbonate, in the appropriate Solvents such as acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethyl sulfoxide, etc. are heated to carry out nucleophilic substitution reaction to obtain the corresponding M1, and the reaction is usually carried out at a temperature ranging from 50 ° C to 110 ° C .

第二步：M1通过水解成酸，再和SM3通过胺酸缩合反应制备II-A；Step 2: M1 is hydrolyzed into acid, and then reacted with SM3 to prepare II-A through amino acid condensation reaction;

所述胺酸缩合反应为如下方案一至三之一：The amino acid condensation reaction is one of the following schemes one to three:

方案一：Option One:

M1和SM3通过胺酸缩合反应得到II-A。所述胺酸缩合是在缩合剂,诸如HATU或HBTU等常规缩合剂和碱，诸如三乙胺、二异丙基乙胺、吡啶、碳酸钾、碳酸铯等的存在下，在适当溶剂诸如乙腈、四氢呋喃或N,N-二甲基甲酰胺、二甲基亚砜等中在0～100℃范围内的温度下进行获得II-A。M1 and SM3 obtained II-A through amine acid condensation reaction. The amine acid condensation is in the presence of a condensing agent, conventional condensing agents 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, or N,N-dimethylformamide, dimethyl sulfoxide, etc. at a temperature in the range of 0 to 100°C to obtain II-A.

方案二：Option II:

在一定温度下，向M1和SM3的吡啶体系缓慢滴加POCl3获得II-A，所述的一定温度下是-10℃～30℃，优选0℃左右。At a certain temperature, POCl 3 is slowly added dropwise to the pyridine system of M1 and SM3 to obtain II-A. The certain temperature is -10°C to 30°C, preferably around 0°C.

方案三：third solution:

先将M1在二氯亚砜或三氯化磷的作用下，制备成酰氯，随后和SM2在碱，诸如三乙胺、二异丙基乙胺、吡啶、碳酸钾、碳酸铯等的存在下，在适当溶剂诸如二氯甲烷、乙酸乙酯、乙腈、四氢呋喃或N,N-二甲基甲酰胺、二甲基亚砜等中获得II-A。M1 is first prepared into an acid chloride under the action of thionyl chloride or phosphorus trichloride, and then mixed with SM2 in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc. , to obtain II-A in a suitable solvent such as dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethylsulfoxide, and the like.

方法二：
Method Two:

第一步：SM1和SM3经胺酸脱水反应制备M2；Step 1: Dehydration of SM1 and SM3 to prepare M2;

所述胺酸脱水反应为如下方案一至三之一：The amino acid dehydration reaction is one of the following schemes 1 to 3:

方案一：Option One:

SM1和SM3通过胺酸缩合反应得到M2。所述胺酸缩合是在缩合剂,诸如HATU或HBTU等常规缩合剂和碱，诸如三乙胺、二异丙基乙胺、吡啶、碳酸钾、碳酸铯等的存在下，在适当溶剂诸如乙腈、四氢呋喃或N,N-二甲基甲酰胺、二甲基亚砜等中在0～100℃范围内的温度下进行获得M2。SM1 and SM3 were condensed with amino acids to obtain M2. The amine acid condensation is in the presence of a condensing agent, conventional condensing agents 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 or N,N-dimethylformamide, dimethyl sulfoxide, etc. at a temperature in the range of 0 to 100°C to obtain M2.

方案二：Option II:

在一定温度下，向SM1和SM3的吡啶体系缓慢滴加POCl3获得M2，所述的一定温度下是-10℃～30℃，优选0℃左右。At a certain temperature, POCl 3 is slowly added dropwise to the pyridine system of SM1 and SM3 to obtain M2, and the certain temperature is -10°C to 30°C, preferably around 0°C.

方案三：third solution:

将SM1在二氯亚砜或三氯化磷的作用下，制备成酰氯，随后和SM3在碱，诸如三乙胺、二异丙基乙胺、吡啶、碳酸钾、碳酸铯等的存在下，在适当溶剂诸如二氯甲烷、乙酸乙酯、乙腈、四氢呋喃或N,N-二甲基甲酰胺、二甲基亚砜等中获得M2。SM1 is prepared into an acid chloride under the action of thionyl chloride or phosphorus trichloride, followed by SM3 in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc., M2 is obtained in appropriate solvents such as dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethylsulfoxide, and the like.

第二步：M2(其中LG为亲核反应离去基团，诸如卤素或S(O)2Me,Y为酸酯基或氰基)和SM2在碱诸如碳酸钾或碳酸铯的存在下，在适当溶剂诸如乙腈、四氢呋喃或N,N-二甲基甲酰胺、二甲基亚砜等中加热进行亲核取代反应得到相应的II-A，所述反应通常在50℃至110℃范围内的温度下进行。The second step: M2 (wherein LG is a nucleophilic reaction leaving group, such as halogen or S(O) 2 Me, Y is an ester group or cyano) and SM2 in the presence of a base such as potassium carbonate or cesium carbonate, in Appropriate solvents such as acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethyl sulfoxide, etc. are heated for nucleophilic substitution reaction to obtain the corresponding II-A, and the reaction is usually in the range of 50°C to 110°C temperature.

路线2：
Route 2:

II-A’化合物与醇在酸催化下，生成Pinner盐，随后加入NHR1R2制备I-A’化合物。Under acid catalysis, II-A'compound and alcohol generate Pinner salt, and then NHR 1 R 2 is added to prepare I-A'compound.

II-A’化合物中R4、R5、R6、R7、R9、R10、X1、X3、X4、X5、X6、X7、X8的定义同I-A’化合物中相应定义。The definitions of R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , and X 8 in the II-A' compound are the same as I-A ' Compounds are defined accordingly.

在一些实施方式中，式II-A’化合物的制备方法为如下方法一和二之一：In some embodiments, the preparation method of the compound of formula II-A' is one of the following methods one and two:

方法一：
method one:

第一步：SM1(其中LG为亲核反应离去基团，诸如卤素或S(O)2Me,Y为酯基或氰基)和SM2在碱诸如碳酸钾或碳酸铯的存在下，在适当溶剂诸如乙腈、四氢呋喃或N,N-二甲基甲酰胺、二甲基亚砜等中加热进行亲核取代反应得到相应的M1,所述反应通常在50℃至110℃范围内的温度下进行。The first step: SM1 (where LG is a nucleophilic reaction leaving group, such as halogen or S(O) 2 Me, Y is an ester group or cyano) and SM2 in the presence of a base such as potassium carbonate or cesium carbonate, in the appropriate Solvents such as acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethyl sulfoxide, etc. are heated to carry out nucleophilic substitution reaction to obtain the corresponding M1, and the reaction is usually carried out at a temperature ranging from 50 ° C to 110 ° C .

第二步：先将M1先进行水解反应成酸，随后和SM4通过胺酸缩合反应制备II-A’；The second step: first hydrolyze M1 into an acid, and then prepare II-A' through amino acid condensation reaction with SM4;

所述胺酸缩合反应为如下方案一至三之一：The amino acid condensation reaction is one of the following schemes one to three:

方案一：Option One:

M1和SM4通过胺酸缩合反应得到II-A’。所述胺酸缩合是在缩合剂,诸如HATU或HBTU等常规缩合剂和碱,诸如三乙胺、二异丙基乙胺、吡啶、碳酸钾、碳酸铯等的存在下，在适当溶剂诸如乙腈、四氢呋喃或N,N-二甲基甲酰胺、二甲基亚砜等中在0～100℃范 围内的温度下进行。M1 and SM4 obtained II-A' through amine acid condensation reaction. The amine acid condensation is carried out in a suitable solvent such as acetonitrile 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. , tetrahydrofuran or N,N-dimethylformamide, dimethyl sulfoxide, etc. in the range of 0 to 100 ° C at a temperature within the range.

方案二：Option II:

在一定温度下，向M1和SM4的吡啶体系缓慢滴加POCl3获得II-A’，所述的一定温度下是-10℃～30℃，优选0℃左右。At a certain temperature, POCl 3 is slowly added dropwise to the pyridine system of M1 and SM4 to obtain II-A'. The certain temperature is -10°C to 30°C, preferably around 0°C.

方案三：third solution:

先将M1在二氯亚砜或三氯化磷的作用下，制备成酰氯，随后和SM4在碱,诸如三乙胺、二异丙基乙胺、吡啶、碳酸钾、碳酸铯等的存在下，在适当溶剂诸如二氯甲烷、乙酸乙酯、乙腈、四氢呋喃或N,N-二甲基甲酰胺、二甲基亚砜等中获得II-A’。M1 is first prepared into an acid chloride under the action of thionyl chloride or phosphorus trichloride, and then with SM4 in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc. , to obtain II-A' in a suitable solvent such as dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethylsulfoxide, etc.

方法二：
Method Two:

第一步：SM1和SM4通过胺酸缩合反应制备M4；The first step: SM1 and SM4 prepare M4 through amino acid condensation reaction;

所述胺酸脱水反应为如下方案一至三之一：The amino acid dehydration reaction is one of the following schemes 1 to 3:

方案一：Option One:

SM1和SM4通过胺酸缩合反应得到M4。所述胺酸缩合是在缩合剂,诸如HATU或HBTU等常规缩合剂和碱,诸如三乙胺、二异丙基乙胺、吡啶、碳酸钾、碳酸铯等的存在下，在适当溶剂诸如乙腈、四氢呋喃或N,N-二甲基甲酰胺、二甲基亚砜等中在0～100℃范围内的温度下进行。Amino acid condensation reaction between SM1 and SM4 gives M4. The amine acid condensation is carried out in a suitable solvent such as acetonitrile 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. , tetrahydrofuran, or N,N-dimethylformamide, dimethyl sulfoxide, etc. at a temperature within the range of 0 to 100°C.

方案二：Option II:

在一定温度下，向SM1和SM4的吡啶体系中缓慢滴加POCl3获得M4，所述的一定温度下是-10℃～30℃，优选0℃左右。At a certain temperature, POCl 3 is slowly added dropwise to the pyridine system of SM1 and SM4 to obtain M4. The certain temperature is -10°C to 30°C, preferably around 0°C.

方案三：third solution:

先将SM1在二氯亚砜或三氯化磷的作用下，制备成酰氯，随后和SM4在碱,诸如三乙胺、二异丙基乙胺、吡啶、碳酸钾、碳酸铯等的存在下，在适当溶剂诸如二氯甲烷、乙酸乙酯、乙腈、四氢呋喃或N,N-二甲基甲酰胺、二甲基亚砜等中获得M4。First prepare SM1 into an acid chloride under the action of thionyl chloride or phosphorus trichloride, and then with SM4 in the presence of a base such as triethylamine, diisopropylethylamine, pyridine, potassium carbonate, cesium carbonate, etc. , M4 was obtained in a suitable solvent such as dichloromethane, ethyl acetate, acetonitrile, tetrahydrofuran or N,N-dimethylformamide, dimethylsulfoxide, etc.

第二步：M4(其中LG为亲核反应离去基团，诸如卤素或S(O)2Me,Y为酸酯基或氰基)和SM2在碱诸如碳酸钾或碳酸铯的存在下，在适当溶剂诸如乙腈、四氢呋喃或N,N-二甲 基甲酰胺、二甲基亚砜等中加热进行亲核取代反应得到相应的II-A’，所述反应通常在50℃至110℃范围内的温度下进行。The second step: M4 (wherein LG is a nucleophilic reaction leaving group, such as halogen or S(O) 2 Me, Y is an ester group or cyano) and SM2 in the presence of a base such as potassium carbonate or cesium carbonate, in Appropriate solvents such as acetonitrile, tetrahydrofuran or N,N-dimethyl Nucleophilic substitution reaction in methyl formamide, dimethyl sulfoxide, etc. is usually carried out at a temperature ranging from 50°C to 110°C to obtain the corresponding II-A'.

路线3：
Route 3:

其中，R1、R2为H，R3为OH，R4、R5、R6、R7、R9、R10、X2、X3、X4、X5、X6、X7、X8的定义同I-A化合物中相应定义；Among them, R 1 and R 2 are 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 The definition of X and X is the same as the corresponding definition in the IA compound;

II-A化合物在无水溶剂和碱存在下，与羟胺或羟胺的盐反应获得I-A化合物；Compound II-A is reacted with hydroxylamine or a salt of hydroxylamine in the presence of anhydrous solvent and base to obtain compound I-A;

其中，所述无水有机溶剂包括但不限于无水甲醇、无水乙醇、无水丙醇、无水丁醇、无水四氢呋喃、无水乙酸乙酯等一种或者多种混合；Wherein, 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.;

所述碱为有机碱，包括但不限于无水三乙胺、无水N,N-二甲基乙胺、无水1,8-二氮杂二环[5.4.0]十一碳-7-烯、1,5-二氮杂双环[4.3.0]壬-5-烯、三乙烯二胺、甲醇钠、乙醇钾、叔丁醇钾等；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.;

所述羟胺的盐包括但不限于盐酸羟胺、硫酸羟胺、磷酸羟胺等。The salts of hydroxylamine include, but are not limited to, hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine phosphate, and the like.

II-A化合物的制备如上文所述。The preparation of II-A compounds was as described above.

路线4：
Route 4:

其中，R1、R2为H，R3为OH，R4、R5、R6、R7、R9、R10、X1、X3、X4、X5、X6、X7、 X8的定义同I-A’化合物中相应定义；Among them, R 1 and R 2 are H, R 3 is OH, R 4 , R 5 , R 6 , R 7 , R 9 , R 10 , X 1 , X 3 , X 4 , X 5 , X 6 , X 7 , The definition of X is the same as the corresponding definition in the I-A'compound;

II-A’化合物在无水溶剂和碱存在下，与羟胺或羟胺的盐反应获得I-A’化合物；II-A' compound is reacted with hydroxylamine or a salt of hydroxylamine in the presence of anhydrous solvent and base to obtain I-A' compound;

其中，所述无水有机溶剂包括但不限于无水甲醇、无水乙醇、无水丙醇、无水丁醇、无水四氢呋喃、无水乙酸乙酯等一种或者多种混合；Wherein, 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.;

所述碱为无水有机碱，包括但不限于无水三乙胺、无水N,N-二甲基乙胺、无水1,8-二氮杂二环[5.4.0]十一碳-7-烯、1,5-二氮杂双环[4.3.0]壬-5-烯、三乙烯二胺、甲醇钠、乙醇钾、叔丁醇钾等；The base is anhydrous organic base, including but not limited to anhydrous triethylamine, anhydrous N,N-dimethylethylamine, anhydrous 1,8-diazabicyclo[5.4.0]undecane -7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, triethylenediamine, sodium methoxide, potassium ethoxide, potassium tert-butoxide, etc.;

所述羟胺的盐包括但不限盐酸羟胺、硫酸羟胺、磷酸羟胺等。The salts of hydroxylamine include, but are not limited to, hydroxylamine hydrochloride, hydroxylamine sulfate, hydroxylamine phosphate, and the like.

II-A’化合物的制备如上文所述。The preparation of II-A' compounds was as described above.

本发明再一方面提供了一种药物组合物，其包括选自式I化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体和其药学上可接受的盐中的一种或多种，以及任选的药学上可接受的辅料。Another aspect of the present invention provides a pharmaceutical composition, which comprises a compound selected from formula I, its tautomers, mesoforms, racemates, enantiomers, diastereoisomers and one or more of its pharmaceutically acceptable salts, and optional pharmaceutically acceptable auxiliary materials.

药学上可接受的辅料包括适于所期望的特定剂型的任一种及所有溶剂、稀释剂或其他液体赋形剂、分散液或悬浮助剂、表面活性剂、等渗剂、增稠剂或乳化剂、防腐剂、固体粘合剂、润滑剂等。任何常用载体介质的使用均涵盖于本发明范围内，除非该常用载体介质与本发明化合物不兼容，例如产生任何不期望的生物学效应或另外以有害方式与药学上可接受的组合物中的任何其他组分相互作用。一些可用作药学上可接受的载体的材料的实例包括但不限于离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(例如，人类血清白蛋白)、缓冲物质(例如，磷酸盐、甘氨酸、山梨酸或山梨酸钾)、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质(例如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶体二氧化硅、三硅酸镁)、聚乙烯毗咯烷酮、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段聚合物、羊毛脂、糖(例如，乳糖、葡萄糖及蔗糖)、淀粉(例如玉米淀粉及马铃薯淀粉)、纤维素及其衍生物(例如毯甲基纤维素钠、乙基纤维素及醋酸纤维素)黄蓍胶粉、麦芽、明胶、滑石粉、赋形剂(例如可可脂及栓剂蜡)、油(例如花生油、棉籽油、红花油、芝麻油、橄榄油、玉米油及大豆油)、二醇(例如丙二醇或聚乙二醇)、酯(例如油酸乙酯及月桂酸乙酯)、琼脂、缓冲剂(例如氢氧化镁及氢氧化铝)、海藻酸、无热原的水等渗盐水、格氏试剂、乙醇及磷酸盐缓冲溶液,以及其他无毒相容性润滑剂(例如，月桂基硫酸钠及硬脂酸镁)，以及根据制剂者的判断,该组合物中还可以存在着色剂、释放剂、包衣剂、甜味剂、矫味剂及芳香剂、防腐剂及抗氧化剂。Pharmaceutically acceptable adjuvants include any and all solvents, diluents or other liquid excipients, dispersion or suspension aids, surfactants, isotonic agents, thickening agents or Emulsifiers, preservatives, solid binders, lubricants, etc. The use of any commonly used carrier medium is encompassed within the scope of the present invention unless such commonly used carrier medium is incompatible with the compounds of this invention, for example produces any undesired biological effect or otherwise interacts in a deleterious manner with the pharmaceutically acceptable composition. interact with any other components. Some examples of materials that can be used as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (e.g., human serum albumin), buffer substances (e.g., phosphoric acid salt, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal Silicon dioxide, magnesium trisilicate), polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, lanolin, sugars (for example, lactose, glucose and sucrose), starch (such as corn starch and potato starch), cellulose and its derivatives (such as sodium methylcellulose, ethyl cellulose and cellulose acetate), tragacanth gum powder, malt, gelatin, talc, excipients (such as cocoa butter and suppository waxes), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil), glycols (such as propylene glycol or polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free aqueous isotonic saline, Grignard reagent, ethanol and phosphate buffered saline, and other nontoxic phases Capacitive lubricants (for example, sodium lauryl sulfate and magnesium stearate), and according to the judgment of the formulator, coloring agents, release agents, coating agents, sweeteners, flavoring agents and Fragrances, preservatives and antioxidants.

本发明再一方面提供了式I化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其药学上可接受的盐或上述药物组合物在制备Nav1.8抑制剂中的用途。Another aspect of the present invention provides the compound of formula I, its tautomer, mesomer, racemate, enantiomer, diastereoisomer or pharmaceutically acceptable salt thereof or the above-mentioned Use of the pharmaceutical composition in the preparation of Nav1.8 inhibitors.

本发明又一方面提供了一种抑制个体的Nav1.8的方法，包括向个体给予选自式I化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体和其药学上可接受的盐 中的一种或多种或上述药物组合物。Another aspect of the present invention provides a method for inhibiting Nav1.8 in an individual, comprising administering to the individual a compound selected from formula I, its tautomer, meso, racemate, and enantiomer , diastereoisomers and pharmaceutically acceptable salts thereof One or more of or the above-mentioned pharmaceutical composition.

本发明再一方面提供了式I化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体或其药学上可接受的盐或上述药物组合物在制备用于治疗和/或减轻疼痛疾病和疼痛相关疾病的药物中的应用。Another aspect of the present invention provides the compound of formula I, its tautomer, mesomer, racemate, enantiomer, diastereoisomer or pharmaceutically acceptable salt thereof or the above-mentioned Application of the pharmaceutical composition in the preparation of medicines for treating and/or alleviating pain diseases and pain-related diseases.

本发明又一方面提供了一种治疗或减轻疼痛疾病和疼痛相关疾病或症状的方法，所述方法包括向有此需要的对象给予选自式I化合物、其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体和其药学上可接受的盐中的一种或多种，或者上述药物组合物。Another aspect of the present invention provides a method for treating or alleviating pain diseases and pain-related diseases or symptoms, the method comprising administering a compound selected from formula I, its tautomer, meso One or more of body, racemate, enantiomer, diastereomer and pharmaceutically acceptable salt thereof, or the above pharmaceutical composition.

所述疼痛疾病包括但不限于伤害性疼痛、炎性疼痛(包括但不限于类风湿性关节炎疼痛或外阴痛)、神经性疼痛(包括但不限于疱疹后神经疼，特发性小纤维神经疼)、肌肉骨骼疼(包括但不限于骨关节炎疼、背痛、冷痛、烧伤疼痛或牙痛)、术后疼痛(包括但不限于拇囊炎切除术后疼痛、腹壁成形术疼痛等)和内状疼痛、功能性疼痛、肌肉或骨骼损伤相关疼痛、盆腔痛、腹腔痛、胸腔痛、腰骶神经痛、术前疼痛、术间疼痛、术后疼痛、肠痛(包括但不限于炎性肠病疼痛、克罗恩病疼痛或间质性膀胱炎)、急性或慢性疼痛、偏头痛、三叉神经痛、胰腺炎、肾绞痛、癌症痛、化学或药物疗法导致的疼痛、糖尿病神经痛、带状疱疹后神经痛、背部疼痛、幻肢痛、坐骨神经痛、小纤维神经痛、红斑性肢痛症等。The pain disorders include but 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 pain), musculoskeletal pain (including but not limited to osteoarthritis pain, back pain, cold pain, burn pain or tooth pain), post-operative pain (including but not limited to post-bunionectomy pain, abdominoplasty pain, etc.) and internal pain, functional pain, pain associated with musculoskeletal injury, pelvic pain, abdominal pain, chest pain, lumbosacral neuralgia, preoperative pain, intraoperative pain, postoperative pain, bowel 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 from chemotherapy or drug therapy, diabetic neuropathy pain, postherpetic neuralgia, back pain, phantom limb pain, sciatica, small fiber neuralgia, erythromelalgia, etc.

所述疼痛相关疾病包括关节炎、瘙痒症、急性或慢性瘙痒、哮喘、多发性硬化症、心律失常、房颤、心衰、Brugada综合症、肾结石、癫痫、惊厥、夏-马-图三氏综合症、失禁等。The pain-related diseases include arthritis, pruritus, acute or chronic pruritus, asthma, multiple sclerosis, cardiac arrhythmia, atrial fibrillation, heart failure, Brugada syndrome, kidney stones, epilepsy, convulsions, Xia-Ma-Figure III Syndrome, incontinence, etc.

有益效果Beneficial effect

本发明提供了一种有别于目前已有结构Nav1.8选择性抑制剂的脒类衍生化合物，具有很好的Nav1.8选择性抑制活性，很好药代性质，具有较好的成药性，作为Nav1.8抑制剂可用于治疗或减轻与疼痛或疼痛相关的疾病，具有重要的临床应用价值。The present invention provides an amidine derivative compound which is different from the currently existing Nav1.8 selective inhibitors, has good Nav1.8 selective inhibitory activity, good pharmacokinetic properties, and good druggability , as a Nav1.8 inhibitor can be used to treat or alleviate pain or pain-related diseases, and has important clinical application value.

在上文中已经详细地描述了本发明，但是上述实施方式本质上仅是例示性，且并不欲限制本发明。此外，本文并不受前述现有技术或发明内容或以下实施例中所描述的任何理论的限制。The present invention has been described in detail above, but the above-described embodiments are merely illustrative in nature and are not intended to limit the present invention. Furthermore, this document is not to be bound by any theory presented in the preceding prior art or brief summary or the following examples.

具体实施方式Detailed ways

下面结合实施例对本发明作进一步的说明，需要说明的是，提供以下实施例仅出于说明目的并不构成对本发明要求保护范围的限制。The present invention will be further described below in conjunction with the examples. It should be noted that the following examples are provided only for the purpose of illustration and do not constitute a limitation to the protection scope of the present invention.

除特殊说明外，在实施例中所采用的原料、试剂、方法等均为本领域常规的原料、试剂、方法。Unless otherwise specified, the raw materials, reagents, and methods used in the examples are conventional raw materials, reagents, and methods in the art.

实验材料和分析仪器：Experimental materials and analytical instruments:

薄层分析(TLC)板型号为HSGF-254(厚度0.15-0.2mm，烟台化工实验厂生产)；柱层析硅胶为青岛海洋化工厂生产200-300目商业化硅胶；1H-NMR，13C-NMR使用Bruker  AM-300、Varian Mercury-500核磁共振仪记录，内标为四甲基硅烷(TMS)；化学位移为(ppm，δ:)，质子耦合标记为单峰(s)，双重峰(d)，三重峰(t)，四重峰(q)，多重峰(m)，宽峰(br)；低分辨质谱使用Finning/MAT-95仪器或者Agilent 6110质谱仪记录。Thin layer analysis (TLC) plate model is HSGF-254 (thickness 0.15-0.2mm, produced by Yantai Chemical Experimental Factory); column chromatography silica gel is 200-300 mesh commercial silica gel produced by Qingdao Ocean Chemical Factory; 1 H-NMR, 13 C-NMR using Bruker AM-300, Varian Mercury-500 nuclear magnetic resonance instrument records, internal standard is tetramethylsilane (TMS); chemical shift is (ppm, δ:), proton coupling is marked as singlet (s), doublet (d), Triplet (t), quartet (q), multiplet (m), broad peak (br); low-resolution mass spectra were recorded using Finning/MAT-95 instruments or Agilent 6110 mass spectrometers.

缩写与注释：Abbreviations and notes:

HEPES：4-(2-羟乙基)哌嗪-1-乙磺酸或N-(2-羟乙基)哌嗪-N′-(2-乙磺酸)；HEPES: 4-(2-hydroxyethyl)piperazine-1-ethanesulfonic acid or N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid);

EGTA：乙二醇双(2-氨基乙基醚)四乙酸；EGTA: Ethylene glycol bis(2-aminoethyl ether) tetraacetic acid;

所有药品均购自Sigma公司。All drugs were purchased from Sigma.

氯化氢-乙酸乙酯体系，氯化氢-二氧六环体系，盐酸-乙酸乙酯体系，盐酸-二氧六环体系均指不含水的氯化氢有机溶液。The hydrogen chloride-ethyl acetate system, the hydrogen chloride-dioxane system, the hydrochloric acid-ethyl acetate system, and the hydrochloric acid-dioxane system all refer to the hydrogen chloride organic solution without water.

实施例1 2-(4-氟-2-甲基苯氧基)-N-(3-(N-羟基氨基甲酰氨基)苯基)-4-(三氟甲基)苯甲酰胺(I-1)的制备
Example 1 2-(4-fluoro-2-methylphenoxy)-N-(3-(N-hydroxycarbamido)phenyl)-4-(trifluoromethyl)benzamide (I -1) Preparation

第一步：2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯腈(1-a)的合成The first step: the synthesis of 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzonitrile (1-a)

先将4-三氟甲基-2-氟苯甲腈(1-SM1)(10.0g,52.9mmol)，4-氟-2甲基苯酚(1-SM2)(6.7g,53.0mmol)，碳酸铯(34.5g,105.8mmol)，加入到无水N,N-二甲基甲酰胺(200mL)中,随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝20：1(v/v)过硅胶柱(200～300目)得到2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯腈(1-a)(10.3g,收率66％)。1H-NMR(400MHz,DMSO-d6)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。First 4-trifluoromethyl-2-fluorobenzonitrile (1-SM1) (10.0g, 52.9mmol), 4-fluoro-2 methylphenol (1-SM2) (6.7g, 53.0mmol), carbonic acid Cesium (34.5g, 105.8mmol) was added into anhydrous N,N-dimethylformamide (200mL), and then heated to 100°C to react until the reaction of the raw materials was complete. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Petroleum ether: ethyl acetate = 20:1 (v/v) for the crude product to pass through a silica gel column (200-300 mesh) 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, 3.2 Hz, 1H), 6.93 (s, 1H), 2.16 (s, 3H); ESI [M+Na] + = 317.7.

第二步：2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酸(1-b)的合成 The second step: the synthesis of 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoic acid (1-b)

将2-(4-氟-2-甲基苯氧基)4-(三氟甲基)苯腈(1-a)(6.0g,20.3mmol)，氢氧化钠(10N,20.3mL,203.2mmol)加入到95％乙醇中回流直到原料完全消失，浓缩除去乙醇，加入水，用2N盐酸调pH值至2～3左右，析出大量固体，静置，过滤得到5.3g 2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酸(1-b)固体。1H-NMR(400MHz,DMSO-d6)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。2-(4-fluoro-2-methylphenoxy) 4-(trifluoromethyl)benzonitrile (1-a) (6.0g, 20.3mmol), sodium hydroxide (10N, 20.3mL, 203.2mmol ) was added to 95% ethanol and refluxed until the raw materials disappeared completely, concentrated to remove ethanol, added water, adjusted the pH value to about 2 to 3 with 2N hydrochloric acid, a large amount of solids were precipitated, stood still, and filtered to obtain 5.3g 2-(4-fluoro- 2-Methylphenoxy)-4-(trifluoromethyl)benzoic acid (1-b) as a solid. 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.

第三步：N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-1)的合成The third step: N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-1) synthesis

干燥体系下，将2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酸(1-b)(1.0g,3.2mmol)，间氨基苯甲氰(0.4g，3.34mmol)加入到无水吡啶(10mL)中溶解，冷却到0℃左右，缓慢滴加三氯氧磷(0.6mL，6.4mmol)，控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全。随后将反应体系倒入到冰水中，用2N稀盐酸调pH值至2～3左右，再用二氯甲烷萃取。有机相干燥，浓缩，得到N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-1)(1.1g,收率83.0％)。1H-NMR(400MHz,CDCl3)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。In a dry system, 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoic acid (1-b) (1.0g, 3.2mmol), m-aminobenzylcyanide ( Add 0.4g, 3.34mmol) into anhydrous pyridine (10mL) to dissolve, cool to about 0°C, slowly add phosphorus oxychloride (0.6mL, 6.4mmol) dropwise, control the temperature below 10°C, after the dropwise addition is completed, continue React until the raw material is completely reacted. Subsequently, the reaction system was poured into ice water, 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 give 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.

第四步：2-(4-氟-2-甲基苯氧基)-N-(3-(N-羟基氨基甲酰氨基)苯基)-4-(三氟甲基)苯甲酰胺(I-1)的合成The fourth step: 2-(4-fluoro-2-methylphenoxy)-N-(3-(N-hydroxycarbamido) phenyl)-4-(trifluoromethyl)benzamide ( I-1) Synthesis

将N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-1)(200.0mg,0.482mmol)，三乙胺(0.4mL,2.90mmol)和盐酸羟胺(67.0mg,0.965mmol)加入到95％乙醇中,回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用石油醚：乙酸乙酯(v/v)＝2：1过柱(200～300目)得到目标化合物(I-1)(180.0mg,收率83.5％)。1H-NMR(400MHz,DMSO-d6)δ:10.59(s,1H),9.66(s,1H),8.04(s,1H),7.85(d,J＝7.6Hz,1H),7.68(d,J＝7.6Hz,1H),7.60(d,J＝7.6Hz,1H),7.33～7.39(m,2H),7.22(d,J＝7.6Hz,1H),7.12(d,J＝6.0Hz,2H),6.95(s,1H),2.18(s,3H)；MS(ESI)m/z[M+H]+＝447.7。N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-1) (200.0mg, 0.482mmol), triethylamine (0.4mL, 2.90mmol) and hydroxylamine hydrochloride (67.0mg, 0.965mmol) were added to 95% ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain a crude product, which was then passed through a column (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=7.6Hz, 1H), 7.68(d ,J=7.6Hz,1H),7.60(d,J=7.6Hz,1H),7.33～7.39(m,2H),7.22(d,J=7.6Hz,1H),7.12(d,J=6.0Hz , 2H), 6.95 (s, 1H), 2.18 (s, 3H); MS (ESI) m/z [M+H] + = 447.7.

实施例2 2-(4-氟-2-甲基苯氧基)-N-(3-(N-甲氧基氨基甲酰)苯基)-4-(三氟甲基)苯甲酰胺(I-2)的制备Example 2 2-(4-fluoro-2-methylphenoxy)-N-(3-(N-methoxycarbamoyl)phenyl)-4-(trifluoromethyl)benzamide ( I-2) Preparation

将实施例1得到的N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-1)(200.0mg,0.48mmol)，三乙胺(0.2mL,1.44mmol)和甲氧基胺盐酸盐(40.3mg,0.48mmol)加入到95％乙醇中，回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用石油醚：乙酸乙酯＝10：1(v/v)过硅胶柱(200～300目)得到目标化合物(I-2)(170.0mg,收率84.6％)。1H-NMR(400MHz,DMSO-d6)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＝9.2Hz,1H),7.11(d,J＝ 6.8Hz,2H),7.00(s,1H),3.35(s,3H),2.16(s,3H)；MS(ESI)m/z[M+H]+＝462.7。N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-1) obtained in Example 1 ) (200.0mg, 0.48mmol), triethylamine (0.2mL, 1.44mmol) and methoxyamine hydrochloride (40.3mg, 0.48mmol) were added to 95% ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain a 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) (170.0mg, yield 84.6% ). 1 H-NMR (400MHz, 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=9.2Hz,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.

实施例3 N-(3-氨基甲酰亚胺酰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-3)的制备Example 3 N-(3-carbamoimidoylphenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-3) preparation of

将实施例1得到的N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-1)(3.1g,7.5mmol)，无水乙醇(4.0mL,58.0mmol)和氯化氢-乙酸乙酯体系(10N,50.0mL)加入到封管反应瓶中，于室温下反应直到原料完全转化为中间体Pinner盐，随后浓缩除去溶剂得粗品中间体Pinner盐(II-Aa)，用二氯甲烷：甲醇＝20:1～15:1(v/v)过硅胶柱(200～300目)得到1.8g 3-(2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺基)苯甲亚胺酸乙酯盐酸盐(II-Aa)固体，MS(ESI)m/z[M+H]+＝461.1。N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-1) obtained in Example 1 ) (3.1g, 7.5mmol), absolute ethanol (4.0mL, 58.0mmol) and hydrogen chloride-ethyl acetate system (10N, 50.0mL) were added to a sealed tube reaction flask, and reacted at room temperature until the raw material was completely converted into intermediate Pinner salt, then concentrated to remove the solvent to obtain the crude intermediate Pinner salt (II-Aa), using dichloromethane: methanol = 20:1 ~ 15:1 (v/v) through a silica gel column (200 ~ 300 mesh) to obtain 1.8 g ethyl 3-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)benzimidate hydrochloride (II-Aa) solid, MS (ESI) m/z [M+H] + = 461.1.

将中间体II-Aa溶于无水甲醇，加入氨甲醇体系(7N,4.2mL)和氯化铵(619.0mg,11.58mmol)于回流下反应完全，随后浓缩得到I-3粗品，随后用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得到目标化合物(I-3)(1.3g,收率54.3％)。1H-NMR(400MHz,DMSO-d6)δ:10.98(s,H),8.25(s,1H),7.90(d,J＝7.8Hz,1H),7.85(d,J＝7.8Hz,1H),7.60(t,J＝8.4,7.8Hz,2H),7.50(d,J＝7.8Hz,1H),7.23～7.25(dd,J＝9.0,2.4Hz,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。Dissolve the intermediate II-Aa in anhydrous methanol, add ammonia methanol system (7N, 4.2mL) and ammonium chloride (619.0mg, 11.58mmol) to complete the reaction under reflux, then concentrate to obtain the crude product I-3, and then use di Chloromethane:methanol=20~15:1 (v/v) was passed through a silica gel column (200~300 mesh) to obtain the target compound (I-3) (1.3g, yield 54.3%). 1 H-NMR (400MHz,DMSO-d 6 )δ:10.98(s,H),8.25(s,1H),7.90(d,J=7.8Hz,1H),7.85(d,J=7.8Hz,1H ), 7.60(t, J＝8.4, 7.8Hz, 2H), 7.50(d, J＝7.8Hz, 1H), 7.23～7.25(dd, J＝9.0, 2.4Hz, 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.

实施例4 2-(4-氟-2-甲基苯氧基)-N-(2-(N-羟基氨基甲酰氨基)吡啶-4-基)-4-(三氟甲基)苯甲酰胺(I-4)的制备Example 4 2-(4-fluoro-2-methylphenoxy)-N-(2-(N-hydroxycarbamoylamino)pyridin-4-yl)-4-(trifluoromethyl)benzyl Preparation of Amide (I-4)

干燥体系下，将实施例1得到的1-b(1.26g,4.0mmol)，4-氨基-2-氰基吡啶(480.0mg，4.0mmol)加入到无水吡啶(10.0mL)中溶解，冷却到0℃左右，缓慢滴加三氯氧磷(1.9mL,20.0mmol)，控制温度在5℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N稀盐酸调pH值至2～3左右，再用二氯甲烷萃取。有机相干燥，浓缩，得到1.1g白色的N-(2-氰基吡啶-4-基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-33)固体,MS(ESI)m/z[M+H]+＝415.7。Under the dry system, 1-b (1.26g, 4.0mmol) obtained in Example 1, 4-amino-2-cyanopyridine (480.0mg, 4.0mmol) was added to anhydrous pyridine (10.0mL) to dissolve, cooled At about 0°C, slowly add phosphorus oxychloride (1.9mL, 20.0mmol) dropwise, control the temperature below 5°C, and continue the reaction until the raw materials are completely reacted, then pour the reaction system into ice water, and use 2N Dilute hydrochloric acid to adjust the pH value to about 2-3, and then extract with dichloromethane. The organic phase was dried and concentrated to give 1.1 g of white N-(2-cyanopyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzene Formamide (II-A-33) solid, MS (ESI) m/z [M+H] + = 415.7.

将II-A-33(150.0mg,0.36mmol)，三乙胺(0.3mL,2.2mmol)和盐酸羟胺(50.0mg,0.72mmol)加入到95％乙醇中，回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得到目标化合物(I-4)(120.0mg,收率74％)。1H-NMR(400MHz,DMSO-d6)δ:10.98(s,1H),9.93(s,1H),8.45(d,J＝5.2Hz,1H),8.24(s,1H),7.87(d,J＝8.0Hz,1H),7.60～7.64(m,2H),7.19(d,J＝9.2Hz 1H),7.10(s,1H),7.09(d,J＝5.2Hz,1H),6.98(s,1H),2.14(s,3H)；Add II-A-33 (150.0mg, 0.36mmol), triethylamine (0.3mL, 2.2mmol) and hydroxylamine hydrochloride (50.0mg, 0.72mmol) into 95% ethanol, and react under reflux until the reaction of the raw materials is complete. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain a crude product, which was then passed through a silica gel column (200-300 mesh) with dichloromethane:methanol=20-15:1 (v/v) to obtain the target compound (I-4) (120.0 mg, yield 74 %). 1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.98(s, 1H), 9.93(s, 1H), 8.45(d, J=5.2Hz, 1H), 8.24(s, 1H), 7.87(d , J＝8.0Hz, 1H), 7.60～7.64(m, 2H), 7.19(d, J＝9.2Hz 1H), 7.10(s, 1H), 7.09(d, J＝5.2Hz, 1H), 6.98( s,1H),2.14(s,3H);

MS(ESI)m/z[M+H]+＝448.7。MS (ESI) m/z [M+H] + = 448.7.

实施例5 2-(4-氟-2-甲基苯氧基)-N-(3-(N-甲基氨基甲酰)苯基)-4-(三氟甲基)苯甲酰胺(I-5)的制备Example 5 2-(4-fluoro-2-methylphenoxy)-N-(3-(N-methylcarbamoyl)phenyl)-4-(trifluoromethyl)benzamide (I -5) Preparation

将实施例1得到的II-A-1(100.0mg,0.24mmol)，无水乙醇(0.14mL,2.4mmol)和氯化氢 -乙酸乙酯体系(10N,5.0mL)加入到封管反应瓶中，于室温下反应直到原料完全转化为中间体，随后浓缩除去溶剂得到粗品中间体Pinner盐(II-Aa)。The II-A-1 (100.0mg, 0.24mmol) obtained in Example 1, absolute ethanol (0.14mL, 2.4mmol) and hydrogen chloride - Ethyl acetate system (10N, 5.0 mL) was added to a sealed reaction flask, reacted at room temperature until the raw material was completely converted into an intermediate, and then concentrated to remove the solvent to obtain the crude intermediate Pinner salt (II-Aa).

粗品中间体溶于无水甲醇，加入甲胺盐酸(27.2mg,0.4mmol)和三乙胺(0.17mL,1.2mmol)于回流下反应，待反应完全后浓缩得到I-5粗品，随后用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得到目标化合物(I-5)(30.0mg,收率28.1％)。1H-NMR(400MHz,DMSO-d6)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。The crude intermediate was dissolved in anhydrous methanol, methylamine hydrochloric acid (27.2mg, 0.4mmol) and triethylamine (0.17mL, 1.2mmol) were added to react under reflux, and after the reaction was complete, it was concentrated to obtain the crude product I-5, which was then treated with two Chloromethane:methanol=20-15:1 (v/v) was passed through a silica gel column (200-300 mesh) 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.

实施例6 N-(3-(N-环丙基氨基甲酰)苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-6)的制备Example 6 N-(3-(N-cyclopropylcarbamoyl) phenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide ( I-6) Preparation

将实施例1得到的II-A-1(100.0mg,0.24mmol)，无水乙醇(0.14mL,2.4mmol)和氯化氢-乙酸乙酯体系(10N,5.0mL)加入到封管反应瓶中，于室温下反应直到原料完全转化为中间体，随后浓缩除去溶剂得粗品中间体Pinner盐(II-Aa)。Add II-A-1 (100.0mg, 0.24mmol) obtained in Example 1, absolute ethanol (0.14mL, 2.4mmol) and hydrogen chloride-ethyl acetate system (10N, 5.0mL) into the sealed tube reaction flask, React at room temperature until the starting material is completely converted into the intermediate, then concentrate to remove the solvent to obtain the crude intermediate Pinner's salt (II-Aa).

粗品中间体溶于无水甲醇(20.0mL)，加入环丙胺(27.2mg,0.4mmol)和三乙胺(0.17mL,1.2mmol)于回流下反应，待反应完全后浓缩得到I-6粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得到目标化合物(I-6)固体(40.0mg,收率36.4％)。1H-NMR(400MHz,DMSO-d6)δ:11.04(s,1H),9.72(s,1H),9.27(s,1H),8.21(s,1H),7.89(d,J＝8.8Hz,1H),7.83(d,J＝8.0Hz,1H),7.55～7.61(m,2H),7.43(d,J＝8.0Hz,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。The crude intermediate was dissolved in anhydrous methanol (20.0 mL), and cyclopropylamine (27.2 mg, 0.4 mmol) and triethylamine (0.17 mL, 1.2 mmol) were added to react under reflux. After the reaction was complete, it was concentrated to obtain the crude product 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 target compound (I-6) as a solid (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＝8.8Hz ,1H),7.83(d,J＝8.0Hz,1H),7.55～7.61(m,2H),7.43(d,J＝8.0Hz,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.

实施例7 N-(3-(N,N-二甲基氨基甲酰)苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-7)的制备Example 7 N-(3-(N,N-dimethylcarbamoyl)phenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzene Preparation of Amide (I-7)

将实施例1得到的II-A-1(100.0mg,0.24mmol)，无水乙醇(0.14mL,2.4mmol)和氯化氢-乙酸乙酯体系(10N,5.0mL)加入到封管反应瓶中，于室温下反应直到原料完全转化为中间体，随后浓缩除去溶剂得粗品中间体Pinner盐(II-Aa)。Add II-A-1 (100.0mg, 0.24mmol) obtained in Example 1, absolute ethanol (0.14mL, 2.4mmol) and hydrogen chloride-ethyl acetate system (10N, 5.0mL) into the sealed tube reaction flask, React at room temperature until the starting material is completely converted into the intermediate, then concentrate to remove the solvent to obtain the crude intermediate Pinner's salt (II-Aa).

粗品中间体溶于无水甲醇(20.0mL)，加入N,N-二甲基盐酸(27.2mg,0.4mmol)和三乙胺(0.17mL,1.2mmol)于回流下反应，待反应完全后浓缩得到I-7粗品。粗品用二氯甲烷：甲醇＝20：1(v/v)过硅胶柱(200～300目)得到目标化合物(I-7)(45.0mg,收率40.8％)。1H-NMR(400MHz,DMSO-d6)δ:11.9(brs,1H),9.37(s,1H),9.16(s,1H),8.07(s,1H),7.84(d,J＝7.8Hz,1H),7.80～7.80(m,1H),7.59(q,2H),7.31(d,J＝7.8Hz,1H),7.21～7.23(dd,J＝9.0,3.0Hz,1H),7.14～7.18(m,1H),7.09～7.12(td,J＝7.8,3.0Hz,1H),6.94(d,J＝4.2Hz,1H),3.23(s,3H),2.98(s,3H),2.16(s,3H)；MS(ESI)m/z[M+H]+＝460.2。Dissolve the crude intermediate in anhydrous methanol (20.0mL), add N,N-dimethyl hydrochloric acid (27.2mg, 0.4mmol) and triethylamine (0.17mL, 1.2mmol) to react under reflux, and concentrate after the reaction is complete Crude I-7 was obtained. The crude product was passed through a 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 H-NMR (400MHz,DMSO-d 6 )δ:11.9(brs,1H),9.37(s,1H),9.16(s,1H),8.07(s,1H),7.84(d,J＝7.8Hz ,1H),7.80～7.80(m,1H),7.59(q,2H),7.31(d,J＝7.8Hz,1H),7.21～7.23(dd,J＝9.0,3.0Hz,1H),7.14～ 7.18(m,1H),7.09～7.12(td,J=7.8,3.0Hz,1H),6.94(d,J=4.2Hz,1H),3.23(s,3H),2.98(s,3H),2.16 (s,3H); MS (ESI) m/z [M+H] + = 460.2.

实施例8 N-(3-氨基甲酰苯基)-2-(4-氟-2-甲基苯氧基)-6-甲基烟酰胺(I-8)的制备
Example 8 Preparation of N-(3-carbamoylphenyl)-2-(4-fluoro-2-methylphenoxy)-6-methylnicotinamide (I-8)

第一步：将4-氯-6-甲基烟酸甲酯(8-SM1)(1.2g，6.5mmol)，4-氟-2-甲基苯酚(897.0mg,7.11mmol)，碳酸铯(4.2g,12.9mmol)，碘化亚铜(12.3mg,0.065mmol)加入到甲苯(10.0mL)中，100℃回流反应。反应完全后，用2N稀盐酸调节pH至2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得到粗品，粗品用石油醚：乙酸乙酯＝40：1(v/v)过柱得2-(4-氟-2-甲基苯氧基)-6-甲基烟酸甲酯(8-a)(1.38g,收率77.25％)。1H-NMR(400MHz,DMSO-d6)δ:8.18(dd,J＝7.6,2.4Hz,1H),7.17(dd,J＝9.5,2.4Hz,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。The first step: methyl 4-chloro-6-methylnicotinate (8-SM1) (1.2g, 6.5mmol), 4-fluoro-2-methylphenol (897.0mg, 7.11mmol), cesium carbonate ( 4.2g, 12.9mmol), cuprous iodide (12.3mg, 0.065mmol) was added to toluene (10.0mL), and the reaction was refluxed at 100°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, which is passed through the column with petroleum ether:ethyl acetate=40:1 (v/v) 2-(4-Fluoro-2-methylphenoxy)-6-methylnicotinic acid methyl ester (8-a) (1.38 g, yield 77.25%) was obtained. 1 H-NMR (400MHz, DMSO-d 6 )δ: 8.18(dd, J=7.6, 2.4Hz, 1H), 7.17(dd, J=9.5, 2.4Hz, 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.

第二步：将2-(4-氟-2-甲基苯氧基)-6-甲基烟酸甲酯(8-a)(1.38g,5.0mmol)溶于氢氧化钠溶液(10N,5.0mL)中，加入甲醇(8.0mL)，回流反应直到原料反应完全。浓缩除去甲醇，加入水，用2N稀盐酸调pH2～3左右，析出大量白色固体，静置，过滤得到2-(4-氟-2-甲基苯氧基)-6-甲基烟酸(8-b)(1.2g，收率91.5％)。1H-NMR(400MHz,DMSO-d6)δ:13.02(s,1H),8.13(d,J＝7.8Hz,1H),7.14(dd,J＝9.2,2.4Hz,1H),7.06～6.98(m,3H),2.25(s,3H),2.04(s,3H)；MS(ESI)m/z[M+H]+＝262.0。The second step: Dissolve 2-(4-fluoro-2-methylphenoxy)-6-methylnicotinic acid methyl ester (8-a) (1.38g, 5.0mmol) in sodium hydroxide solution (10N, 5.0 mL), methanol (8.0 mL) was added, and the reaction was refluxed until the reaction of the raw materials was complete. Concentrate to remove methanol, add water, adjust the pH to about 2-3 with 2N dilute hydrochloric acid, a large amount of white solid precipitates, let it stand, and filter to obtain 2-(4-fluoro-2-methylphenoxy)-6-methylnicotinic acid ( 8-b) (1.2 g, yield 91.5%). 1 H-NMR (400MHz, DMSO-d 6 ) δ: 13.02(s, 1H), 8.13(d, J=7.8Hz, 1H), 7.14(dd, J=9.2, 2.4Hz, 1H), 7.06～6.98 (m,3H), 2.25(s,3H), 2.04(s,3H); MS (ESI) m/z [M+H] + = 262.0.

第三步：将2-(4-氟-2-甲基苯氧基)-6-甲基烟酸(8-b)(1.2g,4.57mmol)，间氨基苯甲腈(567.0mg,4.8mmol)溶于吡啶(12.0mL)中，在0℃下缓慢滴加三氯氧磷(0.9mL,9.2mol),控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N稀盐酸调pH至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用乙酸乙酯重结晶得N-(3-苯腈)-2-(4-氟-2-甲基苯氧基)-6-甲基烟酰胺(II-A-2)(689.0mg，收率42％)。1H-NMR(400MHz,DMSO-d6)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。The third step: 2-(4-fluoro-2-methylphenoxy)-6-methylnicotinic acid (8-b) (1.2g, 4.57mmol), m-aminobenzonitrile (567.0mg, 4.8 mmol) was dissolved in pyridine (12.0mL), and phosphorus oxychloride (0.9mL, 9.2mol) was slowly added dropwise at 0°C, and the temperature was controlled below 10°C. 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 a crude product. The crude product was 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.

第四步：将N-(3-苯腈)-2-(4-氟-2-甲基苯氧基)-6-甲基烟酰胺(II-A-2)(200.0mg,0.553 mmol)，无水乙醇(2.0mL)和盐酸-乙酸乙酯(10N,6.0mL)加入到封管中，室温下封管反应。待反应完全后将反应体系蒸干，加入无水甲醇(3.0mL),氨-甲醇溶液(7N,5.0mL)，2eq氯化铵，于65℃下回流反应。反应完全后直接蒸干，拌样，用二氯甲烷：甲醇＝30：1(v/v)过硅胶柱(200～300目)得目标化合物(I-8)(92.0mg,收率43.9％)。1H-NMR(400MHz,DMSO-d6)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。The fourth step: N-(3-benzonitrile)-2-(4-fluoro-2-methylphenoxy)-6-methylnicotinamide (II-A-2) (200.0mg, 0.553 mmol), absolute ethanol (2.0 mL) and hydrochloric acid-ethyl acetate (10N, 6.0 mL) were added to the sealed tube, and the tube was locked to react at room temperature. After the reaction was complete, the reaction system was evaporated to dryness, anhydrous methanol (3.0 mL), ammonia-methanol solution (7N, 5.0 mL), 2 eq ammonium chloride were added, and the reaction was refluxed at 65°C. After the reaction was complete, evaporate to dryness directly, mix the sample, and pass through a silica gel column (200-300 mesh) with dichloromethane:methanol=30:1 (v/v) to obtain the target compound (I-8) (92.0mg, 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.

实施例9 N-(3-氨基甲酰氨基)-2-(4-(三氟甲氧基)苯氧基)-4-(三氟甲基)苯甲酰胺(I-9)的制备
Example 9 Preparation of N-(3-carbamoylamino)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (I-9)

第一步：将2-氟-4-三氟甲基苯甲酸(9-SM1)(2.08g,10.0mmol),间氨基苯甲腈(1.2g,10.0mmol)溶于吡啶(16.0mL)中，在0℃下缓慢滴加三氯氧磷(1.9mL，20.0mmol),控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N盐酸调节pH至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，蒸干得粗品。粗品用石油醚：乙酸乙酯＝4：1(v/v)过硅胶柱(200～300目)得N-(3-氰基苯基)-2-氟-4-(三氟甲基)苯甲酰胺(9-a)(1.5g，收率48.7％)。1H-NMR(400MHz,CDCl3)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。The first step: Dissolve 2-fluoro-4-trifluoromethylbenzoic acid (9-SM1) (2.08g, 10.0mmol), m-aminobenzonitrile (1.2g, 10.0mmol) in pyridine (16.0mL) , slowly add phosphorus oxychloride (1.9mL, 20.0mmol) dropwise at 0°C, and control the temperature below 10°C. Adjust the pH to about 2-3 with hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and evaporate to dryness to obtain a crude product. Use petroleum ether for the crude product: ethyl acetate = 4:1 (v/v) to pass through a silica gel column (200-300 mesh) 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=5.2 Hz,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.

第二步：将(9-a)(308.0mg，1.0mmol),4-三氟甲氧基苯酚(195.0mg,1.1mmol)和碳酸铯(651.0mg,2.0mmol)加入到N,N-二甲基甲酰胺(7.0mL)中，在100℃下反应。反应完全后，用2N稀盐酸调节pH值至2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：二氯甲烷＝1：1(v/v)过硅胶柱(200～300目)得N-(3-氰基苯基)-2-(4-(三氟甲氧基)苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-3)(346.0mg，收率74.2％)。1H-NMR(400MHz,CDCl3)δ:8.01(s,1H),7.59(d,J＝8.0Hz,1H),7.51(t,1H),7.46(s,1H),7.43(d,J＝8.0Hz,1H),7.24(d,J＝5.6Hz,2H),7.17(d,J＝6.8Hz,2H),7.00(d,J＝8.4Hz,1H),6.79(d,J＝8.4Hz,1H)； MS(ESI)m/z[M+H]+＝467.1。The second step: (9-a) (308.0mg, 1.0mmol), 4-trifluoromethoxyphenol (195.0mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were added to N,N-di Methylformamide (7.0 mL) was reacted 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 a crude product. Petroleum ether for the crude product: dichloromethane = 1:1 (v/v) through a silica gel column (200-300 mesh) 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=8.0Hz, 1H), 7.51(t, 1H), 7.46(s, 1H), 7.43(d, J =8.0Hz, 1H), 7.24(d, J=5.6Hz, 2H), 7.17(d, J=6.8Hz, 2H), 7.00(d, J=8.4Hz, 1H), 6.79(d, J=8.4 Hz,1H); MS (ESI) m/z [M+H] + = 467.1.

第三步：将N-(3-氰基苯基)-2-(4-(三氟甲氧基)苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-3)(149.0mg,0.32mmol)加入到无水乙醇(2.0mL)和盐酸-乙酸乙酯体系(10N,0.6mL)中，室温下封管反应。待反应完全后将反应体系蒸干，加入无水甲醇(3.0mL)，氨-甲醇体系(7N,5.0mL)，氯化铵(68.6.0mg,1.3mmol)，于65℃下回流反应3h。反应完全后直接蒸干得粗品。粗品用二氯甲烷：甲醇＝30：1(v/v)过硅胶柱(200～300目)得目标化合物(I-9)(50.0mg，收率32.7％)。1H-NMR(400MHz,DMSO-d6)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。The third step: N-(3-cyanophenyl)-2-(4-(trifluoromethoxy)phenoxy)-4-(trifluoromethyl)benzamide (II-A-3 ) (149.0mg, 0.32mmol) was added to absolute ethanol (2.0mL) and hydrochloric acid-ethyl acetate system (10N, 0.6mL), and the reaction was sealed at room temperature. After the reaction was complete, the reaction system was evaporated to dryness, anhydrous methanol (3.0 mL), ammonia-methanol system (7N, 5.0 mL), ammonium chloride (68.6.0 mg, 1.3 mmol) were added, and the reaction was refluxed at 65° C. for 3 h. After the reaction was complete, it was directly evaporated to dryness to obtain the crude product. The crude product was passed through a 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 (400MHz,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.

实施例10 N-(3-氨基甲酰氨基)-4-(三氟甲基)-2-(4-(三氟甲基)苯氧基)苯甲酰胺(I-10)的制备Example 10 Preparation of N-(3-carbamoylamino)-4-(trifluoromethyl)-2-(4-(trifluoromethyl)phenoxy)benzamide (I-10)

第一步：将实施例9得到的9-a(308.0mg，1.0mmol)，4-三氟甲苯酚(178.0mg,1.1mmol)和碳酸铯(651.0mg,2.0mmol)加入到N,N-二甲基甲酰胺(7.0mL)中，在80℃下反应。反应完全后，用2N稀盐酸调节pH值至2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：乙酸乙酯＝4：1(v/v)过硅胶柱(200～300目)得N-(3-氰基苯基)-4-(三氟甲基)-2-(4-(三氟甲基)苯氧基)苯甲酰胺(II-A-4)(360.0mg，收率80％)。1H-NMR(400MHz,CDCl3)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。The first step: 9-a (308.0mg, 1.0mmol) obtained in Example 9, 4-trifluorocresol (178.0mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were added to N,N- Dimethylformamide (7.0 mL) was reacted 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 a crude product. Use petroleum ether for the crude product: ethyl acetate = 4:1 (v/v) to pass through a silica gel column (200-300 mesh) 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 = 8.4 Hz, 1H), 6.80 (d, J = 7.8 Hz, 1 H); MS (ESI) m/z [M+H] + = 451.2.

第二步：将N-(3-氰基苯基)-4-(三氟甲基)-2-(4-(三氟甲基)苯氧基)苯甲酰胺(II-A-4)(149.0mg,0.32mmol)和无水乙醇(2.0mL)加入盐酸-乙酸乙酯体系(10N,0.6mL)中，室温下封管反应。反应完全后将反应体系蒸干，加入无水甲醇(3.0mL),氨-甲醇溶液(5.0mL)，氯化铵(68.6mg,1.3mmol)，于65℃下回流反应。反应完全后直接蒸干，拌样，用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-10)(55.0mg,收率35.7％)。1H-NMR(400MHz,DMSO-d6)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。The second step: N-(3-cyanophenyl)-4-(trifluoromethyl)-2-(4-(trifluoromethyl)phenoxy)benzamide (II-A-4) (149.0mg, 0.32mmol) and absolute ethanol (2.0mL) were added to hydrochloric acid-ethyl acetate system (10N, 0.6mL), and the reaction was sealed 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), ammonium chloride (68.6 mg, 1.3 mmol) were added, and the reaction was refluxed at 65°C. After the reaction was complete, evaporate to dryness directly, mix the sample, and use dichloromethane:methanol=20~15:1 (v/v) to pass through a silica gel column (200~300 mesh) to obtain the target compound (I-10) (55.0mg, 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 = 7.8 Hz, 1H), 7.06 (td, 2H); MS (ESI) m/z [M+H] + = 468.1.

实施例11 N-(3-氨基甲酰苯基)-2-(4-氟-2-甲氧基苯氧基)-4-(三氟甲基)苯甲酰胺(I-11)的制备Example 11 Preparation of N-(3-carbamoylphenyl)-2-(4-fluoro-2-methoxyphenoxy)-4-(trifluoromethyl)benzamide (I-11)

第一步：将实施例9得到的9-a(308.0mg，1.0mmol),4-氟-2-甲氧基苯酚(156.2mg,1.1mmol)和碳酸铯(651.0mg,2.0mmol)溶于N,N-二甲基甲酰胺(7.0mL)中，在100℃下反应。反应完全后，用2N稀盐酸调节pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：乙酸乙酯＝6：1(v/v)过硅胶柱(200～300目)得N-(3-氰基苯基)-2-(4-氟-2-甲氧基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-5)(360.0mg，收率83.7％)。1H-NMR(400MHz,CDCl3)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。The first step: 9-a (308.0mg, 1.0mmol), 4-fluoro-2-methoxyphenol (156.2mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) obtained in Example 9 were dissolved in In N,N-dimethylformamide (7.0 mL), 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 a crude product. Petroleum ether for the crude product: ethyl acetate = 6:1 (v/v) through a silica gel column (200-300 mesh) to obtain N-(3-cyanophenyl)-2-(4-fluoro-2-methoxy Phenoxy)-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.

第二步：将N-(3-氰基苯基)-2-(4-氟-2-甲氧基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-5)(180.0mg,0.42mmol)，无水乙醇(2mL)和盐酸-乙酸乙酯体系(10N,8.0mL)加入到封管中，室温下封管反应。待反应完全后将反应体系蒸干，加入无水甲醇(3.0mL)，氨-甲醇溶液(5.0mL)，氯化铵(89.4mg,1.68mmol)，于回流反应直到原料反应完全。反应完全后直接浓缩得到粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-11)(93.0mg，收率49.7％)。1H-NMR(400MHz,DMSO-d6)δ:10.87(s,1H),8.28(s,1H),7.92(d,J＝8.4Hz,1H),7.82(d,J＝7.8Hz,1H),7.61(t,J＝8.4Hz,1H),7.56(d,J＝8.4Hz,1H),7.50(d,J＝7.8Hz,1H),7.35(t,J＝7.8Hz,1H),7.17(d,J＝8.4Hz,1H),7.88(t,J＝7.8Hz,1H),6.83(s,1H),3.76(s,3H)；MS(ESI)m/z[M+H]+＝448.2。The second step: N-(3-cyanophenyl)-2-(4-fluoro-2-methoxyphenoxy)-4-(trifluoromethyl)benzamide (II-A-5 ) (180.0mg, 0.42mmol), absolute ethanol (2mL) and hydrochloric acid-ethyl acetate system (10N, 8.0mL) were added to the locked tube, and the tube was locked to react 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), ammonium chloride (89.4 mg, 1.68 mmol) were added, and the reaction was carried out under reflux until the raw materials were completely reacted. After the reaction was complete, it was directly concentrated to obtain the crude product. The crude product was passed through a 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=8.4Hz, 1H), 7.82(d, J=7.8Hz, 1H ),7.61(t,J=8.4Hz,1H),7.56(d,J=8.4Hz,1H),7.50(d,J=7.8Hz,1H),7.35(t,J=7.8Hz,1H), 7.17(d,J=8.4Hz,1H),7.88(t,J=7.8Hz,1H),6.83(s,1H),3.76(s,3H); MS(ESI)m/z[M+H] + = 448.2.

实施例12 N-(3-氨基甲脒酰基苯基)-2-(3-氟-4-甲氧基苯氧基)-4-(三氟甲基)苯甲酰胺(I-12)的制备Example 12 N-(3-aminocarbamidinoylphenyl)-2-(3-fluoro-4-methoxyphenoxy)-4-(trifluoromethyl)benzamide (I-12) preparation

第一步：将实施例9得到的9-a(308.0mg，1.0mmol),3-氟4-甲氧基苯酚(156.3mg,1.1mmol)和碳酸铯(651.0mg,2.0mmol)加入到N,N-二甲基甲酰胺(7.0mL)中，在100℃下反应。反应完全后，用2N稀盐酸调节pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝6：1(v/v)过硅胶柱(200～300目)得N-(3-氰基苯基)-2-(3-氟-4-甲氧基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-6)(217.0mg，收率50.5％)。1H-NMR(400MHz,CDCl3)δ:7.97(s,2H),7.51(m,1H),7.44～7.46(m,3H),7.15(s,1H),7.10(d,J＝8.4Hz,1H),6.81～6.93(q,4H),3.86(s,3H)；MS(ESI)m/z[M+H]+＝431.3。The first step: 9-a (308.0mg, 1.0mmol), 3-fluoro4-methoxyphenol (156.3mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) obtained in Example 9 were added to N , in N-dimethylformamide (7.0 mL), 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 a crude product. Use petroleum ether for the crude product: ethyl acetate = 6:1 (v/v) to pass through a silica gel column (200-300 mesh) to obtain N-(3-cyanophenyl)-2-(3-fluoro-4-methoxy Phenoxy)-4-(trifluoromethyl)benzamide (II-A-6) (217.0 mg, yield 50.5%). 1 H-NMR (400MHz, 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＝8.4Hz , 1H), 6.81~6.93 (q, 4H), 3.86 (s, 3H); MS (ESI) m/z [M+H] + = 431.3.

第二步：将N-(3-氰基苯基)-2-(3-氟-4-甲氧基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-6)(175.0mg,0.42mmol)，无水乙醇(2.0mL)和盐酸-乙酸乙酯体系(10N,10.0mL)加入到封管中，室温下封管反应。反应完全后将反应体系蒸干得到中间体，加入无水甲醇(3.0mL)溶解,氨-甲醇溶液(5mL),氯化铵(87.0mg,1.67mmol)，于回流反应直到原料反应完全。随后直接蒸干，拌样，用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-12)(67.0mg，收率36.8％)。1H-NMR(600MHz,DMSO-d6)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。The second step: N-(3-cyanophenyl)-2-(3-fluoro-4-methoxyphenoxy)-4-(trifluoromethyl)benzamide (II-A-6 ) (175.0mg, 0.42mmol), absolute ethanol (2.0mL) and hydrochloric acid-ethyl acetate system (10N, 10.0mL) were added to the locked tube, and the tube was locked to react at room temperature. After the reaction was complete, the reaction system was evaporated to dryness to obtain an intermediate, which was dissolved by adding anhydrous methanol (3.0 mL), ammonia-methanol solution (5 mL), ammonium chloride (87.0 mg, 1.67 mmol), and reacted under reflux until the raw materials were completely reacted. Then directly evaporate to dryness, mix the sample, and use dichloromethane:methanol=20～15:1 (v/v) to pass through a silica gel column (200～300 mesh) to obtain the target compound (I-12) (67.0mg, 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.

实施例13 N-(5-氨基甲脒酰基2-氯苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-13)的制备Example 13 N-(5-carbamidinoyl 2-chlorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-13 ) preparation

第一步：将实施例1得到的1-b(628.0mg,2.0mmol)，3-氨基-4-氯苯甲腈(305.0mg,2.0mmol)溶于吡啶(6.0mL)中，在0℃下缓慢滴加三氯氧磷(0.38mL,4.0mmol),控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N 稀盐酸调pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：乙酸乙酯＝10～4：1(v/v)过硅胶柱(200～300目)得N-(2-氯-5-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-7)(510.0mg，收率56.9％)。1H-NMR(400MHz,DMSO-d6)δ:10.56(s,1H),8.45(s,1H),8.11(d,J＝7.6Hz,1H),7.78(d,J＝8.0Hz,1H),7.73(d,J＝8.4Hz,1H),7.64(d,J＝8.4Hz,1H),7.30(d,J＝2.8Hz,1H),7.20(d,J＝2.8Hz,1H),7.15(t,1H),6.92(s,1H),2.20(s,3H)；MS(ESI)m/z[M+H]+＝448.9。The first step: 1-b (628.0mg, 2.0mmol) obtained in Example 1, 3-amino-4-chlorobenzonitrile (305.0mg, 2.0mmol) was dissolved in pyridine (6.0mL), at 0 ° C Phosphorus oxychloride (0.38mL, 4.0mmol) was slowly added dropwise under low temperature, and the temperature was controlled below 10°C. After the dropwise addition was completed, the reaction was continued until the raw materials were completely reacted, and then the reaction system was poured into ice water and washed with 2N Adjust the pH value to about 2-3 with dilute hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain a crude product. Use petroleum ether for the crude product: ethyl acetate = 10~4:1 (v/v) to pass through a silica gel column (200~300 mesh) 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=7.6Hz, 1H), 7.78(d, J=8.0Hz, 1H ),7.73(d,J=8.4Hz,1H),7.64(d,J=8.4Hz,1H),7.30(d,J=2.8Hz,1H),7.20(d,J=2.8Hz,1H), 7.15 (t, 1H), 6.92 (s, 1H), 2.20 (s, 3H); MS (ESI) m/z [M+H] + = 448.9.

第二步：将N-(2-氯-5-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-7)(134.0mg,0.3mmol)，无水乙醇(0.17mL)和盐酸-乙酸乙酯体系(10N,7.0mL)加入到封管中，室温下反应。待反应完全生成中间体后将反应体系蒸干，加入无水甲醇(4.0mL)，氨-甲醇溶液(5.0mL)，氯化铵(62.0mg,0.6mmol)，于回流反应直到中间体反应完全，随后直接蒸干，拌样，用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-13),(70.0mg,收率50％)。1H-NMR(400MHz,DMSO-d6)δ:10.60(brs,1H),8.51(s,1H),8.10(d,J＝8.0Hz,1H),7.83(d,J＝8.0Hz,1H),7.66(t,J＝8.8Hz,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)。The second step: N-(2-chloro-5-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II- A-7) (134.0mg, 0.3mmol), absolute ethanol (0.17mL) and hydrochloric acid-ethyl acetate system (10N, 7.0mL) were added into a sealed tube and reacted at room temperature. After the reaction is complete to generate the intermediate, the reaction system is evaporated to dryness, and anhydrous methanol (4.0mL), ammonia-methanol solution (5.0mL), ammonium chloride (62.0mg, 0.6mmol) are added, and the reaction is carried out under reflux until the intermediate is completely reacted , then directly evaporated to dryness, mixed samples, and passed through a silica gel column (200-300 mesh) with dichloromethane:methanol=20～15:1 (v/v) to obtain the target compound (I-13), (70.0mg, yield 50%). 1 H-NMR (400MHz, DMSO-d 6 )δ: 10.60(brs, 1H), 8.51(s, 1H), 8.10(d, J=8.0Hz, 1H), 7.83(d, J=8.0Hz, 1H ), 7.66(t, J＝8.8Hz, 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).

实施例14 N-(5-氨基甲脒酰基2-甲基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-14)的制备Example 14 N-(5-carbamidinoyl 2-methylphenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I- 14) Preparation

第一步：将实施例1得到的1-b(628.0mg,2.0mmol)，3-氨基-4-甲基苯甲腈(285.8mg,2mmol)溶于吡啶(6.0mL)中，在0℃下缓慢滴加三氯氧磷(0.38mL,4.0mmol),控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N稀盐酸调pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝10～4：1(v/v)过硅胶柱(200～300目)得N-(2-甲基-5-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-8)(624.0mg，收率72.9％)。1H-NMR(400MHz,DMSO-d6)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。The first step: 1-b (628.0mg, 2.0mmol) obtained in Example 1, 3-amino-4-methylbenzonitrile (285.8mg, 2mmol) was dissolved in pyridine (6.0mL), at 0°C Phosphorus oxychloride (0.38mL, 4.0mmol) was slowly added dropwise under low temperature, and the temperature was controlled below 10°C. After the dropwise addition was completed, the reaction was continued until the raw materials were completely reacted, then the reaction system was poured into ice water, and the pH was adjusted with 2N dilute hydrochloric acid. value to about 2 to 3, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. Use petroleum ether for the crude product: ethyl acetate = 10～4:1 (v/v) to pass through a silica gel column (200～300 mesh) 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.

第二步：将N-(2-甲基-5-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-8)(214.0mg,0.5mmol)，无水乙醇(1.5mL)和盐酸-乙酸乙酯体系(10N,7.0mL)加入到封管中，室温下封管反应。待反应完全后生成中间体后将反应体系蒸干，加入无水甲醇(3.0mL),氨-甲醇溶液(5.0mL),氯化铵(53.0mg,1mmol)，于回流反应直到中间体反应完全。反应完全后直接浓缩得到粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-14)(90.0mg,收率40.5％)。1H-NMR(400MHz,DMSO-d6)δ:10.30(s,1H),9.42(s,1H),9.22(s,1H),8.11(s,1H),7.97(d,J＝7.2Hz,1H),7.63(d,J＝7.2Hz,1H),7.51(d,J＝7.2Hz,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。The second step: N-(2-methyl-5-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II -A-8) (214.0mg, 0.5mmol), absolute ethanol (1.5mL) and hydrochloric acid-ethyl acetate system (10N, 7.0mL) were added to the locked tube, and the tube was locked to react at room temperature. After the reaction is complete, the intermediate is formed and the reaction system is evaporated to dryness. Add anhydrous methanol (3.0 mL), ammonia-methanol solution (5.0 mL), ammonium chloride (53.0 mg, 1 mmol), and react at reflux until the intermediate is completely reacted. . After the reaction was complete, it was directly concentrated to obtain the crude product. The crude product was passed through a 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=7.2Hz ,1H),7.63(d,J=7.2Hz,1H),7.51(d,J=7.2Hz,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.

实施例15 N-(5-氨基甲脒酰基2-氟苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-15)的制备Example 15 N-(5-aminocarbamidinoyl 2-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-15 ) preparation

第一步：将实施例1得到的1-b(628.0mg,2.0mmol)，3-氨基-4-氟苯甲腈(285.8mg,2mmol)溶于吡啶(6mL)中，在0℃下缓慢滴加三氯氧磷(0.38mL,4.0mmol),控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N稀盐酸调pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝10～4：1(v/v)过硅胶柱(200～300目)得N-(2-甲基-5-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-9)(520.0mg,收率60.2％)。1H-NMR(400MHz,DMSO-d6)δ:10.65(s,1H),8.41(d,J＝6.4Hz,1H),7.97(d,J＝7.6Hz,1H),7.76(brs,1H),7.62(d,J＝8.0Hz,1H),7.56(t,J＝10.0Hz,1H),7.26(d,J＝10.0Hz,1H),7.10～7.15(m,2H),6.95(s,1H),2.18(s,3H)；MS(ESI)m/z[M+H]+＝433.1。The first step: 1-b (628.0mg, 2.0mmol) obtained in Example 1, 3-amino-4-fluorobenzonitrile (285.8mg, 2mmol) was dissolved in pyridine (6mL), and slowly Add phosphorus oxychloride (0.38mL, 4.0mmol) dropwise, control the temperature below 10°C, continue the reaction until the raw materials are completely reacted, then pour the reaction system into ice water, and adjust the pH value to 2 to 3, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Use petroleum ether for the crude product: ethyl acetate = 10～4:1 (v/v) to pass through a silica gel column (200～300 mesh) 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 (400MHz, DMSO-d 6 )δ: 10.65(s, 1H), 8.41(d, J=6.4Hz, 1H), 7.97(d, J=7.6Hz, 1H), 7.76(brs, 1H ),7.62(d,J=8.0Hz,1H),7.56(t,J=10.0Hz,1H),7.26(d,J=10.0Hz,1H),7.10～7.15(m,2H),6.95(s ,1H), 2.18(s,3H); MS (ESI) m/z [M+H] + = 433.1.

第二步：将N-(2-甲基-5-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-9)(214.0mg,0.5mmol)，无水乙醇(1.5mL)和盐酸-乙酸乙酯体系(10N,5.0mL)加入到封管中，室温下封管反应。待反应完全生成中间体后将反应体系蒸干，加入氨-甲醇溶液(7N,5.0mL),氯化铵(53.0mg,1mmol)，于回流反应直到中间体反应完全。反应完全后直接浓缩得到粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-15)(97.0mg,收率43.6％)。1H-NMR(400MHz,DMSO-d6)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。The second step: N-(2-methyl-5-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II -A-9) (214.0mg, 0.5mmol), absolute ethanol (1.5mL) and hydrochloric acid-ethyl acetate system (10N, 5.0mL) were added to the locked tube, and the tube was locked to react at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, ammonia-methanol solution (7N, 5.0 mL), ammonium chloride (53.0 mg, 1 mmol) was added, and the reaction was carried out under reflux until the intermediate was completely reacted. After the reaction was complete, it was directly concentrated to obtain the crude product. The crude product was passed through a 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.

实施例16 N-(3-氨基甲酰苯基)-4-氯-2-(4-氟-2-甲基苯氧基)苯甲酰胺(I-16)的制备
Example 16 Preparation of N-(3-carbamoylphenyl)-4-chloro-2-(4-fluoro-2-methylphenoxy)benzamide (I-16)

第一步：将2-氟-4-氯苯甲酸(16-SM1)(1.0g,5.73mmol),间氨基苯甲腈(710.6mg,6.02mmol)溶于吡啶(9.0mL)中，在0℃下缓慢滴加三氯氧磷(1.0mL，11.5mmol),控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N 盐酸调节pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，蒸干得粗品。粗品用石油醚：乙酸乙酯＝10：1(v/v)过硅胶柱(200～300目)得化合物(16-a)(630.0mg,收率40.1％)。1H-NMR(400MHz,DMSO-d6)δ:10.81(s,1H),8.18(s,1H),7.94(d,J＝7.6Hz,1H),7.74(t,J＝8.0Hz,1H),7.66(d,J＝10.0Hz,1H),7.60(brs,2H),7.47(d,J＝8.0Hz,1H)；MS(ESI)m/z[M+H]+＝275.1。The first step: 2-fluoro-4-chlorobenzoic acid (16-SM1) (1.0g, 5.73mmol), m-aminobenzonitrile (710.6mg, 6.02mmol) were dissolved in pyridine (9.0mL), at 0 Slowly add phosphorus oxychloride (1.0mL, 11.5mmol) dropwise at ℃, control the temperature below 10℃, continue the reaction until the raw materials are completely reacted, then pour the reaction system into ice water, and use 2N Adjust the pH value to about 2-3 with hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and evaporate to dryness to obtain a crude product. The crude product was passed through a 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=7.6Hz, 1H), 7.74(t, J=8.0Hz, 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.

第二步：将16-a(275.0mg，1.0mmol),4-氟-2-甲基苯酚(138.0mg,1.1mmol)和碳酸铯(651.0mg,2.0mmol)溶于N,N-二甲基甲酰胺(7.0mL)中，在80℃下反应。反应完全后，用2N稀盐酸调节pH值至2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：乙酸乙酯＝4：1(v/v)过硅胶柱(200～300目)得4-氯-N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)苯甲酰胺(II-A-10)(264.0mg，收率69.5％)。1H-NMR(400MHz,DMSO-d6)δ:10.74(s,1H),8.14(s,1H),7.90(brs,1H),7.69(d,J＝8.4Hz,1H),7.57(s,1H),7.56(sq,1H),7.31(dd,J＝8.4,1.6Hz,1H),7.19(d,J＝8.8Hz,1H),7.09(dd,J＝6.4,1.6Hz,2H),6.75(d,J＝2.0Hz,1H),2.16(s,3H)；MS(ESI)m/z[M+H]+＝381.1,382.9(3:1)。The second step: 16-a (275.0mg, 1.0mmol), 4-fluoro-2-methylphenol (138.0mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were dissolved in N,N-dimethyl In methyl formamide (7.0 mL), 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 a crude product. Use petroleum ether for the crude product: ethyl acetate = 4:1 (v/v) to pass through a silica gel column (200-300 mesh) 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 (400MHz, DMSO-d 6 )δ: 10.74(s, 1H), 8.14(s, 1H), 7.90(brs, 1H), 7.69(d, J=8.4Hz, 1H), 7.57(s ,1H),7.56(sq,1H),7.31(dd,J=8.4,1.6Hz,1H),7.19(d,J=8.8Hz,1H),7.09(dd,J=6.4,1.6Hz,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).

第三步：将4-氯-N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)苯甲酰胺(II-A-10)(197.0mg,0.5mmol)，无水乙醇(0.2mL)和盐酸-乙酸乙酯体系(10N,5.0mL)加入到封管中，室温下封管反应。待反应完全生成中间体后将反应体系蒸干，随后加入氨-甲醇溶液(7N，5.0mL),氯化铵(53.0mg,1mmol)，于回流反应直到中间体反应完全。反应完全后直接浓缩得粗品，粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得固体目标化合物(I-16)(104.0mg,收率68％)。1H-NMR(400MHz,DMSO-d6)δ:10.78(s,1H),8.25(s,1H),7.88(d,J＝7.8Hz,1H),7.67(d,J＝8.4Hz,1H),7.59(t,J＝7.8Hz,1H),7.48(d,J＝8.8Hz,1H),7.31(d,J＝7.8Hz,1H),7.21～7.23(dd,J＝9.6,3.0Hz,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)。The third step: 4-chloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (II-A-10) (197.0mg, 0.5 mmol), absolute ethanol (0.2mL) and hydrochloric acid-ethyl acetate system (10N, 5.0mL) were added to the sealed tube, and the tube was locked to react at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, then ammonia-methanol solution (7N, 5.0 mL) and ammonium chloride (53.0 mg, 1 mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted. After the reaction was complete, it was directly concentrated to obtain the crude product, which 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-16) (104.0 mg, yield 68%). 1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.78(s, 1H), 8.25(s, 1H), 7.88(d, J=7.8Hz, 1H), 7.67(d, J=8.4Hz, 1H ), 7.59(t, J＝7.8Hz, 1H), 7.48(d, J＝8.8Hz, 1H), 7.31(d, J＝7.8Hz, 1H), 7.21～7.23(dd, J＝9.6, 3.0Hz ,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).

实施例17 N-(3-氨基甲酰苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酰胺(I-17)的制备
Example 17 Preparation of N-(3-carbamoylphenyl)-2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamide (I-17)

第一步：将2-氟-5-三氟甲基苯甲酸(17-SM1)(1.0g,4.81mmol),间氨基苯甲腈(694.0mg,5.05mmol)溶于吡啶(7mL)中，在0℃下缓慢滴加三氯氧磷(0.9mL，9.6mmol),控制温度在 10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N盐酸调节PH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，蒸干得粗品。粗品用石油醚：乙酸乙酯＝8：1(v/v)过硅胶柱(200～300目)得化合物(17-a)(850.0mg，收率57.4％)。1H-NMR(400MHz,DMSO-d6)δ:10.95(brs,1H),8.18(s,1H),8.12(d,J＝8.4Hz,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。The first step: 2-fluoro-5-trifluoromethylbenzoic acid (17-SM1) (1.0g, 4.81mmol), m-aminobenzonitrile (694.0mg, 5.05mmol) were dissolved in pyridine (7mL), Phosphorus oxychloride (0.9mL, 9.6mmol) was slowly added dropwise at 0°C, and the temperature was controlled at Below 10°C, the dropwise addition is completed, 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, evaporate Dried rough. The crude product was passed through a 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=8.4Hz, 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.

第二步：将17-a(275.0mg，1.0mmol),4-氟-2-甲基苯酚(138.0mg,1.1mmol)和碳酸铯(651.0mg,2.0mmol)溶于N,N-二甲基甲酰胺(7.0mL)中，在80℃下反应。反应完全后，用2N稀盐酸调节pH值至2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：乙酸乙酯＝4：1(v/v)过硅胶柱(200～300目)得N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酰胺(II-A-11)(363.0mg，收率87.7％)。1H-NMR(400MHz,DMSO-d6)δ:10.87(s,1H),8.18(s,1H),8.02(sd,J＝2.4Hz,1H),7.92～7.94(q,1H),7.80(dd,J＝8.8,2.4Hz,1H),7.59(s,1H),7.58(st,1H),7.24(dd,J＝9.2,2.4Hz,1H),7.10～7.20(q,2H),6.84(d,J＝8.8Hz,1H),2.12(s,3H)；MS(ESI)m/z[M+H]+＝415.1。The second step: 17-a (275.0mg, 1.0mmol), 4-fluoro-2-methylphenol (138.0mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were dissolved in N,N-dimethyl In methyl formamide (7.0 mL), 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 a crude product. Use petroleum ether for the crude product: ethyl acetate = 4:1 (v/v) to pass through a silica gel column (200-300 mesh) to obtain N-(3-cyanophenyl)-2-(4-fluoro-2-methylbenzene Oxy)-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=2.4Hz, 1H), 7.92～7.94(q, 1H), 7.80 (dd,J=8.8,2.4Hz,1H),7.59(s,1H),7.58(st,1H),7.24(dd,J=9.2,2.4Hz,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.

第三步：将N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)苯甲酰胺(II-A-11)(197.0mg,0.5mmol)，无水乙醇(0.2mL)和盐酸-乙酸乙酯体系(10N,5.0mL)加入到封管中，室温下封管反应。待反应完全生成中间体后将反应体系蒸干，随后加入氨-甲醇溶液(7N，5.0mL),氯化铵(53.0mg,1mmol)，于回流反应直到中间体反应完全。反应完全后直接浓缩得粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-17)(118mg,收率57％)。1H-NMR(400MHz,DMSO-d6)δ:10.94(s,1H),8.24(s,1H),7.96(sd,2H),7.80(d,J＝8.4Hz,1H),7.61(t,J＝8.4Hz,1H),7.50(d,J＝7.2Hz,1H),7.22～7.27(m,2H),7.15(t,J＝8.4Hz,1H),6.82(d,J＝9.0Hz,1H),2.15(s,3H)；MS(ESI)m/z[M+H]+＝432.2。The third step: N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)benzamide (II-A-11) (197.0mg, 0.5mmol), absolute ethanol (0.2mL) and hydrochloric acid-ethyl acetate system (10N, 5.0mL) were added to the locked tube, and the tube was locked to react at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, then ammonia-methanol solution (7N, 5.0 mL) and ammonium chloride (53.0 mg, 1 mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted. After the reaction was complete, it was directly concentrated to obtain the crude product. The crude product was passed through a 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=8.4Hz, 1H), 7.61(t ,J＝8.4Hz, 1H), 7.50(d, J＝7.2Hz, 1H), 7.22～7.27(m, 2H), 7.15(t, J＝8.4Hz, 1H), 6.82(d, J＝9.0Hz , 1H), 2.15 (s, 3H); MS (ESI) m/z [M+H] + = 432.2.

实施例18 5-氯-N-(3-氨基甲酰苯基)-2-(4-氟-2-甲基苯氧基)苯甲酰胺(I-18)的制备
Example 18 Preparation of 5-chloro-N-(3-carbamoylphenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (I-18)

第一步：将2-氟-5-氯苯甲酸(18-SM1)(1.0g,5.73mmol),间氨基苯甲腈(710.6mg,6.02mmol)溶于吡啶(9.0mL)中，在0℃下缓慢滴加三氯氧磷(1.0mL，11.5mmol),控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N 盐酸调节pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩析出固体得化合物(18-a)(360.0mg,收率24.4％)。1H-NMR(400MHz,DMSO-d6)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)。The first step: 2-fluoro-5-chlorobenzoic acid (18-SM1) (1.0g, 5.73mmol), m-aminobenzonitrile (710.6mg, 6.02mmol) were dissolved in pyridine (9.0mL), at 0 Slowly add phosphorus oxychloride (1.0mL, 11.5mmol) dropwise at ℃, control the temperature below 10℃, continue the reaction until the raw materials are completely reacted, then pour the reaction system into ice water, and use 2N Adjust the pH value to about 2-3 with hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate and precipitate a solid to obtain compound (18-a) (360.0 mg, yield 24.4%). 1 H-NMR (400MHz, 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).

第二步：将18-a(275.0mg，1.0mmol),4-氟-2-甲基苯酚(138.0mg,1.1mmol)和碳酸铯(651.0mg,2.0mmol)加入到N,N-二甲基甲酰胺(7.0mL)中，在80℃下反应。反应完全后，用2N稀盐酸调节pH 2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：乙酸乙酯＝4：1(v/v)过硅胶柱(200～300目)得5-氯-N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)苯甲酰胺(II-A-12)(126.0mg，收率33.1％)。1H-NMR(400MHz,CDCl3)δ:10.79(s,1H),8.13(s,1H),7.89(sq,1H),7.72(d,J＝2.8Hz,1H),7.57(s,1H),7.56～7.57(sq,1H),7.51(dd,J＝8.8,2.4Hz,1H),7.17(dd,J＝9.6,2.4Hz,1H),7.01～7.10(m,2H),6.77(d,J＝8.8Hz,1H),2.15(s,3H)；MS(ESI)m/z[M+H]+＝381.8。The second step: 18-a (275.0mg, 1.0mmol), 4-fluoro-2-methylphenol (138.0mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were added to N,N-dimethyl In methyl formamide (7.0 mL), 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 a crude product. Use petroleum ether for the crude product: ethyl acetate = 4:1 (v/v) to pass through a silica gel column (200-300 mesh) 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=2.8Hz, 1H), 7.57(s, 1H ),7.56～7.57(sq,1H),7.51(dd,J＝8.8,2.4Hz,1H),7.17(dd,J＝9.6,2.4Hz,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.

第三步：将5-氯-N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)苯甲酰胺(II-A-12)(97.0mg,0.25mmol)，无水乙醇(0.1mL)和盐酸-乙酸乙酯体系(10N,5.0mL)加入封管中，室温下封管反应。待反应完全后生成中间体后将反应体系蒸干，随后加入氨-甲醇溶液(7N，5.0mL),氯化铵(30.0mg,1.0mmol)，于回流反应直到中间体反应完全。反应完全后直接浓缩得粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-18)(46.0mg,收率45％)。1H-NMR(400MHz,DMSO-d6)δ:10.87(s,1H),9.42(brs,2H),9.21(brs,2H),8.23(s,1H),7.91(d,J＝6.0Hz,1H)7.67(s,1H),7.59(brs,1H),7.50(brs,2H),7.21(d,J＝10.0Hz,1H),7.10(brs,2H),6.73(d,J＝8.4Hz,1H),2.15(s,3H)；MS(ESI)m/z[M+H]+＝398.1。The third step: 5-chloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (II-A-12) (97.0mg, 0.25 mmol), absolute ethanol (0.1 mL) and hydrochloric acid-ethyl acetate system (10N, 5.0 mL) were added to the sealed tube, and the tube was sealed to react at room temperature. After the reaction was complete and the intermediate was formed, the reaction system was evaporated to dryness, then ammonia-methanol solution (7N, 5.0mL) and ammonium chloride (30.0mg, 1.0mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted. After the reaction was complete, it was directly concentrated to obtain the crude product. The crude product was passed through a silica gel column (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=6.0Hz ,1H)7.67(s,1H),7.59(brs,1H),7.50(brs,2H),7.21(d,J=10.0Hz,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.

实施例19 4,5-二氯-N-(3-氨基甲酰苯基)-2-(4-氟-2-甲基苯氧基)苯甲酰胺(I-19)的制备
Example 19 Preparation of 4,5-dichloro-N-(3-carbamoylphenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (I-19)

第一步：将2-氟-4,5-二氯苯甲酸(19-SM1)(2.0g,9.6mmol),间氨基苯甲腈(1.2g,10.0mmol)溶于吡啶(15.0mL)中，在0℃下缓慢滴加三氯氧磷(1.8mL，19.2mmol)，控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N盐酸调节pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩析出固体得化合物(19-a)(1.6g，收率54.1％)。1H-NMR(400MHz,DMSO-d6)δ:10.9(s,1H,NH),8.17(s,1H), 8.03(d,J＝6.8Hz,1H),7.93(t,2H),7.61(t,2H)；MS(ESI)m/z[M+H]+＝309.0,311.0(3:1)。The first step: Dissolve 2-fluoro-4,5-dichlorobenzoic acid (19-SM1) (2.0g, 9.6mmol), m-aminobenzonitrile (1.2g, 10.0mmol) in pyridine (15.0mL) , slowly add phosphorus oxychloride (1.8mL, 19.2mmol) dropwise at 0°C, and control the temperature below 10°C. Adjust the pH value to about 2-3 with hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to precipitate a solid to obtain compound (19-a) (1.6 g, yield 54.1%). 1 H-NMR (400MHz,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).

第二步：将19-a(309.0mg，1.0mmol),4-氟苯酚(123.0mg,1.1mmol)和碳酸铯(651.0mg,2.0mmol)加入到N,N-二甲基甲酰胺(10.0mL)中，在80℃下反应直到原料反应完全。冷却，将反应体系倒入到冰水中，用2N稀盐酸调节pH值至2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩析出大量固体，过滤得到4,5-二氯-N-(3-氰基苯基)-2-(4-氟苯氧基)苯甲酰胺(II-A-13)(216.0mg，收率53.9％)。1H-NMR(400MHz,DMSO-d6)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)。The second step: 19-a (309.0mg, 1.0mmol), 4-fluorophenol (123.0mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were added to N,N-dimethylformamide (10.0 mL), 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 over anhydrous sodium sulfate, concentrate and precipitate a large amount of solid, filter to obtain 4,5-dichloro-N -(3-cyanophenyl)-2-(4-fluorophenoxy)benzamide (II-A-13) (216.0 mg, yield 53.9%). 1 H-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).

第三步：将4,5-二氯-N-(3-氰基苯基)-2-(4-氟苯氧基)苯甲酰胺(II-A-13)(202.0mg,0.49mmol)，无水乙醇(1.0mL)和盐酸-乙酸乙酯体系(10N,5.0mL)加入到封管中，室温下封管反应。待反应完全后生成中间体后将反应体系蒸干，随后加入氨-甲醇溶液(7N，5.0mL)，氯化铵(52.4mg,1mmol)，于回流反应直到中间体反应完全。反应完全后直接浓缩得到粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-19)(110.0mg,收率52％)。1H-NMR(600MHz,DMSO-d6)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)。The third step: 4,5-dichloro-N-(3-cyanophenyl)-2-(4-fluorophenoxy)benzamide (II-A-13) (202.0mg, 0.49mmol) , absolute ethanol (1.0 mL) and hydrochloric acid-ethyl acetate system (10N, 5.0 mL) were added to the sealed tube, and the tube was locked to react at room temperature. After the reaction was complete and the intermediate was formed, the reaction system was evaporated to dryness, then ammonia-methanol solution (7N, 5.0mL) and ammonium chloride (52.4mg, 1mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted. After the reaction was complete, it was directly concentrated to obtain the crude product. The crude product was passed through a 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).

实施例20 4,5-氯-N-(3-氨基甲酰苯基)-2-(4-氟-2-甲氧基苯氧基)苯甲酰胺(I-20)的制备Example 20 Preparation of 4,5-chloro-N-(3-carbamoylphenyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide (I-20)

第一步：将实施例19得到的19-a(309.0mg，1.0mmol)，4-氟-2-甲氧基苯酚(156.3mg,1.1mmol)和碳酸铯(651.0mg,2.0mmol)溶于N,N-二甲基甲酰胺(5.0mL)中，在80℃下反应直到原料反应完全。冷却，将反应体系倒入到冰水中，用2N稀盐酸调节pH值至2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩析出固体，过滤得到4,5-二氯-N-(3-氰基苯基)-2-(4-氟-2-甲氧基苯氧基)苯甲酰胺(II-A-14)(300.0mg,收率69.6％)。1H-NMR(400MHz,DMSO-d6)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。The first step: 19-a (309.0mg, 1.0mmol) obtained in Example 19, 4-fluoro-2-methoxyphenol (156.3mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were dissolved in In N,N-dimethylformamide (5.0 mL), react at 80°C until the starting material is 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 over 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.

第二步：将4,5-二氯-N-(3-氰基苯基)-2-(4-氟-2-甲氧基苯氧基)苯甲酰胺(II-A-14)(200.0mg,0.49mmol)，无水乙醇(1.0mL)和盐酸-乙酸乙酯体系(10N,5.0mL)加入到封管中，室温下封管反应。待反应完全生成中间体后将反应体系蒸干，随后加入氨-甲醇溶液(7N，5.0mL),氯化铵(50.0mg,1mmol)，于回流反应直到中间体反应完全。冷却,直接浓缩得粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-20)(74.0mg,收率35.2％)。1H-NMR(400MHz,DMSO-d6):10.79(brs,1H),8.24(s,1H),7.88～7.92(brs,2H),7.60(t,J＝8.0Hz,1H),7.49(d,J＝7.6Hz,1H),7.31(t,J＝8.0Hz,1H),7.15(dd,J＝10.4,3.2Hz,1H),6.87(dd,J＝10.4,3.2Hz,1H),6.84(s,1H),3.76(s,3H)；MS(ESI)m/z[M+H]+＝448.1/450.1(3:1)。 The second step: 4,5-dichloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide (II-A-14) ( 200.0mg, 0.49mmol), absolute ethanol (1.0mL) and hydrochloric acid-ethyl acetate system (10N, 5.0mL) were added to the locked tube, and the tube was locked to react at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, then ammonia-methanol solution (7N, 5.0 mL) and ammonium chloride (50.0 mg, 1 mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted. Cooling, concentrated directly to the crude product. The crude product was passed through a 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=8.0Hz, 1H), 7.49 ( d,J=7.6Hz,1H),7.31(t,J=8.0Hz,1H),7.15(dd,J=10.4,3.2Hz,1H),6.87(dd,J=10.4,3.2Hz,1H), 6.84 (s, 1H), 3.76 (s, 3H); MS (ESI) m/z [M+H] + = 448.1/450.1 (3:1).

实施例21 4-氯-N-(3-氨基甲酰苯基)-2-(4-氟-2-甲氧基苯氧基)苯甲酰胺(I-21)的制备Example 21 Preparation of 4-chloro-N-(3-carbamoylphenyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide (I-21)

第一步：将实施例16得到的16-a(275.0mg，1.0mmol),4-氟-2-甲氧基苯酚(156.3mg,1.1mmol)和碳酸铯(651.0mg,2.0mmol)加入到N,N-二甲基甲酰胺(7.0mL)中，在80℃下反应。反应完全后，用2N稀盐酸调节pH值至2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：乙酸乙酯＝10：1(v/v)过硅胶柱(200～300目)得4-氯-N-(3-氰基苯基)-2-(4-氟-2-甲氧基苯氧基)苯甲酰胺(II-A-15)(260.0mg,收率65.6％)。1H-NMR(400MHz,DMSO-d6)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)。The first step: 16-a (275.0mg, 1.0mmol) obtained in Example 16, 4-fluoro-2-methoxyphenol (156.3mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were added to In N,N-dimethylformamide (7.0 mL), 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 a crude product. Use petroleum ether for the crude product: ethyl acetate = 10:1 (v/v) to pass through a silica gel column (200-300 mesh) 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).

第二步：将4-氯-N-(3-氰基苯基)-2-(4-氟-2-甲氧基苯氧基)苯甲酰胺(II-A-15)(200.0mg,0.47mmol)，无水乙醇(1.0mL)和盐酸-乙酸乙酯体系(10N,10.0mL)加入到封管中，室温下封管反应。待反应完全生成中间体后将反应体系蒸干，加入氨-甲醇溶液(7N，10.0mL),氯化铵(55.0mg,1mmol)，于回流反应直到中间体反应完全。随后直接浓缩得粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得固体目标化合物(I-21)(80.0mg,收率38％)。1H-NMR(400MHz,DMSO-d6)δ:10.70(s,1H),8.25(s,1H),7.93(d,J＝9.2Hz,1H),7.66(d,J＝8.0Hz,1H),7.59(t,J＝8.0Hz,1H),7.49(d,J＝7.6Hz,1H),7.36(t,J＝8.0Hz,1H),7.26(d,J＝8.8Hz,1H),7.15(d,J＝7.6Hz,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)。The second step: 4-chloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide (II-A-15) (200.0mg, 0.47mmol), absolute ethanol (1.0mL) and hydrochloric acid-ethyl acetate system (10N, 10.0mL) were added to the sealed tube, and the tube was locked to react at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, ammonia-methanol solution (7N, 10.0 mL), ammonium chloride (55.0 mg, 1 mmol) was added, and the reaction was carried out under reflux until the intermediate was completely reacted. Subsequent direct concentration gave the crude product. 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-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=9.2Hz, 1H), 7.66(d, J=8.0Hz, 1H ),7.59(t,J=8.0Hz,1H),7.49(d,J=7.6Hz,1H),7.36(t,J=8.0Hz,1H),7.26(d,J=8.8Hz,1H), 7.15(d,J=7.6Hz,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).

实施例22 N-(3-氨基甲酰亚胺酰基苯基)-4,5-二氯-2-(3-氟-4-甲氧基苯氧基)苯甲酰胺(I-22)的制备Example 22 N-(3-carbamoimidoylphenyl)-4,5-dichloro-2-(3-fluoro-4-methoxyphenoxy)benzamide (I-22) preparation

第一步：将实施例19得到的19-a(309.0mg，1.0mmol),3-氟-4-甲氧基苯酚(161.0mg,1.1mmol)和碳酸铯(651.0mg,2.0mmol)溶于N,N-二甲基甲酰胺(10.0mL)中，在80℃下反应直到原料反应完全。冷却，将反应体系倒入到冰水中，用2N稀盐酸调节pH 2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩析出大量固体，过滤得到将4,5-二氯-N-(3-氰基苯基)-2-(4-氟-3-甲氧基苯氧基)苯甲酰胺(II-A-16)(216.0mg,收率50.1％)。1H-NMR(400MHz,DMSO-d6)δ:10.77(s,1H),8.11(s,1H),7.96(s,1H),7.88(d,J＝7.2Hz,1H),7.57(sq,2H),7.14～7.21(m,3H),6.95(d,J＝6.6Hz,1H),3.82(s,3H)；MS(ESI)m/z[M+H]+＝431.0,433.1(3:1)。The first step: 19-a (309.0mg, 1.0mmol), 3-fluoro-4-methoxyphenol (161.0mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) obtained in Example 19 were dissolved in In N,N-dimethylformamide (10.0 mL), react at 80°C until the starting material is completely reacted. 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 over anhydrous sodium sulfate, concentrate and precipitate a large amount of solid, 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 (400MHz, DMSO-d 6 )δ: 10.77(s, 1H), 8.11(s, 1H), 7.96(s, 1H), 7.88(d, J=7.2Hz, 1H), 7.57(sq ,2H),7.14～7.21(m,3H),6.95(d,J＝6.6Hz,1H),3.82(s,3H); MS(ESI)m/z[M+H] + ＝431.0,433.1( 3:1).

第二步：将4,5-二氯-N-(3-氰基苯基)-2-(4-氟-3-甲氧基苯氧基)苯甲酰胺(II-A-16)(100.0mg,0.23mmol)，无水乙醇(0.1mL)和入盐酸-二氧六环体系(4N,10.0mL)加入到封管中，室温下封管反应。待反应完全生成中间体后将反应体系浓缩，随后加入氨-甲醇溶液(4N，10.0mL),氯化铵(24.0mg,0.46mmol)，于回流下反应直到中间体反应完全。随后直接浓缩得粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得固体目标化合物 (I-22)(50.0mg,收率48％)。1H-NMR(400MHz,DMSO-d6)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)。The second step: 4,5-dichloro-N-(3-cyanophenyl)-2-(4-fluoro-3-methoxyphenoxy)benzamide (II-A-16) ( 100.0mg, 0.23mmol), absolute ethanol (0.1mL) and hydrochloric acid-dioxane system (4N, 10.0mL) were added to the locked tube, and the tube was locked to react at room temperature. After the reaction was complete to generate the intermediate, the reaction system was concentrated, then ammonia-methanol solution (4N, 10.0mL) and ammonium chloride (24.0mg, 0.46mmol) were added, and reacted under reflux until the intermediate was completely reacted. Subsequent direct concentration gave the crude product. 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-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).

实施例23 N-(5-氨基甲酰亚胺酰基2-甲基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-23)的制备Example 23 N-(5-carbamoimidoyl 2-methylphenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide ( I-23) Preparation

第一步：将实施例9中的2-氟-4-三氟甲基苯甲酸(9-SM1)(1.0g,4.8mmol),3-氨基-4-甲基苯甲腈(667.0mg,5.05mmol)溶于吡啶(10.0mL)中，在0℃下缓慢滴加三氯氧磷(0.9mL，9.6mmol),控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N盐酸调节pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩析出固体，过滤得到N-(5-氰基-2-甲基苯基)-2-氟-4-(三氟甲基)苯甲酰胺(23-a)(450.0mg，收率24.6％)。1H-NMR(400MHz,DMSO-d6)δ:10.27(s,1H),7.91～8.01(m,3H),7.77(d,J＝8.0Hz,1H),7.65(d,J＝8.0Hz,1H),7.52(d,J＝8.0Hz,1H),2.36(s,3H)；MS(ESI)m/z[M+H]+＝323.1。The first step: 2-fluoro-4-trifluoromethylbenzoic acid (9-SM1) (1.0g, 4.8mmol) in Example 9, 3-amino-4-methylbenzonitrile (667.0mg, 5.05mmol) was dissolved in pyridine (10.0mL), and phosphorus oxychloride (0.9mL, 9.6mmol) was slowly added dropwise at 0°C, and the temperature was controlled below 10°C. 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, concentrate to precipitate a solid, and filter to obtain N-(5-cyano-2-methyl phenyl)-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=8.0Hz, 1H), 7.65(d, J=8.0Hz , 1H), 7.52 (d, J = 8.0 Hz, 1H), 2.36 (s, 3H); MS (ESI) m/z [M+H] + = 323.1.

第二步：将N-(5-氰基-2-甲基苯基)-2-氟-4-(三氟甲基)苯甲酰胺(23-a)(322.0mg，1.0mmol),4-氟苯酚(123.3mg,1.1mmol)和碳酸铯(651.0mg,2.0mmol)加入到N,N-二甲基甲酰胺(7.0mL)中，在80℃下反应。反应完全后，用2N稀盐酸调节pH 2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：乙酸乙酯＝10：1(v/v)过硅胶柱(200～300目)得N-(5-氰基-2-甲基苯基)-2-(4-氟苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-23)(330.0mg，收率79.7％)。1H-NMR(400MHz,DMSO-d6)δ:10.18(s,1H),8.00(s,1H),7.99(d,J＝8.0Hz,1H),7.66(d,J＝7.6Hz,1H),7.59(d,J＝8.0Hz,1H),7.45(d,J＝8.0Hz,1H),7.25～7.34(m,4H),7.15(s,1H),2.27(s,3H)；MS(ESI)m/z[M+H]+＝415.1。The second step: N-(5-cyano-2-methylphenyl)-2-fluoro-4-(trifluoromethyl)benzamide (23-a) (322.0mg, 1.0mmol), 4 -Fluorophenol (123.3 mg, 1.1 mmol) and cesium carbonate (651.0 mg, 2.0 mmol) were added to N,N-dimethylformamide (7.0 mL), and reacted 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 a crude product. Use petroleum ether for the crude product: ethyl acetate = 10:1 (v/v) to pass through a silica gel column (200-300 mesh) to obtain N-(5-cyano-2-methylphenyl)-2-(4-fluorobenzene Oxy)-4-(trifluoromethyl)benzamide (II-A-23) (330.0 mg, yield 79.7%). 1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.18(s, 1H), 8.00(s, 1H), 7.99(d, J=8.0Hz, 1H), 7.66(d, J=7.6Hz, 1H ), 7.59(d, J＝8.0Hz, 1H), 7.45(d, J＝8.0Hz, 1H), 7.25～7.34(m, 4H), 7.15(s, 1H), 2.27(s, 3H); MS (ESI) m/z [M+H] + = 415.1.

第三步：将N-(5-氰基-2-甲基苯基)-2-(4-氟苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-23)(200.0mg,0.48mmol)和无水乙醇(0.3mL)加入盐酸-二氧六环体系(4N,12.0mL)加入到封管中，于室温下封管反应。反应完全后将反应体系浓缩干得中间体，随后加入氨-甲醇溶液(4N，10.0mL),氯化铵(51.6mg,0.46mmol)，于回流反应直到中间体反应完全。浓缩得到粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-23)(20.0mg,收率9.6％)。1H-NMR(400MHz,DMSO-d6)δ:10.27(brs,1H),8.10(s,1H),7.95(d,J＝7.2Hz,1H),7.66(d,J＝7.2Hz,1H),7.60(d,J＝8.8Hz,1H),7.49(d,J＝7.6Hz,1H),7.33(m,4H),7.13(s,1H),2.29(s,3H)；MS(ESI)m/z[M+H]+＝432.1。The third step: N-(5-cyano-2-methylphenyl)-2-(4-fluorophenoxy)-4-(trifluoromethyl)benzamide (II-A-23) (200.0mg, 0.48mmol) and absolute ethanol (0.3mL) were added to hydrochloric acid-dioxane system (4N, 12.0mL) into the sealed tube, and reacted at room temperature. After the reaction was complete, the reaction system was concentrated to dryness to obtain the intermediate, and then ammonia-methanol solution (4N, 10.0 mL) and ammonium chloride (51.6 mg, 0.46 mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted. Concentration gave the crude product. The crude product was passed through a 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 (400MHz, DMSO-d 6 )δ: 10.27(brs, 1H), 8.10(s, 1H), 7.95(d, J=7.2Hz, 1H), 7.66(d, J=7.2Hz, 1H ),7.60(d,J=8.8Hz,1H),7.49(d,J=7.6Hz,1H),7.33(m,4H),7.13(s,1H),2.29(s,3H); MS(ESI ) m/z [M+H] + = 432.1.

实施例24 N-(3-氨基甲脒酰基苯基)-5-氯2-(4-氟-2-甲氧基苯氧基)苯甲酰胺(I-24)的制备Example 24 Preparation of N-(3-aminocarbamidinoylphenyl)-5-chloro 2-(4-fluoro-2-methoxyphenoxy)benzamide (I-24)

第一步：将实施例18得到的18-a(275.0mg，1.0mmol),4-氟-2-甲氧基苯酚(156.0mg,1.1mmol)和碳酸铯(651.0mg,2.0mmol)加入到N,N-二甲基甲酰胺(7.0mL)中，在80℃下反应直到原料反应完全。用2N稀盐酸调节pH 2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩 得到粗品。粗品用石油醚：乙酸乙酯＝10：1(v/v)过硅胶柱(200～300目)得5-氯-N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)苯甲酰胺(II-A-18)(50.0mg,收率12.6％)。1H-NMR(400MHz,DMSO-d6)δ:10.72(brs,1H),8.18(s,1H),7.93(brs,1H),7.68(sd,J＝2.4Hz,1H),7.57(d,J＝5.2Hz,2H),7.47(dd,J＝9.2,2.8Hz,1H),7.24(q,1H),7.11(dd,J＝10.4,2.8Hz,1H),6.80～6.86(td,J＝10.4,4.0Hz,1H),6.70(d,J＝8.8Hz,1H),3.73(s,3H)；MS(ESI)m/z[M+H]+＝397.1,389.9(3:1)。The first step: 18-a (275.0mg, 1.0mmol) obtained in Example 18, 4-fluoro-2-methoxyphenol (156.0mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were added to In N,N-dimethylformamide (7.0 mL), react at 80°C until the starting material is completely reacted. Use 2N dilute hydrochloric acid to adjust the pH to about 2~3, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate get crude. Use petroleum ether for the crude product: ethyl acetate = 10:1 (v/v) to pass through a silica gel column (200-300 mesh) 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 (400MHz, DMSO-d 6 ) δ: 10.72(brs, 1H), 8.18(s, 1H), 7.93(brs, 1H), 7.68(sd, J=2.4Hz, 1H), 7.57(d ,J=5.2Hz,2H),7.47(dd,J=9.2,2.8Hz,1H),7.24(q,1H),7.11(dd,J=10.4,2.8Hz,1H),6.80～6.86(td, J=10.4,4.0Hz,1H),6.70(d,J=8.8Hz,1H),3.73(s,3H); MS(ESI)m/z[M+H] + =397.1,389.9(3:1 ).

第二步：将5-氯-N-(3-氰基苯基)-2-(4-氟-2-甲氧基苯氧基)苯甲酰胺(II-A-18)(50.0mg,0.13mmol)和无水乙醇(0.1mL)加入到盐酸-二氧六环体系(4N,10mL)中，室温下封管反应。反应完全后将反应体系浓缩得中间体，随后加入氨-甲醇溶液(4N,5mL),氯化铵(22.0mg,0.26mmol)，于回流反应直到中间体反应完全。浓缩得粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-24)(10.0mg,收率19.8％)。1H-NMR(400MHz,DMSO-d6)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)。The second step: 5-chloro-N-(3-cyanophenyl)-2-(4-fluoro-2-methoxyphenoxy)benzamide (II-A-18) (50.0mg, 0.13mmol) and absolute ethanol (0.1mL) were added to hydrochloric acid-dioxane system (4N, 10mL), and the reaction was sealed at room temperature. After the reaction was complete, the reaction system was concentrated to obtain an intermediate, then ammonia-methanol solution (4N, 5mL) and ammonium chloride (22.0mg, 0.26mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted. Concentrated crude. The crude product was passed through a 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 = 9.0 Hz, 1H), 3.75 (s, 3H); MS (ESI) m/z [M+H] + = 414.1/416.1 (3:1).

实施例25 N-(3-氨基甲酰亚胺酰基苯基)-4-乙炔基-2-(4-氟-2-甲基苯氧基)苯甲酰胺(I-25)的制备
Example 25 Preparation of N-(3-carbamoimidoylphenyl)-4-ethynyl-2-(4-fluoro-2-methylphenoxy)benzamide (I-25)

第一步：将4-溴-2-氟苯甲腈(19-SM1)(4.0g，20.0mmol),4-氟-2-甲基苯酚(2.52g,20.0mmol)和碳酸铯(13.0g,40.0mmol)加入到N,N-二甲基甲酰胺(60.0mL)中，在80℃下直到主原料反应完全。加入乙酸乙酯和水进行搅拌分液。乙酸乙酯相用无水硫酸钠干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝10：1(v/v)过硅胶柱(200～300目)得化合物(19-a)(5.7g，收率93.1％)。1H-NMR(400MHz,DMSO-d6)δ:7.87(d,J＝8.4Hz,1H),7.47～7.49(dd,J＝8.4, 2.0Hz,1H),7.28～7.31(dd,J＝9.2,3.2Hz,1H),7.21～7.24(q,1H),7.13～7.18(td,J＝8.4,3.2Hz,1H),6.85(s,1H),2.15(s,3H)；MS(ESI)m/z[M+H]+＝305.1,307.1(1:1)。The first step: 4-bromo-2-fluorobenzonitrile (19-SM1) (4.0g, 20.0mmol), 4-fluoro-2-methylphenol (2.52g, 20.0mmol) and cesium carbonate (13.0g , 40.0mmol) was added into N,N-dimethylformamide (60.0mL) at 80°C until the main raw material was completely reacted. Ethyl acetate and water were added to carry out stirring and liquid separation. The ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated to give the crude product. The crude product was passed through a 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=8.4Hz, 1H), 7.47～7.49 (dd, J=8.4, 2.0Hz, 1H), 7.28～7.31(dd, J＝9.2, 3.2Hz, 1H), 7.21～7.24(q, 1H), 7.13～7.18(td, J＝8.4, 3.2Hz, 1H), 6.85(s ,1H), 2.15(s,3H); MS (ESI) m/z [M+H] + = 305.1, 307.1 (1:1).

第二步：将19-a(5.0g,16.3mmol)加入到甲醇(100.0mL)中,随后加入氢氧化钠(6.6g,16.3mmol)和水(20.0mL)回流反应直到完全水解,浓缩,除去甲醇,加入水稀释,用稀盐酸调pH值到酸性,析出大量固体,过滤得到化合物(19-b)(3.9g，收率73.4％)。MS(ESI)m/z[M+H]+＝325.0,327.0(1:1)。The second step: 19-a (5.0g, 16.3mmol) was added to methanol (100.0mL), then sodium hydroxide (6.6g, 16.3mmol) and water (20.0mL) were added to reflux reaction until complete hydrolysis, concentrated, Methanol was removed, diluted with water, and the pH value was adjusted to acidic with dilute hydrochloric acid, a large amount of solid was precipitated, and compound (19-b) (3.9 g, yield 73.4%) was obtained by filtration. MS (ESI) m/z [M+H] + = 325.0, 327.0 (1:1).

第三步：将19-b(3.9g,12.0mmol)，间氨基苯甲腈(1.42g,12.0mmol)溶于吡啶(20.0mL)中，在0℃下缓慢滴加三氯氧磷(2.25mL,24.0mmol),控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N稀盐酸调pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩得到粗品，粗品用乙酸乙酯重结晶得化合物(19-c)(1.4g，收率27.5％)。MS(ESI)m/z[M+H]+＝425.0,427.0(1:1)。The third step: Dissolve 19-b (3.9g, 12.0mmol), m-aminobenzonitrile (1.42g, 12.0mmol) in pyridine (20.0mL), slowly add phosphorus oxychloride (2.25 mL, 24.0mmol), the temperature is controlled below 10°C, the dropwise addition is completed, and the reaction is continued until the reaction of the raw materials is complete, then the reaction system is poured into ice water, and the pH value is adjusted to about 2-3 with 2N dilute hydrochloric acid, and the Ester was extracted, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was recrystallized from 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).

第四步：氮气保护下，将19-c(850.0mg,2.0mmol)，三甲基硅乙炔(294.5mg,3.0mmol)，碘化亚铜(76.0mg,0.02mmol)，四三苯基膦钯(206.0mg,0.2mmol)和三乙胺(0.56mL,4.0mmol)加入到甲苯(10mL)中于回流下反应直到主原料反应完全,冷却,将反应体系倒入到冰水中,用乙酸乙酯萃取,干燥,浓缩得到粗品。粗品用石油醚：乙酸乙酯＝10：1(v/v)过柱得到化合物(19-d)(600.0mg，收率67.8％)。1H-NMR(400MHz,DMSO-d6)δ:10.75(s,1H),8.15(s,1H),7.90(brs,1H),7.65(d,J＝8.0Hz,1H),7.56(sd,2H),7.30(d,J＝8.0Hz,1H),7.21(d,J＝10.0Hz,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。Step 4: Under nitrogen protection, mix 19-c (850.0mg, 2.0mmol), trimethylsilylacetylene (294.5mg, 3.0mmol), cuprous iodide (76.0mg, 0.02mmol), tetrakistriphenylphosphine Palladium (206.0mg, 0.2mmol) and triethylamine (0.56mL, 4.0mmol) were added to toluene (10mL) and reacted under reflux until the main raw material was completely reacted. After cooling, the reaction system was poured into ice water and washed with ethyl acetate. Ester extraction, drying, and concentration gave the crude product. The crude product was columned with petroleum ether:ethyl acetate=10:1 (v/v) to obtain compound (19-d) (600.0 mg, yield 67.8%). 1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.75(s, 1H), 8.15(s, 1H), 7.90(brs, 1H), 7.65(d, J=8.0Hz, 1H), 7.56(sd ,2H),7.30(d,J=8.0Hz,1H),7.21(d,J=10.0Hz,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.

第五步：将19-d(331.0mg,0.75mmol)加入到甲酸(10mL)于80℃反应，浓缩得粗品。粗品用石油醚：乙酸乙酯＝4：1(v/v)过硅胶柱(200～300目)得到化合物(II-A-19)110.0mg。1H-NMR(400MHz,DMSO-d6)δ:10.75(s,1H),8.14(s,1H),7.90(brs,1H),7.66(d,J＝5.2Hz,1H),7.56(d,2H),7.33(d,J＝5.2Hz,1H),7.19(d,J＝6.8Hz,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。Step 5: Add 19-d (331.0mg, 0.75mmol) to formic acid (10mL) to react at 80°C and concentrate to obtain a crude product. The crude product was passed through a 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 (400MHz, DMSO-d 6 ) δ: 10.75(s, 1H), 8.14(s, 1H), 7.90(brs, 1H), 7.66(d, J=5.2Hz, 1H), 7.56(d ,2H),7.33(d,J=5.2Hz,1H),7.19(d,J=6.8Hz,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.

第六步：将N-(3-氰基苯基)-4-乙炔基-2-(4-氟-2-甲基苯氧基)苯甲酰胺(II-A-19)(65.0mg,0.175mmol)和无水乙醇(0.1mL)加入到盐酸-乙酸乙酯体系(10N,10.0mL)中，室温下封管反应。待反应完全生成中间体后将反应体系蒸干，加入氨-甲醇溶液(4N，8.0mL),氯化铵(18.7mg,0.34mmol)，于回流反应直到中间体反应完全。随后直接浓缩得粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-25)(37.0mg,收率54.4％)。1H-NMR(400MHz,DMSO-d6)δ:10.79(brs,1H),8.26(s,1H),7.87(d,J＝9.2Hz,1H),7.64(d,J＝7.6Hz,1H),7.58(t,J＝7.6Hz,1H),7.48(d,J＝9.2Hz,1H),7.33(d,J＝8.8Hz,1H),7.22(d,J＝9.2Hz,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。 The sixth step: N-(3-cyanophenyl)-4-ethynyl-2-(4-fluoro-2-methylphenoxy)benzamide (II-A-19) (65.0mg, 0.175mmol) and absolute ethanol (0.1mL) were added to hydrochloric acid-ethyl acetate system (10N, 10.0mL), and the reaction was sealed at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, ammonia-methanol solution (4N, 8.0mL) and ammonium chloride (18.7mg, 0.34mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted. Subsequent direct concentration gave the crude product. The crude product was passed through a 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 (400MHz, DMSO-d 6 )δ: 10.79 (brs, 1H), 8.26 (s, 1H), 7.87 (d, J = 9.2Hz, 1H), 7.64 (d, J = 7.6Hz, 1H ),7.58(t,J=7.6Hz,1H),7.48(d,J=9.2Hz,1H),7.33(d,J=8.8Hz,1H),7.22(d,J=9.2Hz,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.

实施例26 N-(3-氨基甲酰亚胺酰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(4-甲基-1-4-甲基-1-戊炔基)苯甲酰胺(I-26)的制备Example 26 N-(3-carbamoimidoylphenyl)-2-(4-fluoro-2-methylphenoxy)-4-(4-methyl-1-4-methyl-1 Preparation of -pentynyl)benzamide (I-26)

第一步：氮气保护下，将实施例25得到的19-c(425.0mg,1.0mmol)，4-甲基-1-戊炔(353mg,3.0mmol)，碘化亚铜(38.0mg,0.01mmol)，四三苯基膦钯(103mg,0.1mmol)和三乙胺(0.28mL,2.0mmol)加入到甲苯(10.0mL)中于回流下反应直到主原料反应完全,冷却,将反应体系倒入到冰水中,用乙酸乙酯萃取,干燥,浓缩得粗品。粗品用石油醚:乙酸乙酯＝10:1(v/v)过柱得到N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(4-甲基-1-4-甲基-1-戊炔基)苯甲酰胺(II-A-20)(280.0mg，收率80.8％)。1H-NMR(400MHz,DMSO-d6)δ:10.69(s,1H),8.14(s,1H),7.91(s,1H),7.63(d,J＝7.8Hz,1H),7.56(d,J＝4.8Hz,2H),7.23(d,J＝7.8Hz,1H),7.17～7.19(dd,J＝9.0,2.4Hz,1H),7.06～7.08(q,2H),2.29(d,J＝6.6Hz,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。The first step: under nitrogen protection, 19-c (425.0mg, 1.0mmol) obtained in Example 25, 4-methyl-1-pentyne (353mg, 3.0mmol), cuprous iodide (38.0mg, 0.01 mmol), tetrakistriphenylphosphine palladium (103mg, 0.1mmol) and triethylamine (0.28mL, 2.0mmol) were added in toluene (10.0mL) and reacted under reflux until the main raw material was completely reacted, cooled, and the reaction system was poured Pour into ice water, extract with ethyl acetate, dry and concentrate to obtain the crude product. Crude petroleum ether: ethyl acetate=10:1 (v/v) cross column to obtain N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-( 4-Methyl-1-4-methyl-1-pentynyl)benzamide (II-A-20) (280.0 mg, yield 80.8%). 1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.69(s, 1H), 8.14(s, 1H), 7.91(s, 1H), 7.63(d, J=7.8Hz, 1H), 7.56(d , J＝4.8Hz, 2H), 7.23(d, J＝7.8Hz, 1H), 7.17～7.19(dd, J＝9.0, 2.4Hz, 1H), 7.06～7.08(q, 2H), 2.29(d, J＝6.6Hz,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.

第二步：将N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(4-甲基-1-4-甲基-1-戊炔基)苯甲酰胺(II-A-20)(140mg,0.34mmol)和无水乙醇(0.1mL)加入到盐酸/乙酸乙酯(10N,16.0mL)中，室温下封管反应。待反应完全生成中间体后将反应体系蒸干，加入氨-甲醇溶液(7N，3.0mL),氯化铵(35.0mg,0.68mmol)，于回流反应直到中间体反应完全。随后直接浓缩得粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-26)(65.0mg,收率44.6％)。1H-NMR(400MHz,DMSO-d6)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。The second step: N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(4-methyl-1-4-methyl-1-pentane Alkynyl)benzamide (II-A-20) (140mg, 0.34mmol) and absolute ethanol (0.1mL) were added to hydrochloric acid/ethyl acetate (10N, 16.0mL), and the reaction was sealed at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, ammonia-methanol solution (7N, 3.0mL) and ammonium chloride (35.0mg, 0.68mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted. Subsequent direct concentration gave the crude product. The crude product was passed through a 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 = 5.6 Hz, 3H); MS (ESI) m/z [M+H] + = 443.8.

实施例27 N-(3-氨基甲酰亚胺酰基苯基)-6-氯-5-氟-(4-氟-2-甲基苯氧基)-烟酰胺(I-27)的制备
Example 27 Preparation of N-(3-carbamoimidoylphenyl)-6-chloro-5-fluoro-(4-fluoro-2-methylphenoxy)-nicotinamide (I-27)

第一步：将2,6-二氯-5-氟烟酸(27-SM1)(1.05g,5.0mmol),间氨基苯甲腈(587mg,5.0mmol)溶于吡啶(4.0mL)中，在0℃下缓慢滴加三氯氧磷(0.9mL，2.0mmol),控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N盐 酸调节pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，蒸干得粗品。粗品用石油醚：乙酸乙酯＝4：1(v/v)过硅胶柱(200～300目)得化合物(27-a)(500.0mg，收率32.3％)。1H-NMR(400MHz,DMSO-d6)δ:11.10(s,1H),8.51(d,J＝7.6Hz,1H),8.15(s,1H),7.89(d,J＝7.6Hz,1H),7.60～7.66(m,2H)；MS(ESI)m/z[M+H]+＝311.0,311.9(3:1)。Step 1: Dissolve 2,6-dichloro-5-fluoronicotinic acid (27-SM1) (1.05g, 5.0mmol), m-aminobenzonitrile (587mg, 5.0mmol) in pyridine (4.0mL), Phosphorus oxychloride (0.9mL, 2.0mmol) was slowly added dropwise at 0°C, and the temperature was controlled below 10°C. After the dropwise addition was completed, the reaction was continued until the raw materials were completely reacted, and then the reaction system was poured into ice water and washed with 2N salt Adjust the pH value to about 2-3 with acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and evaporate to dryness to obtain a crude product. The crude product was passed through a 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=7.6Hz, 1H), 8.15(s, 1H), 7.89(d, J=7.6Hz, 1H ), 7.60～7.66 (m, 2H); MS (ESI) m/z [M+H] + = 311.0, 311.9 (3:1).

第二步：将27-a(310.0mg，1.0mmol),4-氟-2-甲基苯酚(126.0mg,1.1mmol)，碘化亚铜(2.0mg,0.01mmol)和碳酸铯(651.0mg,2.0mmol)加入到甲苯(7.0mL)中，在100℃下反应。反应完全后，用2N稀盐酸调节pH值至2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：乙酸乙酯＝8：1(v/v)过硅胶柱(200～300目)得N-(3-氰基苯基)-6-氯-5-氟-(4-氟-2-甲基苯氧基)-烟酰胺(II-A-21)(100.0mg，收率25％)。1H-NMR(400MHz,DMSO-d6)δ:10.96(s,1H),8.38(d,J＝9.2Hz,1H),8.15(s,1H),7.898(td,1H),7.58～7.63(m,2H),7.25～7.28(dd,J＝6.8,4.0Hz,2H),7.12～7.17(td,8.0,3.2Hz,1H),2.14(s,3H)；MS(ESI)m/z[M+H]+＝399.9,401.9(3:1)。The second step: 27-a (310.0mg, 1.0mmol), 4-fluoro-2-methylphenol (126.0mg, 1.1mmol), cuprous iodide (2.0mg, 0.01mmol) and cesium carbonate (651.0mg , 2.0mmol) was added to toluene (7.0mL) and reacted 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 a crude product. Use petroleum ether for the crude product: ethyl acetate = 8:1 (v/v) to pass through a silica gel column (200-300 mesh) to obtain N-(3-cyanophenyl)-6-chloro-5-fluoro-(4-fluoro -2-methylphenoxy)-nicotinamide (II-A-21) (100.0 mg, yield 25%). 1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.96(s, 1H), 8.38(d, J=9.2Hz, 1H), 8.15(s, 1H), 7.898(td, 1H), 7.58～7.63 (m,2H),7.25～7.28(dd,J＝6.8,4.0Hz,2H),7.12～7.17(td,8.0,3.2Hz,1H),2.14(s,3H); MS(ESI)m/z [M+H] + = 399.9, 401.9 (3:1).

第三步：将N-(3-氰基苯基)-6-氯-5-氟-(4-氟-2-甲基苯氧基)-烟酰胺(II-A-21)(100.0mg,0.25mmol)和无水乙醇(0.2mL)加入到盐酸-乙酸乙酯体系(10N,16.0mL)中，室温下封管反应。反应完全后将反应体系蒸干，加入氨-甲醇溶液(7N，5.0mL),氯化铵(27.0mg,0.5mmol)，于回流反应直到原料反应完全。随后直接浓缩得粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-27)(40.0mg,收率38.4％)。1H-NMR(600MHz,DMSO-d6)δ:11.03(brs,1H),8.34(d,J＝9.0Hz,1H),8.18(s,1H),7.90(d,J＝8.4Hz,1H),7.62(t,J＝8.4Hz,7.8Hz,1H),7.52(d,J＝7.8Hz,1H),7.26～7.28(dt,2H),7.13～7.17(td,J＝9.0,3.0Hz,1H),2.15(s,3H)；MS(ESI)m/z[M+H]+＝416.7。The third step: N-(3-cyanophenyl)-6-chloro-5-fluoro-(4-fluoro-2-methylphenoxy)-nicotinamide (II-A-21) (100.0mg , 0.25mmol) and absolute ethanol (0.2mL) were added to hydrochloric acid-ethyl acetate system (10N, 16.0mL), and the reaction was sealed at room temperature. After the reaction was complete, the reaction system was evaporated to dryness, ammonia-methanol solution (7N, 5.0 mL) and ammonium chloride (27.0 mg, 0.5 mmol) were added, and the reaction was carried out under reflux until the reaction of the raw materials was complete. Subsequent direct concentration gave the crude product. The crude product was passed through a 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 H-NMR (600MHz, DMSO-d 6 )δ: 11.03(brs, 1H), 8.34(d, J=9.0Hz, 1H), 8.18(s, 1H), 7.90(d, J=8.4Hz, 1H ), 7.62(t, J＝8.4Hz, 7.8Hz, 1H), 7.52(d, J＝7.8Hz, 1H), 7.26～7.28(dt, 2H), 7.13～7.17(td, J＝9.0, 3.0Hz , 1H), 2.15 (s, 3H); MS (ESI) m/z [M+H] + = 416.7.

实施例28 N-(3-氨基甲酰亚胺酰基苯基)-2-(4-氟-2-甲基苯氧基)苯甲酰胺(I-28)的制备
Example 28 Preparation of N-(3-carbamoimidoylphenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (I-28)

第一步：将2-氟苯甲酸(28-SM1)(1.4g,10.0mmol)，间氨基苯甲腈(1.2g,10.0mmol)溶于吡啶(8.0mL)中，在0℃下缓慢滴加三氯氧磷(1.9mL，20.0mmol),控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N盐酸调节 pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：乙酸乙酯＝10：1(v/v)过硅胶柱(200～300目)得1.0g化合物(28-a)。1H-NMR(400MHz,DMSO-d6)δ:10.77(s,1H),8.21(s,1H),7.96(brm,1H),7.70(t,J＝7.6Hz,1H),7.58～7.64(m,3H),7.38(q,J＝7.6Hz,2H)；MS(ESI)m/z[M+H]+＝241.1。Step 1: Dissolve 2-fluorobenzoic acid (28-SM1) (1.4g, 10.0mmol), m-aminobenzonitrile (1.2g, 10.0mmol) in pyridine (8.0mL), drop slowly at 0°C Add phosphorus oxychloride (1.9mL, 20.0mmol), control the temperature below 10°C, dropwise, continue the reaction until the reaction of the raw materials is complete, then pour the reaction system into ice water, adjust with 2N hydrochloric acid When the pH value was about 2-3, it was extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was passed through a 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(400MHz,DMSO-d 6 )δ:10.77(s,1H),8.21(s,1H),7.96(brm,1H),7.70(t,J=7.6Hz,1H),7.58～7.64 (m, 3H), 7.38 (q, J = 7.6 Hz, 2H); MS (ESI) m/z [M+H] + = 241.1.

第二步：氮气保护下,将28-a(480.0mg，2.0mmol),4-氟-2-甲基苯酚(252.0mg,2.0mmol)和碳酸铯(1.3mg,4.0mmol)和碘化亚铜(38.0mg,0.2mmol)加入到甲苯(20.0mL)中，在90℃下反应。反应完全后，倒入到冰水中,用2N稀盐酸调节pH 2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：乙酸乙酯＝10：1(v/v)过硅胶柱(200～300目)得N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)苯甲酰胺(II-A-22)320.0mg。1H-NMR(400MHz,DMSO-d6)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。The second step: under the protection of nitrogen, 28-a (480.0mg, 2.0mmol), 4-fluoro-2-methylphenol (252.0mg, 2.0mmol) and cesium carbonate (1.3mg, 4.0mmol) and iodide Copper (38.0mg, 0.2mmol) was added to toluene (20.0mL) and reacted at 90°C. After the reaction is complete, pour it 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 a crude product. Use petroleum ether for the crude product: ethyl acetate = 10:1 (v/v) to pass through a silica gel column (200-300 mesh) to obtain N-(3-cyanophenyl)-2-(4-fluoro-2-methylbenzene Oxy)benzamide (II-A-22) 320.0 mg. 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 = 8.4 Hz, 1H), 2.16 (s, 3H); MS (ESI) m/z [M+H] + = 346.8.

第三步：将N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)苯甲酰胺(II-A-22)(250.0mg,0.72mmol)和无水乙醇(0.4mL)加入到盐酸-乙酸乙酯体系(10N,14.0mL)中，室温下封管反应。待反应完全生成中间体后将反应体系蒸干，加入氨-甲醇溶液(7N，5.0mL),氯化铵(77.0mg,1.4mmol)，于回流反应直到中间体反应完全。随后直接浓缩得粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-28)(74.0mg,收率28.6％)。1H-NMR(400MHz,DMSO-d6)δ:10.74(s,1H),8.27(s,1H),7.92(d,J＝7.6Hz,1H),7.64(dd,J＝7.6,1.6Hz,1H),7.58(t,J＝7.6Hz,1H),7.44～7.50(q,2H),7.18～7.24(q,2H),7.08(d,J＝6.4Hz,2H),6.72(d,J＝8.4Hz,1H),2.17(s,3H)；MS(ESI)m/z[M+H]+＝363.8。The third step: N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (II-A-22) (250.0mg, 0.72mmol) and no Water ethanol (0.4mL) was added to hydrochloric acid-ethyl acetate system (10N, 14.0mL), and the reaction was sealed at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, ammonia-methanol solution (7N, 5.0 mL), ammonium chloride (77.0 mg, 1.4 mmol) was added, and the reaction was carried out under reflux until the intermediate was completely reacted. Subsequent direct concentration gave the crude product. The crude product was passed through a silica gel column (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=7.6Hz, 1H), 7.64(dd, J=7.6, 1.6Hz ,1H),7.58(t,J=7.6Hz,1H),7.44～7.50(q,2H),7.18～7.24(q,2H),7.08(d,J=6.4Hz,2H),6.72(d, J = 8.4 Hz, 1H), 2.17 (s, 3H); MS (ESI) m/z [M+H] + = 363.8.

实施例29 N-(3-氨基甲酰亚胺酰基苯基)-5-氟-(4-氟-2-甲基苯氧基)-6-甲基烟酰胺(I-29)的制备
Example 29 Preparation of N-(3-carbamoimidoylphenyl)-5-fluoro-(4-fluoro-2-methylphenoxy)-6-methylnicotinamide (I-29)

第一步：将5-氯-2-氟-6-甲基烟酸乙酯(29-SM1)(434.0mg，2.0mmol)，4-氟-2-甲基苯酚(252.0mg,2.0mmol)，碳酸铯(1.3g,4.0mmol)，碘化亚铜(38.0mg,0.2mmol)加入到甲苯(20.0 mL)中，在100℃下回流反应。反应完全后，用2N稀盐酸调节pH值至2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：乙酸乙酯＝10：1(v/v)过硅胶柱(200～300目)得目标化合物(29-a)(440.0mg,收率67％)。1H-NMR(400MHz,DMSO-d6)δ:8.24(s,1H),7.17(dd,J＝9.2,2.4Hz,1H),7.05～7.12(q,2H),4.31(q,2H),2.33(s,3H),2.08(s,3H),1.30(t,J＝6.8Hz,3H)；MS(ESI)m/z[M+H]+＝323.8。The first step: 5-chloro-2-fluoro-6-methylnicotinic acid ethyl ester (29-SM1) (434.0mg, 2.0mmol), 4-fluoro-2-methylphenol (252.0mg, 2.0mmol) , cesium carbonate (1.3g, 4.0mmol), cuprous iodide (38.0mg, 0.2mmol) was added to toluene (20.0 mL), the reaction was refluxed 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 a crude product. The crude product was passed through a silica gel column (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 H-NMR (400MHz, DMSO-d 6 ) δ: 8.24(s, 1H), 7.17(dd, J=9.2, 2.4Hz, 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.

第二步：将5-氯-2-(4-氟-2-甲基苯氧基)-6-甲基烟酸乙酯(29-a)(323.0mg,1.0mmol)溶于氢氧化钠溶液(10N,5.0mL)中，加入甲醇(8.0mL)，80℃下回流反应1h。浓缩除去甲醇，加入水，用2N稀盐酸调pH值至2～3左右，析出大量白色固体，静置，过滤，干燥得到5-氯-2-(4-氟-2-甲基苯氧基)-6-甲基烟酸(29-b)290.0mg直接下一步；The second step: Dissolve ethyl 5-chloro-2-(4-fluoro-2-methylphenoxy)-6-methylnicotinate (29-a) (323.0mg, 1.0mmol) in sodium hydroxide To the solution (10N, 5.0 mL), methanol (8.0 mL) was added, and the reaction was refluxed at 80° C. for 1 h. Concentrate to remove methanol, add water, adjust the pH value to about 2-3 with 2N dilute hydrochloric acid, a large amount of white solid precipitates, let stand, filter, and dry to obtain 5-chloro-2-(4-fluoro-2-methylphenoxy )-6-methylnicotinic acid (29-b) 290.0mg to the next step directly;

将2-(4-氟-2-甲基苯氧基)-6-甲基烟酸(29-b)(140.0mg,0.5mmol)，间氨基苯甲腈(59.2mg,0.5mmol)溶于吡啶(4mL)中，在0℃下缓慢滴加三氯氧磷(0.1mL,1.0mmol),控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N稀盐酸调pH 2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，蒸干，用乙酸乙酯重结晶得化合物(II-A-23)(150.0mg，收率78.9％)。1H-NMR(400MHz,DMSO-d6)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。Dissolve 2-(4-fluoro-2-methylphenoxy)-6-methylnicotinic acid (29-b) (140.0mg, 0.5mmol), m-aminobenzonitrile (59.2mg, 0.5mmol) in In pyridine (4mL), slowly drop phosphorus oxychloride (0.1mL, 1.0mmol) at 0°C, control the temperature below 10°C, after the dropwise addition is complete, continue the reaction until the raw materials are completely reacted, then pour the reaction system into In ice water, use 2N dilute hydrochloric acid to adjust the pH to about 2~3, extract with ethyl acetate, dry over anhydrous sodium sulfate, evaporate to dryness, and recrystallize with ethyl acetate to obtain compound (II-A-23) (150.0 mg, yield 78.9%). 1 H-NMR (400MHz,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.

第三步：将N-(3-氰基苯基)-5-氟-(4-氟-2-甲基苯氧基)-6-甲基烟酰胺(II-A-23)(100.0mg,0.25mmol)和无水乙醇(0.2mL)加入到盐酸-乙酸乙酯体系(10N,10.0mL)中，室温下封管反应。待反应完全生成中间体后将反应体系浓缩。随后加入氨-甲醇溶液(7N，5.0mL),氯化铵(27.0mg,0.5mmol)，于回流反应直到中间体反应完全。随后直接浓缩得粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-29)(32mg,收率30.7％)。1H-NMR(400MHz,DMSO-d6)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。The third step: N-(3-cyanophenyl)-5-fluoro-(4-fluoro-2-methylphenoxy)-6-methylnicotinamide (II-A-23) (100.0mg , 0.25mmol) and absolute ethanol (0.2mL) were added to hydrochloric acid-ethyl acetate system (10N, 10.0mL), and the reaction was sealed at room temperature. The reaction system was concentrated after the intermediate was completely generated in the reaction. Then ammonia-methanol solution (7N, 5.0mL) and ammonium chloride (27.0mg, 0.5mmol) were added, and the mixture was refluxed until the intermediate was completely reacted. Subsequent direct concentration gave the crude product. The crude product was passed through a silica gel column (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 (400MHz,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.

实施例30 N-(3-氨基甲酰苯基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酰胺(I-30)的制备
Example 30 N-(3-carbamoylphenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (I-30 ) preparation

第一步：将6-溴-2-氟-3-(三氟甲基)苯甲酸(30-SM1)(628.0mg,2.2mmol)，间氨基苯甲腈(272.0mg,2.3mmol)溶于吡啶(3.5mL)中，在0℃下缓慢滴加三氯氧磷(0.4mL，4.4mmol),控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N盐酸调节pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，蒸干得粗品。粗品用石油醚：乙酸乙酯＝10：1(v/v)过硅胶柱(200～300目)得化合物(30-a)(430.0mg,收率50.6％)。1H-NMR(400MHz,CDCl3)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)。The first step: Dissolve 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (30-SM1) (628.0mg, 2.2mmol), m-aminobenzonitrile (272.0mg, 2.3mmol) in In pyridine (3.5mL), slowly add phosphorus oxychloride (0.4mL, 4.4mmol) dropwise at 0°C, control the temperature below 10°C, after the dropwise addition is complete, continue the reaction until the raw materials are completely reacted, then pour the reaction system into 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 a crude product. The crude product was passed through a 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).

第二步：将30-a(200.0mg，0.52mmol)，4-氟-2-甲基苯酚(1-SM2)(78.2mg,0.62mmol)，碳酸铯(336.0mg,2.0mmol)，碘化亚铜(9.0mg,0.05mmol)加入到甲苯(10.0mL)中，在100℃下回流反应。反应完全后，用2N稀盐酸调节pH值至2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：乙酸乙酯＝8：1(v/v)过硅胶柱(200～300目)得化合物(II-A-24)(90.0mg,收率67％)。1H-NMR(400MHz,DMSO-d6)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。The second step: 30-a (200.0mg, 0.52mmol), 4-fluoro-2-methylphenol (1-SM2) (78.2mg, 0.62mmol), cesium carbonate (336.0mg, 2.0mmol), iodide Cuprous (9.0mg, 0.05mmol) was added into toluene (10.0mL), and the reaction was refluxed 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 a crude product. The crude product was passed through a 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.

第三步：将N-(3-氰基苯基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酰胺(II-A-24)(90.0mg,0.21mmol)和无水乙醇(0.1mL)加入到盐酸-乙酸乙酯体系(10N,10.0mL)中，室温下封管反应。待反应完全生成中间体后将反应体系蒸干，随后加入氨-甲醇溶液(7N，8.0mL),氯化铵(23.0mg,1.4mmol)，于回流反应直到中间体反应完全。随后直接浓缩得粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-30)(30.0mg,收率30％)。1H-NMR(600MHz,DMSO-d6)δ:11.34(s,1H),9.41(s,1.5H),9.07(s,1.5H),8.24(s,1H),7.91(d,J＝7.8Hz,1H),7.81(t,J＝9.0Hz,1H),7.63(t,J＝7.8Hz,1H),7.52(d,J＝7.8Hz,1H),7.27～7.29(dd,J＝9.0,3.0Hz,1H),7.23～7.25(q,1H),7.15～7.18(td,J＝8.4,3.0Hz,1H),6.61(d,J＝9.0Hz,1H),2.14(s,3H)；MS(ESI)m/z[M+H]+＝450.1。The third step: N-(3-cyanophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (II- A-24) (90.0mg, 0.21mmol) and absolute ethanol (0.1mL) were added to hydrochloric acid-ethyl acetate system (10N, 10.0mL), and the reaction was blocked at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, then ammonia-methanol solution (7N, 8.0mL) and ammonium chloride (23.0mg, 1.4mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted. Subsequent direct concentration gave the crude product. The crude product was passed through a silica gel column (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= 7.8Hz, 1H), 7.81(t, J=9.0Hz, 1H), 7.63(t, J=7.8Hz, 1H), 7.52(d, J=7.8Hz, 1H), 7.27～7.29(dd, J= 9.0, 3.0Hz, 1H), 7.23～7.25(q, 1H), 7.15～7.18(td, J＝8.4, 3.0Hz, 1H), 6.61(d, J＝9.0Hz, 1H), 2.14(s, 3H ); MS (ESI) m/z [M+H] + = 450.1.

实施例31 N-(3-氨基甲酰亚胺酰基苯基)(4-氟-2-甲基苯氧基)-烟酰胺(I-31)的制备 Example 31 Preparation of N-(3-carbamoimidoylphenyl)(4-fluoro-2-methylphenoxy)-nicotinamide (I-31)

第一步：将2-氯烟酸(31-SM1)(3.0g,19.04mmol)，间氨基苯甲腈(2.25g,19.04mmol)溶于吡啶(20.0mL)中，在0℃下缓慢滴加三氯氧磷(3.55mL,38.08mmol),控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N稀盐酸调pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用乙酸乙酯重结晶得2-氯-N-(3-苯腈)烟酰胺(31-a)(301mg，收率6.13％)。1H-NMR(400MHz,DMSO-d6)δ:11.02(s,1H),8.57(dd,J＝4.8,1.9Hz,1H),8.19～8.17(m,1H),8.13(dd,J＝7.6,1.9Hz,1H),7.92(dt,J＝6.7,2.4Hz,1H),7.65～7.57(m,3H)；MS(ESI)m/z[M+H]+＝257.8。Step 1: Dissolve 2-chloronicotinic acid (31-SM1) (3.0g, 19.04mmol), m-aminobenzonitrile (2.25g, 19.04mmol) in pyridine (20.0mL), drop slowly at 0°C Add phosphorus oxychloride (3.55mL, 38.08mmol), control the temperature below 10°C, and continue the reaction until the raw materials are completely reacted, then pour the reaction system into ice water, and adjust the pH value to 2 with 2N dilute hydrochloric acid. ~3 or so, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product was 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, 1.9Hz, 1H), 8.19～8.17(m, 1H), 8.13(dd, J= 7.6, 1.9Hz, 1H), 7.92 (dt, J = 6.7, 2.4Hz, 1H), 7.65-7.57 (m, 3H); MS (ESI) m/z [M+H]+ = 257.8.

第二步：将2-氯-N-(3-苯腈)烟酰胺(31-a)(250.0mg，0.97m mmol)，4-氟-2-甲基苯酚(122.4mg,0.97mmol)，碳酸铯(632.2mg,1.94mmol)，碘化亚铜(1.85mg,0.0097mmol)加入到甲苯(6.0mL)中，100℃回流反应。反应完全后，用2N稀盐酸调节pH值至2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：乙酸乙酯＝20：1(v/v)过硅胶柱(200～300目)得N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)-烟酰胺(II-A-25)(158mg,收率46.89％)。1H-NMR(400MHz,DMSO-d6)δ:10.82(s,1H),8.22(dd,J＝4.8,2.0Hz,2H),8.13(dd,J＝7.4,2.0Hz,1H),7.97(q,J＝4.8,4.0Hz,1H),7.62～7.57(m,2H),7.25(ddd,J＝13.8,8.1,5.0Hz,2H),7.16(dd,J＝9.4,3.2Hz,1H),7.08(td,J＝8.6,3.2Hz,1H),2.07(s,3H)；MS(ESI)m/z[M+H]+＝347.8。The second step: 2-chloro-N-(3-benzonitrile)nicotinamide (31-a) (250.0mg, 0.97mmol), 4-fluoro-2-methylphenol (122.4mg, 0.97mmol), Cesium carbonate (632.2mg, 1.94mmol) and cuprous iodide (1.85mg, 0.0097mmol) were added to toluene (6.0mL) and refluxed 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 a crude product. Use petroleum ether for the crude product: ethyl acetate = 20:1 (v/v) to pass through a silica gel column (200-300 mesh) to obtain N-(3-cyanophenyl)-2-(4-fluoro-2-methylbenzene Oxy)-nicotinamide (II-A-25) (158 mg, yield 46.89%). 1 H-NMR (400MHz, DMSO-d 6 )δ: 10.82(s, 1H), 8.22(dd, J=4.8, 2.0Hz, 2H), 8.13(dd, J=7.4, 2.0Hz, 1H), 7.97 (q,J=4.8,4.0Hz,1H),7.62～7.57(m,2H),7.25(ddd,J=13.8,8.1,5.0Hz,2H),7.16(dd,J=9.4,3.2Hz,1H ), 7.08 (td, J = 8.6, 3.2 Hz, 1H), 2.07 (s, 3H); MS (ESI) m/z [M+H]+ = 347.8.

第三步：将N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)-烟酰胺(II-A-25)(100.0mg,0.2mmol)和无水乙醇(0.2mL)加入到盐酸-乙酸乙酯体系(10N,10.0mL)中，于室温下封管反应。待反应完全生成中间体后将反应体系蒸干，加入氨-甲醇溶液(7N，5.0mL),氯化铵(21mg,0.4mmol)，于回流反应直到中间体反应完全。随后直接浓缩得粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-31)(34mg,收率48.4％)。1H-NMR(400MHz,DMSO-d6)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。The third step: N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-nicotinamide (II-A-25) (100.0mg, 0.2mmol) and no Water ethanol (0.2 mL) was added to hydrochloric acid-ethyl acetate system (10N, 10.0 mL), and the reaction was sealed at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, ammonia-methanol solution (7N, 5.0mL) and ammonium chloride (21mg, 0.4mmol) were added, and the reaction was carried out under reflux until the intermediate was completely reacted. Subsequent direct concentration gave the crude product. The crude product was passed through a 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%). 1 H-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.

实施例32甲基((3-(2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰氨基)苯基)(亚氨基)甲基)氨基甲酸甲酯(I-32)的制备Example 32 Methyl ((3-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamido)phenyl)(imino)methyl)amino Preparation of methyl formate (I-32)

将实施例3得到的N-(3-氨基甲酰亚胺酰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-3)(215mg,0.5mmol)溶于四氢呋喃(10.0mL),冷却到0℃左右加入氢氧化钠(10N,74.76mmL),随后缓慢加入氯甲酸甲酯(56.5mg,0.6mmol)于室温下反应直到原料反应完全。再用乙酸乙酯萃取。有机相干燥，浓缩得粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-32)(160.0mg,收率65.6％)。1H-NMR(400MHz,DMSO-d6)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。N-(3-aminocarboximidoylphenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I -3) (215mg, 0.5mmol) was dissolved in tetrahydrofuran (10.0mL), cooled to about 0°C and added sodium hydroxide (10N, 74.76mmL), then slowly added methyl chloroformate (56.5mg, 0.6mmol) at room temperature React until the raw material is completely reacted. Then extract with ethyl acetate. The organic phase was dried and concentrated to give the crude product. The crude product was passed through a 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.

实施例33 N-(3-氨基甲酰亚胺酰基苯基)甲基((3-(2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰氨基)苯基)(亚氨基)甲基)氨基甲酸乙酯(I-33)的制备Example 33 N-(3-carbamoimidoylphenyl)methyl ((3-(2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzene Preparation of amido) phenyl) (imino) methyl) ethyl carbamate (I-33)

将实施例3得到的N-(3-氨基甲酰亚胺酰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-3)(215.0mg,0.5mmol)溶于四氢呋喃(10.0mL),冷却到0℃左右加入氢氧化钠(10N,74.8mmL),随后缓慢加入氯甲酸乙酯(64.8mg,0.6mmol)于室温下反应直到原料反应完全。再用乙酸乙酯萃取，有机相干燥，浓缩得粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-33)(70mg,收率27.9％)。1H-NMR(400MHz,DMSO-d6)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。N-(3-aminocarboximidoylphenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I -3) (215.0mg, 0.5mmol) was dissolved in tetrahydrofuran (10.0mL), cooled to about 0°C and added sodium hydroxide (10N, 74.8mmL), then slowly added ethyl chloroformate (64.8mg, 0.6mmol) at room temperature Lower the reaction until the raw material is completely reacted. Then extracted with ethyl acetate, 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 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.

实施例34 N-(3-氨基甲酰亚胺酰基苯基)-5-氯-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-34)的制备Example 34 N-(3-carbamoimidoylphenyl)-5-chloro-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide ( I-34) Preparation

第一步：将5-氯-2-氟-4-(三氟甲基)苯甲酸(34-SM1)(485.0mg,2.0mmol)，间氨基苯甲腈(268.3mg,20mmol)溶于吡啶(6.0mL)中，在0℃下缓慢滴加三氯氧磷(0.38mL，4.0mmol),控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N盐酸调节pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩析出固体得到类白色5-氯-N-(3-氰基苯基)-2-氟-4-(三氟甲基)苯甲酰胺(34-a)(469.0mg,收率58.3％)。1H-NMR(400MHz,DMSO-d6)δ:11.04(s,1H),8.17(s,1H),8.12(d,J＝8.4Hz,1H),8.05(d,J＝14.4Hz,1H),7.91～7.94(dt,J＝10.8,2.4Hz,1H),7.64(s,1H),7.60(q,1H)；MS(ESI)m/z[M+H]+＝343.1。Step 1: Dissolve 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (34-SM1) (485.0mg, 2.0mmol), m-aminobenzonitrile (268.3mg, 20mmol) in pyridine (6.0mL), slowly drop phosphorus oxychloride (0.38mL, 4.0mmol) at 0°C, control the temperature below 10°C, after the dropwise addition is complete, continue the reaction until the raw materials are completely reacted, then pour the reaction system into In ice water, use 2N hydrochloric acid to adjust the pH value to about 2~3, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate and precipitate the 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=8.4Hz, 1H), 8.05(d, J=14.4Hz, 1H ), 7.91～7.94 (dt, J=10.8, 2.4Hz, 1H), 7.64 (s, 1H), 7.60 (q, 1H); MS (ESI) m/z[M+H] + =343.1.

第二步：将5-氯-N-(3-氰基苯基)-2-氟-4-(三氟甲基)苯甲酰胺(34-a)(342.0mg，1.0mmol),4-氟-2甲基苯酚(140.0mg,1.1mmol)和碳酸铯(651.0mg,2.0mmol)加入到N,N-二甲基甲酰胺(7.0mL)中，在100℃下反应。待反应完全后，用2N稀盐酸调节pH值至2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝10:1(v/v)过硅胶柱(200～300目)得5-氯-N-(3-氰基苯基)-2-(4-氟-3-甲氧基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-26)(380.0mg，收率84.8％)。1H-NMR(400MHz,DMSO-d6)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＝8.8Hz,1H),7.05～7.09(q,3H),2.13(s,3H)；MS(ESI)m/z[M+H]+＝448.8.。The second step: 5-chloro-N-(3-cyanophenyl)-2-fluoro-4-(trifluoromethyl)benzamide (34-a) (342.0mg, 1.0mmol), 4- Fluoro-2-methylphenol (140.0 mg, 1.1 mmol) and cesium carbonate (651.0 mg, 2.0 mmol) were added to N,N-dimethylformamide (7.0 mL), and reacted 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 a crude product. Use petroleum ether for the crude product: ethyl acetate = 10:1 (v/v) to pass through a silica gel column (200-300 mesh) 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 H-NMR(400MHz,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 = 8.8Hz, 1H), 7.05~7.09 (q, 3H), 2.13 (s, 3H); MS (ESI) m/z [M+H] + = 448.8.

第三步：将5-氯-N-(3-氰基苯基)-2-(4-氟-3-甲氧基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-26)(224.0mg,0.5mmol)，无水乙醇(0.2mL)加入到盐酸-乙酸乙酯体系(10N,10.0mL)中，室温下封管反应。待反应完全生成中间体后将反应体系蒸干，加入氨-甲醇溶液(4N，10mL),氯化铵(54.0mg,1mmol)，于回流反应直到中间体反应完全，随后浓缩得粗品。粗 品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-34)(120.0mg,收率51.6％)；1H-NMR(400MHz,DMSO-d6)δ:11.06(brs,1H),8.20(s,1H),8.03(s,1H),7.99(d,J＝8.0Hz,1H),7.61(t,J＝8.0Hz,1H),7.49(d,J＝8.0Hz,1H),7.23(dd,J＝9.6,3.2Hz,1H),7.11～7.17(m,2H),7.05(s,1H),2.17(s,3H)；MS(ESI)m/z[M+H]+＝465.9。The third step: 5-chloro-N-(3-cyanophenyl)-2-(4-fluoro-3-methoxyphenoxy)-4-(trifluoromethyl)benzamide (II -A-26) (224.0mg, 0.5mmol), absolute ethanol (0.2mL) were added to hydrochloric acid-ethyl acetate system (10N, 10.0mL), and the reaction was sealed at room temperature. After the reaction was complete to generate the intermediate, the reaction system was evaporated to dryness, ammonia-methanol solution (4N, 10mL) and ammonium chloride (54.0mg, 1mmol) were added, and the mixture was refluxed until the intermediate was completely reacted, then concentrated to obtain the crude product. thick Product used dichloromethane:methanol=20～15:1 (v/v) through a silica gel column (200～300 mesh) to obtain the target compound (I-34) (120.0mg, yield 51.6%); 1 H-NMR ( 400MHz,DMSO-d 6 )δ:11.06(brs,1H),8.20(s,1H),8.03(s,1H),7.99(d,J＝8.0Hz,1H),7.61(t,J＝8.0Hz ,1H),7.49(d,J＝8.0Hz,1H),7.23(dd,J＝9.6,3.2Hz,1H),7.11～7.17(m,2H),7.05(s,1H),2.17(s, 3H); MS (ESI) m/z [M+H] + = 465.9.

实施例35 N-(3-(N-氰基氨基甲酰亚胺酰基)苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-35)的制备Example 35 N-(3-(N-cyanocarbamoimidoyl)phenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzene Preparation of Amide (I-35)

将实施例1得到的N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-1)(115.0mg,0.25mmol)，无水乙醇(0.2mL)加入到盐酸-乙酸乙酯体系(10N,10.0mL)中，于室温下封管反应。待反应完全生成中间体后将反应体系蒸干的残留物，将残留物溶于乙醇中，随后加入50％氰胺水溶液(0.21mL)反应回流直到中间体反应完全，随后加入氨-甲醇溶液(4N，10.0mL),继续于回流反应。反应完全后浓缩得粗品。粗品用石油醚：乙酸乙酯＝4～2：1(v/v)过硅胶柱(200～300目)得N-(3-(N-氰基氨基甲酰亚胺酰基)苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-35)(43.0mg，收率37.7％)；1H-NMR(400MHz,DMSO-d6)δ:10.75(s,1H),8.69(brs,1H),8.24(brs,1H),7.85(d,J＝7.6Hz,2H),7.60(d,J＝7.6Hz,2H),7.48(t,1H),7.21(d,J＝8.8Hz,1H),7.11(d,J＝7.2Hz,2H),6.95(s,1H),6.21(brs,1H),2.16(s,3H)；MS(ESI)m/z[M+H]+＝456.9。N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-1) obtained in Example 1 ) (115.0mg, 0.25mmol), absolute ethanol (0.2mL) were added to hydrochloric acid-ethyl acetate system (10N, 10.0mL), and the reaction was sealed at room temperature. After the reaction is complete to generate the intermediate, the reaction system is evaporated to dryness, the residue is dissolved in ethanol, then 50% cyanamide aqueous solution (0.21 mL) is added and the reaction is refluxed until the intermediate is completely reacted, then ammonia-methanol solution ( 4N, 10.0mL), continue to reflux reaction. After the reaction was complete, it was concentrated to obtain a crude product. Use petroleum ether for the crude product: ethyl acetate = 4~2:1 (v/v) to pass through a silica gel column (200~300 mesh) to obtain N-(3-(N-cyanocarbimidoyl)phenyl)- 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-35) (43.0mg, yield 37.7%); 1 H-NMR (400MHz, DMSO -d6)δ:10.75(s,1H),8.69(brs,1H),8.24(brs,1H),7.85(d,J=7.6Hz,2H),7.60(d,J=7.6Hz,2H), 7.48(t,1H),7.21(d,J=8.8Hz,1H),7.11(d,J=7.2Hz,2H),6.95(s,1H),6.21(brs,1H),2.16(s,3H ); MS (ESI) m/z [M+H] + = 456.9.

实施例36 2-(4-氟-2-甲基苯氧基)-N-(3-(N-甲酰基氨基甲酰亚胺酰基)苯基)-4-(三氟甲基)苯甲酰胺(I-36)的制备Example 36 2-(4-fluoro-2-methylphenoxy)-N-(3-(N-formylcarbaimidoyl)phenyl)-4-(trifluoromethyl)benzidine Preparation of Amide (I-36)

将实施例3得到的N-(3-氨基甲酰亚胺酰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-3)(43.0mg,0.01mmol)溶于乙腈(5.0mL),随后加入甲酸(13.8mg,0.03mmol)和锌粉(1.3mg,0.2eq)反应回流直到完全澄清。再用乙酸乙酯萃取，有机相干燥，浓缩得粗品。粗品用二氯甲烷：甲醇＝20：1(v/v)过硅胶柱(200～300目)得目标化合物(I-36)(45.0mg,收率98％)。1H-NMR(400MHz,DMSO-d6)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。N-(3-aminocarboximidoylphenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I -3) (43.0mg, 0.01mmol) was dissolved in acetonitrile (5.0mL), then formic acid (13.8mg, 0.03mmol) and zinc powder (1.3mg, 0.2eq) were added and the reaction was refluxed until completely clarified. Then extracted with ethyl acetate, 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 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.

实施例37 N-(2-氨基甲酰吡啶-4-基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-37)的制备Example 37 N-(2-carbamoylpyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-37) preparation of

将实施例4得到的2-(4-氟-2-甲基苯氧基)-N-(2-(N-羟基氨基甲酰氨基)吡啶-4-基)-4-(三氟甲基)苯甲酰胺(I-4)(112.0mg,0.25mmol)溶于甲醇(10.0mL)中，随后加入甲酸铵(157.0mg,2.5mmol)和用0.5N稀盐酸、丙酮洗涤,干燥的新制镁粉(60.0mg,2.5mmol)于40℃反应直到原料反应完全,再用乙酸乙酯萃取，有机相干燥，浓缩得粗品。粗品用二氯甲烷：甲醇＝20:1(v/v)过硅胶柱(200～300目)得目标化合物(I-37)(20.0mg,收率18.5％)。1H-NMR(400MHz,DMSO-d6)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。2-(4-fluoro-2-methylphenoxy)-N-(2-(N-hydroxycarbamoylamino)pyridin-4-yl)-4-(trifluoromethyl) obtained in Example 4 ) benzamide (I-4) (112.0mg, 0.25mmol) was dissolved in methanol (10.0mL), then ammonium formate (157.0mg, 2.5mmol) was added and washed with 0.5N dilute hydrochloric acid, acetone, dried fresh magnesium The powder (60.0mg, 2.5mmol) was reacted at 40°C until the raw material was completely reacted, then extracted with ethyl acetate, the organic phase was dried and concentrated to obtain a crude product. The crude product was passed through a 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.

实施例38 N-(3-氨基甲酰苯基)-2-(2-环丙基-4-氟苯氧基)-4-(三氟甲基)苯甲酰胺的合成(I-38)的制备Example 38 Synthesis of N-(3-carbamoylphenyl)-2-(2-cyclopropyl-4-fluorophenoxy)-4-(trifluoromethyl)benzamide (I-38) preparation of

第一步：将2-溴-4-氟苯酚(1.33g,6.96mmol)、磷酸钾(5.12g,24.4mmol)、三环己基膦(218.2mg,0.696mmol)、环丙基硼酸(897.0mg,10.4mmol)，加入甲苯(30.0mL)、水(1.5mL)混合液中,氩气置换3次。加入醋酸钯(78.1mg,0.35mmol),氩气置换3次，100℃回流反应16h。反应完全后用乙酸乙酯萃取，无水硫酸钠干燥乙酸乙酯相，浓缩得粗品。粗品用石油醚过硅胶柱(200～300目)得2-环丙基-4-氟苯酚(38-a)(943.0mg,收率89.0％)。1H-NMR(400MHz,CDCl3)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。The first step: 2-bromo-4-fluorophenol (1.33g, 6.96mmol), potassium phosphate (5.12g, 24.4mmol), tricyclohexylphosphine (218.2mg, 0.696mmol), cyclopropylboronic acid (897.0mg , 10.4mmol), added toluene (30.0mL), water (1.5mL) mixture, argon replacement 3 times. Palladium acetate (78.1mg, 0.35mmol) was added, argon was replaced three times, and the reaction was refluxed at 100°C for 16h. After the reaction was complete, it was extracted with ethyl acetate, and the ethyl acetate phase was dried over anhydrous sodium sulfate and concentrated to obtain a crude product. The crude product was passed 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 (400MHz, 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.

第二步：将N-(3-苯腈)-2-氟-4-(三氟甲基)苯甲酰胺(9-a)(1.0g,3.24mmol)、2-环丙基-4-氟苯酚(38-a)(518.4mg，3.41mmol)、碳酸铯(2.11g,6.49mmol)加入到N,N-二甲基甲酰胺(10.0mL)中,100℃反应。反应完全后，加入水，用2N盐酸调节pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：乙酸乙酯＝40：1(v/v)过柱得N-(3-苯腈)-2-(2-环丙基-4-氟苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-27)(840.0mg,收率58.8％)。1H-NMR(400MHz,DMSO-d6)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。The second step: N-(3-benzonitrile)-2-fluoro-4-(trifluoromethyl)benzamide (9-a) (1.0g, 3.24mmol), 2-cyclopropyl-4- Fluorophenol (38-a) (518.4mg, 3.41mmol) and cesium carbonate (2.11g, 6.49mmol) were added to N,N-dimethylformamide (10.0mL) and reacted 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 a crude product. Petroleum ether: ethyl acetate = 40:1 (v/v) for the crude product was passed through the column to obtain N-(3-benzonitrile)-2-(2-cyclopropyl-4-fluorophenoxy)-4-(tri Fluoromethyl)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.

第三步：将N-(3-苯腈)-2-(2-环丙基-4-氟苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-27)(200.0mg,0.454mmol)，无水乙醇(2.6mL)加入到盐酸-乙酸乙酯体系(10N,7.0mL)中，于室温下封管反应。待反应完全后浓缩得中间体直接下一步。中间体加入无水甲醇(4.0mL),氨-甲醇溶液(5.0mL),2eq氯化铵，于回流反应直到中间体完全反应。反应完全后直接浓缩得粗品，粗品用二氯甲烷：甲醇＝20:1(v/v)过硅胶柱(200～300目)得目标化合物(I-38),(91mg收率43.8％)。1H-NMR(400MHz,DMSO-d6)δ:11.03(s,1H),9.41(s,2H),9.29(s,2H),8.28(s,1H),7.92(d,J＝8.0Hz,1H),7.84(d,J＝8.0Hz,1H),7.65～7.56(m,2H),7.51(d,J＝8.0Hz,1H),7.22(dd,J＝9.0,5.1Hz,1H),7.08(td,J＝8.4,3.0Hz,1H),6.86(q,J＝3.6Hz,2H),2.02～1.97(m,1H),0.86～0.80(m,2H),0.69(d,J＝5.4Hz,2H)；MS(ESI)m/z[M+H]+＝458.0。The third step: N-(3-benzonitrile)-2-(2-cyclopropyl-4-fluorophenoxy)-4-(trifluoromethyl)benzamide (II-A-27)( 200.0mg, 0.454mmol), absolute ethanol (2.6mL) was added to hydrochloric acid-ethyl acetate system (10N, 7.0mL), and the reaction was sealed at room temperature. After the reaction is complete, the intermediate is concentrated to the next step. Add anhydrous methanol (4.0mL), ammonia-methanol solution (5.0mL), 2eq ammonium chloride to the intermediate, and react under reflux until the intermediate is completely reacted. After the reaction was complete, the crude product was concentrated directly to obtain the crude product, which was passed through a silica gel column (200-300 mesh) with dichloromethane:methanol=20:1 (v/v) 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＝8.0Hz ,1H),7.84(d,J=8.0Hz,1H),7.65～7.56(m,2H),7.51(d,J=8.0Hz,1H),7.22(dd,J=9.0,5.1Hz,1H) ,7.08(td,J＝8.4,3.0Hz,1H),6.86(q,J＝3.6Hz,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.

实施例39 N-(3-氨基甲酰苯基)-2-(4-氟-2-甲基苯氧基)-4,5-二甲氧基苯甲酰胺(I-39)的制备Example 39 Preparation of N-(3-carbamoylphenyl)-2-(4-fluoro-2-methylphenoxy)-4,5-dimethoxybenzamide (I-39)

第一步：将2-溴-4,5-二甲氧基苯甲酸(3.0g,11.5mmol),间氨基苯甲腈(1.43g,12.1mmol)溶于吡啶(8.0mL)中，在0℃下缓慢滴加三氯氧磷(2.14mL，23mmol),控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N 盐酸调节pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩得2-溴-N-(3-氰基苯基)-4,5-二甲氧基苯甲酰胺(39-a)粗品3.2g，直接下一步。MS(ESI)m/z[M+H]+＝362.9The first step: 2-bromo-4,5-dimethoxybenzoic acid (3.0g, 11.5mmol), m-aminobenzonitrile (1.43g, 12.1mmol) were dissolved in pyridine (8.0mL), at 0 Slowly add phosphorus oxychloride (2.14mL, 23mmol) dropwise at ℃, control the temperature below 10℃, continue the reaction until the raw materials are completely reacted, then pour the reaction system into ice water, and use 2N Adjust the pH value to about 2-3 with hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain 2-bromo-N-(3-cyanophenyl)-4,5-dimethoxybenzamide (39-a) 3.2g of crude product, directly to the next step. MS (ESI) m/z [M+H] + = 362.9

第二步：将2-溴-N-(3-氰基苯基)-4,5-二甲氧基苯甲酰胺(39-a)(3.0g，8.31mmol)，4-氟-2-甲基苯酚(1.1g,8.72mmol)，碳酸铯(5.4g,16.6mmol)，碘化亚铜(15.8mg,0.083mmol)溶于N,N-二甲基甲酰胺(10mL)中，在80℃下反应。反应结束后，用2N稀盐酸调节pH值至2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：二氯甲烷＝1:1(v/v)过硅胶柱(200～300目)得N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4,5-二甲氧基苯甲酰胺(II-A-28)(832mg，收率为24.6％)。1H-NMR(400MHz,DMSO-d6)δ:10.42(s,1H),8.04(d,J＝8.1Hz,1H),7.83(d,J＝6.7Hz,1H),7.54～7.46(m,2H),7.27(dd,J＝8.0,3.2Hz,1H),7.06(d,J＝9.2Hz,1H),6.94(d,J＝9.2Hz,1H),6.70(td,J＝9.0,4.6Hz,1H),6.62(dd,J＝8.0,3.2Hz,1H),3.81(s,3H),3.72(s,3H),2.22(s,3H)；MS(ESI)m/z[M+H]+＝407.0。The second step: 2-bromo-N-(3-cyanophenyl)-4,5-dimethoxybenzamide (39-a) (3.0g, 8.31mmol), 4-fluoro-2- Methylphenol (1.1g, 8.72mmol), cesium carbonate (5.4g, 16.6mmol), cuprous iodide (15.8mg, 0.083mmol) were dissolved in N,N-dimethylformamide (10mL), at 80 Reaction at ℃. After the reaction, 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 a crude product. Petroleum ether for crude product: dichloromethane = 1:1 (v/v) through a silica gel column (200-300 mesh) to obtain N-(3-cyanophenyl)-2-(4-fluoro-2-methylbenzene Oxy)-4,5-dimethoxybenzamide (II-A-28) (832 mg, yield 24.6%). 1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.42(s, 1H), 8.04(d, J=8.1Hz, 1H), 7.83(d, J=6.7Hz, 1H), 7.54～7.46(m ,2H),7.27(dd,J=8.0,3.2Hz,1H),7.06(d,J=9.2Hz,1H),6.94(d,J=9.2Hz,1H),6.70(td,J=9.0, 4.6Hz,1H),6.62(dd,J＝8.0,3.2Hz,1H),3.81(s,3H),3.72(s,3H),2.22(s,3H); MS(ESI)m/z[M +H] + = 407.0.

第三步：将N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4,5-二甲氧基苯甲酰胺(II-A-28)(200.0mg,0.492mmol)，无水乙醇(2.0mL)加入到盐酸-乙酸乙酯体系(10N,6.0mL)中，室温下封管反应。待原料反应完全后将反应体系蒸干的中间体粗品，随后加入无水甲醇(3.0mL),氨-甲醇溶液(5.0mL),2eq氯化铵于回流反应直到中间体转化完全。反应完全后浓缩得粗品。粗品用二氯甲烷：甲醇＝20：1(v/v)过硅胶柱(200～300目)得目标化合物(I-39)(93mg，收率44.6％)。1H-NMR(400MHz,DMSO-d6)δ:10.43(s,1H),9.35(s,2H),9.06(s,2H),8.33(s,1H),8.19(t,J＝2.0Hz,1H),7.83(d,J＝8.8Hz,1H),7.56(t,J＝8.0Hz,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。The third step: N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4,5-dimethoxybenzamide (II-A-28) (200.0mg, 0.492mmol), absolute ethanol (2.0mL) were added to hydrochloric acid-ethyl acetate system (10N, 6.0mL), and the reaction was sealed at room temperature. After the reaction of the raw materials was complete, the reaction system was evaporated to dryness to obtain the crude intermediate, and then anhydrous methanol (3.0 mL), ammonia-methanol solution (5.0 mL), and 2 eq ammonium chloride were added to react under reflux until the conversion of the intermediate was complete. After the reaction was complete, it was concentrated to obtain a crude product. The crude product was passed through a 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 H-NMR (400MHz,DMSO-d 6 )δ:10.43(s,1H),9.35(s,2H),9.06(s,2H),8.33(s,1H),8.19(t,J=2.0Hz ,1H),7.83(d,J＝8.8Hz,1H),7.56(t,J＝8.0Hz,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.

实施例40 N-(4-氨基甲酰亚胺酰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-40)的制备Example 40 N-(4-carbamoimidoylphenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-40) preparation of

第一步：干燥体系下，将实施例1得到的2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酸(1-b)(314.0mg,1.0mmol)，间氨基苯甲腈(0.4g,3.34mmol)加入到无水吡啶(4.0mL)中溶解，冷却到0℃左右，缓慢滴加三氯氧磷(0.5mL,5mmol)，控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N稀盐酸调pH值至2～3左右，再用二氯甲烷萃取。有机相干燥，浓缩得到N-(4-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(II-B-1)(295mg，收率71.3％)。1H-NMR(400MHz,CDCl3)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。The first step: under the drying system, the 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoic acid (1-b) (314.0mg, 1.0 mmol), m-aminobenzonitrile (0.4g, 3.34mmol) was added to anhydrous pyridine (4.0mL) to dissolve, cooled to about 0°C, slowly added dropwise phosphorus oxychloride (0.5mL, 5mmol), and the temperature was controlled at Below 10°C, the dropwise addition is completed, 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, and then extract with dichloromethane. The organic phase was dried and concentrated to give 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=8.8 Hz,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.

第二步：将N-(4-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(II-B-1)(250.0mg,0.6mmol)，无水乙醇(0.1mL)和氯化氢-乙酸乙酯体系(10N,20.0mL)加入到封管反应瓶中，于室温下反应直到原料完全转化为中间体，随后浓缩除去溶剂得粗品中间体，用二氯 甲烷：甲醇＝40:1(v/v)过硅胶柱(200～300目)得到相应的Pinner盐中间体163mg固体。1H-NMR(400MHz,CDCl3)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。The second step: N-(4-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-B-1) (250.0mg, 0.6mmol), absolute ethanol (0.1mL) and hydrogen chloride-ethyl acetate system (10N, 20.0mL) were added to a sealed reaction flask, reacted at room temperature until the raw material was completely converted into an intermediate, and then concentrated Remove the solvent to obtain the crude product intermediate, dichloro Methane:methanol=40:1 (v/v) was passed through a silica gel column (200-300 mesh) to obtain 163 mg of the corresponding Pinner salt intermediate as a solid. 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=8.4 Hz, 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 = 7.2 Hz, 3H); MS (ESI) m/z [M+H] + = 461.1.

将Pinner盐中间体(92.0mg,0.2mol)和氯化铵(20.8mg,0.4mmol)加入氨-甲醇体系(12mL)于回流下反应，浓缩得到粗品。粗品用二氯甲烷:甲醇＝20:1～15:1(v/v)过硅胶柱(200～300目)得到固体N-(4-氨基甲酰亚胺酰基苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-40)(45mg，收率47.4％)。1H-NMR(400MHz,DMSO-d6)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。Pinner's salt intermediate (92.0 mg, 0.2 mol) and ammonium chloride (20.8 mg, 0.4 mmol) were added into ammonia-methanol system (12 mL) to react under reflux, and concentrated to obtain a crude product. The crude product was passed through a silica gel column (200-300 mesh) with dichloromethane:methanol=20:1～15:1 (v/v) to obtain solid N-(4-carbamoimidoylphenyl)-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.

实施例41 N-(3-氨基甲脒酰基苯基)-2-(4-氟-2-甲基苯氧基)-4-甲氧基苯甲酰胺(I-41)的制备Example 41 Preparation of N-(3-aminocarbamidinoylphenyl)-2-(4-fluoro-2-methylphenoxy)-4-methoxybenzamide (I-41)

第一步：将2-溴-4-甲氧基苯甲酸(41-SM1)(300.0mg,1.30mmol),间氨基苯甲腈(153.4mg,1.30mmol)溶于吡啶(4.0mL)中，在0℃下缓慢滴加三氯氧磷(0.242mL,2.60mmol),控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N稀盐酸调pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：乙酸乙酯＝8：1(v/v)过硅胶柱(200～300目)分离纯化得2-溴-N-(3-氰基苯基)-4-甲氧基苯甲酰胺(41-a)(150mg，收率34.9％)。1H-NMR(400MHz,DMSO-d6)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。The first step: 2-bromo-4-methoxybenzoic acid (41-SM1) (300.0mg, 1.30mmol), m-aminobenzonitrile (153.4mg, 1.30mmol) were dissolved in pyridine (4.0mL), Phosphorus oxychloride (0.242mL, 2.60mmol) was slowly added dropwise at 0°C, and the temperature was controlled below 10°C. After the dropwise addition was completed, the reaction was continued until the reaction of the raw materials was complete, and then the reaction system was poured into ice water and diluted with 2N Adjust the pH value to about 2-3 with hydrochloric acid, extract with ethyl acetate, dry over anhydrous sodium sulfate, and concentrate to obtain a crude product. Use petroleum ether: ethyl acetate = 8:1 (v/v) to separate and purify the crude product through a silica gel column (200-300 mesh) to obtain 2-bromo-N-(3-cyanophenyl)-4-methoxybenzene Formamide (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.

第二步：将2-溴-N-(3-苯腈)-4-甲氧基苯甲酰胺(41-a)(250.0mg，0.755mmmol)，4-氟-2-甲基苯酚(95.2mg,0.755mmol)，碳酸铯(491.9mg,1.51mmol)，碘化亚铜(1.4mg,0.00755mmol)溶于甲苯(7.35mL)中，100℃回流反应。反应完全后，用2N稀盐酸调节pH值至2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝20：1(v/v)过硅胶柱(200～300目)得N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4-甲氧基苯甲酰胺(II-A-29)(239.0mg,收率84.1％)。1H-NMR(400MHz,DMSO-d6)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。The second step: 2-bromo-N-(3-benzonitrile)-4-methoxybenzamide (41-a) (250.0mg, 0.755mmmol), 4-fluoro-2-methylphenol (95.2 mg, 0.755mmol), cesium carbonate (491.9mg, 1.51mmol), cuprous iodide (1.4mg, 0.00755mmol) were dissolved in toluene (7.35mL), 100 ℃ reflux reaction. 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 a crude product. Use petroleum ether for the crude product: ethyl acetate = 20:1 (v/v) to pass through a silica gel column (200-300 mesh) to obtain N-(3-cyanophenyl)-2-(4-fluoro-2-methylbenzene Oxy)-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.

第三步：将N-(3-氰基苯基)-2-(4-氟-2-甲基苯氧基)-4-甲氧基苯甲酰胺(II-A-29)(100mg,0.27mmol)加入到无水乙醇(0.1mL)和盐酸-乙酸乙酯中(6mL)，室温下封管反应。反应完全后将反应体系蒸干，加入无水甲醇(3mL),氨-甲醇溶液(5mL),2eq氯化铵，于65℃下回流反应。待反应完全后浓缩得粗品。粗品用二氯甲烷：甲醇＝20:1(v/v)过硅胶柱(200～300目)得N-(3-氨基甲脒酰基苯基)-2-(4-氟-2-甲基苯氧基)-4-甲氧基苯甲酰胺(I-41)(35.0mg,收率 33.5％)。1H-NMR(400MHz,DMSO-d6)δ:10.49(s,1H),8.23(s,1H),7.90(d,J＝7.6Hz,1H),7.70(d,J＝8.4Hz,1H),7.56(t,J＝8.0Hz,1H),7.47(s,1H),7.20(d,J＝9.2Hz,1H),7.08(sd,2H),6.82(d,J＝8.4Hz,1H),6.18(s,1H),3.72(s,3H),2.18(s,3H)；MS(ESI)m/z[M+H]+＝393.8。The third step: N-(3-cyanophenyl)-2-(4-fluoro-2-methylphenoxy)-4-methoxybenzamide (II-A-29) (100mg, 0.27mmol) was added into absolute ethanol (0.1mL) and hydrochloric acid-ethyl acetate (6mL), and the reaction was sealed at room temperature. After the reaction was complete, the reaction system was evaporated to dryness, anhydrous methanol (3mL), ammonia-methanol solution (5mL), 2eq ammonium chloride were added, and the reaction was refluxed at 65°C. After the reaction was complete, it was concentrated to obtain a crude product. The crude product was passed through a silica gel column (200-300 mesh) with dichloromethane:methanol=20:1 (v/v) to obtain N-(3-aminocarbamidinoylphenyl)-2-(4-fluoro-2-methyl Phenoxy)-4-methoxybenzamide (I-41) (35.0mg, yield 33.5%). 1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.49(s, 1H), 8.23(s, 1H), 7.90(d, J=7.6Hz, 1H), 7.70(d, J=8.4Hz, 1H ),7.56(t,J=8.0Hz,1H),7.47(s,1H),7.20(d,J=9.2Hz,1H),7.08(sd,2H),6.82(d,J=8.4Hz,1H ), 6.18 (s, 1H), 3.72 (s, 3H), 2.18 (s, 3H); MS (ESI) m/z [M+H] + = 393.8.

实施例42 N-(2-(N-乙酰氨基甲脒酰基)吡啶-4-基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-42)的制备Example 42 N-(2-(N-acetylcarbamidinoyl)pyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzyl Preparation of Amide (I-42)

将2-(4-氟-2-甲基苯氧基)-N-(2-(N-羟基氨基甲酰氨基)吡啶-4-基)-4-(三氟甲基)苯甲酰胺(I-4)(112.0mg,0.25mmol)，乙酸酐(30.6mg,0.3mmol)和5％的钯/碳(10mg)加入到乙酸(5mL中，氮气置换3次，随后氢气置换3次再进行氢化直到原料完全转化，过滤，浓缩得到粗品。粗品用二氯甲烷:甲醇＝20:1～15:1(v/v)过硅胶柱(200～300目)得到N-(2-(N-乙酰氨基甲脒酰基)吡啶-4-基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-42)(45.0mg,收率38.9％)。1H-NMR(400MHz,DMSO-d6)δ:8.62(d,J＝5.6Hz,1H),8.47(s,1H),7.88(t,J＝8.0Hz,2H),7.62(d,J＝8.0Hz,1H),7.22(dd,J＝9.2,2.0Hz,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。2-(4-fluoro-2-methylphenoxy)-N-(2-(N-hydroxycarbamoylamino)pyridin-4-yl)-4-(trifluoromethyl)benzamide ( I-4) (112.0mg, 0.25mmol), acetic anhydride (30.6mg, 0.3mmol) and 5% palladium/carbon (10mg) were added to acetic acid (5mL, nitrogen replacement 3 times, followed by hydrogen replacement 3 times and then carried out Hydrogenate until the raw material is completely converted, filter, and concentrate to obtain the crude product. The crude product is passed through a silica gel column (200～300 mesh) with dichloromethane:methanol=20:1～15:1 (v/v) to obtain N-(2-(N- Acetamidocarbamidinoyl)pyridin-4-yl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I-42) (45.0mg, received 38.9%). 1 H-NMR (400MHz, DMSO-d 6 )δ: 8.62 (d, J = 5.6Hz, 1H), 8.47 (s, 1H), 7.88 (t, J = 8.0Hz, 2H), 7.62(d, J＝8.0Hz, 1H), 7.22(dd, J＝9.2, 2.0Hz, 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.

实施例43 N-(3-氨基甲脒酰基-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-43)的制备Example 43 N-(3-carbamidine-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I- 43) Preparation

第一步：N-(3-氰基-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-30)的合成The first step: N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A -30) synthesis

干燥体系下，将实施例1得到的2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酸(1-b)(628.0mg,2.0mmol)，4-氨基-2-氟苯腈(286.0mg，2.1mmol)加入到无水吡啶(3.0mL)中溶解，冷却到0℃左右，缓慢滴加三氯氧磷(0.4mL,4.1mmol)，控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N稀盐酸调pH值至2～3左右，再用二氯甲烷萃取。有机相干燥，浓缩得粗品。粗品用石油醚：乙酸乙酯＝10:1(v/v)过层析硅胶柱(200～300目)得到N-(3-氰基-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-30)(558.0mg，收率64.6％)。1H-NMR(400MHz,DMSO-d6)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。In a dry system, 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoic acid (1-b) (628.0mg, 2.0mmol) obtained in Example 1, 4 -Amino-2-fluorobenzonitrile (286.0mg, 2.1mmol) was added to anhydrous pyridine (3.0mL) to dissolve, cooled to about 0°C, and phosphorus oxychloride (0.4mL, 4.1mmol) was slowly added dropwise to control the temperature Below 10°C, the dropwise addition is completed, 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, and then extract with dichloromethane. The organic phase was dried and concentrated to give the crude product. Use petroleum ether for the crude product: ethyl acetate = 10:1 (v/v) to pass through a chromatographic silica gel column (200-300 mesh) to obtain N-(3-cyano-4-fluorophenyl)-2-(4-fluorophenyl) -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.

第二步：N-(3-氨基甲脒酰基-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(I-43)的合成The second step: N-(3-aminocarbamidinoyl-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (I -43) synthesis

将N-(3-氰基-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-30)(216mg,0.5mmol)，无水乙醇(0.3mL)加入到盐酸-乙酸乙酯体系(10N,10.0mL)中，室温下封管反应。待原料反应完全后将反应体系蒸干得到Pinner盐，随后加入无水甲醇(3.0mL),氨-甲醇溶液(7N,5.0mL),2eq氯化铵，于下回流反应直到中间体反应完全。反应完全后直接浓缩得粗品。粗品用二氯甲烷:甲醇＝20：1(v/v)过硅胶(200～300目)柱得目标化合物(I-43)(38mg，收 率16.9％)。1H-NMR(400MHz,DMSO-d6)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＝8.8Hz,1H)，7.49(t,J＝8.4Hz,1H),7.23(d,J＝8.4Hz,1H),7.11～7.15(m,2H),6.95(s,1H),2.16(s,3H)；MS(ESI)m/z[M+H]+＝450.1。N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (II-A-30) (216mg, 0.5mmol), absolute ethanol (0.3mL) were added to hydrochloric acid-ethyl acetate system (10N, 10.0mL), and the reaction was sealed at room temperature. After the reaction of the raw materials was complete, the reaction system was evaporated to dryness to obtain Pinner's salt, then anhydrous methanol (3.0 mL), ammonia-methanol solution (7N, 5.0 mL), and 2 eq ammonium chloride were added, and the mixture was refluxed until the intermediate was completely reacted. After the reaction was complete, it was directly concentrated to obtain the crude product. The crude product was passed through a silica gel (200-300 mesh) column with dichloromethane:methanol=20:1 (v/v) to obtain the target compound (I-43) (38 mg, yield rate of 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=8.8Hz, 1H), 7.49(t, J=8.4Hz, 1H), 7.23(d, J=8.4Hz, 1H), 7.11～7.15(m, 2H), 6.95( s,1H), 2.16(s,3H); MS (ESI) m/z [M+H] + = 450.1.

实施例44 N-(3-氨基甲酰苯基)-2-(2-氯-4-氟苯氧基)-4-(三氟甲基)苯甲酰胺(I-44)的制备Example 44 Preparation of N-(3-carbamoylphenyl)-2-(2-chloro-4-fluorophenoxy)-4-(trifluoromethyl)benzamide (I-44)

第一步：将N-(3-苯腈)-2-氟-4-(三氟甲基)苯甲酰胺(9-a)(1.0g,3.24mmol)、2-氯-4-氟苯酚(523mg，3.57mmol)、碳酸铯(2.11g,6.49mmol)加入到N,N-二甲基甲酰胺(10.0mL)中,在60℃下反应。待反应完全后，用乙酸乙酯萃取，用2N盐酸调节pH值至2～3左右，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：二氯甲烷＝1：1(v/v)过硅胶柱(200～300目)得2-(2-氯-4-氟苯氧基)-N-(3-苯腈)-4-(三氟甲基)苯甲酰胺(II-A-31)(180mg,收率12.8％)。1H-NMR(400MHz,DMSO-d6)δ:10.91(s,1H),8.13(s,1H),7.97～7.88(m,3H),7.68(d,J＝8.0Hz,1H),7.63(dd,J＝8.5,2.5Hz,1H),7.58(s,1H),7.31(dd,J＝7.6,3.7Hz,2H),7.12(s,1H)；MS(ESI)m/z[M+H]+＝434.9。The first step: N-(3-benzonitrile)-2-fluoro-4-(trifluoromethyl)benzamide (9-a) (1.0g, 3.24mmol), 2-chloro-4-fluorophenol (523mg, 3.57mmol) and cesium carbonate (2.11g, 6.49mmol) were added to N,N-dimethylformamide (10.0mL) and reacted 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 over anhydrous sodium sulfate, and concentrate to obtain a crude product. Petroleum ether for the crude product: dichloromethane = 1:1 (v/v) through a silica gel column (200-300 mesh) to obtain 2-(2-chloro-4-fluorophenoxy)-N-(3-benzonitrile) -4-(Trifluoromethyl)benzamide (II-A-31) (180 mg, yield 12.8%). 1 H-NMR (400MHz,DMSO-d 6 )δ:10.91(s,1H),8.13(s,1H),7.97～7.88(m,3H),7.68(d,J＝8.0Hz,1H),7.63 (dd, J=8.5,2.5Hz,1H),7.58(s,1H),7.31(dd,J=7.6,3.7Hz,2H),7.12(s,1H); MS(ESI)m/z[M +H] + = 434.9.

第二步：将2-(2-氯-4-氟苯氧基)-N-(3-苯腈)-4-(三氟甲基)苯甲酰胺(II-A-31)(170mg,0.391mmol)，无水乙醇(2.0mL)加入到盐酸-乙酸乙酯体系(10N,6.0mL)中，室温下封管反应。待反应完全后将反应体系浓缩得到Pinner盐，随后加入无水甲醇(3.0mL),氨-甲醇溶液(7N，5.0mL),2eq氯化铵，于回流反应直到Pinner盐反应完全。反应完全后直接浓缩得粗品。粗品用二氯甲烷：甲醇＝30：1(v/v)过硅胶柱(200～300目)得目标化合物(I-44),(21mg,收率11.9％)。1H-NMR(400MHz,DMSO-d6)δ:11.00(s,1H),9.39(s,2H),9.17(s,2H),8.25(s,1H),7.88(t,J＝8.4Hz,2H),7.69～7.64(m,2H),7.60(t,J＝8.0Hz,1H),7.50(d,J＝7.8Hz,1H),7.44～7.39(m,1H),7.34(td,J＝8.4,2.9Hz,1H),7.06(s,1H)；MS(ESI)m/z[M+H]+＝451.9。The second step: 2-(2-chloro-4-fluorophenoxy)-N-(3-benzonitrile)-4-(trifluoromethyl)benzamide (II-A-31) (170mg, 0.391mmol), absolute ethanol (2.0mL) was added to hydrochloric acid-ethyl acetate system (10N, 6.0mL), and the reaction was sealed at room temperature. After the reaction was complete, the reaction system was concentrated to obtain Pinner's salt, then anhydrous methanol (3.0 mL), ammonia-methanol solution (7N, 5.0 mL), and 2 eq ammonium chloride were added, and the mixture was refluxed until the Pinner's salt was completely reacted. After the reaction was complete, it was directly concentrated to obtain the crude product. The crude product was passed through a silica gel column (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＝8.4Hz ,2H),7.69～7.64(m,2H),7.60(t,J＝8.0Hz,1H),7.50(d,J＝7.8Hz,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.

实施例45 N-(3-氨基甲脒酰基-4-氟苯基)-4,5-二氯-2-(4-氟-2-甲基苯氧基)苯甲酰胺(I-45)的制备Example 45 N-(3-carbamidine-4-fluorophenyl)-4,5-dichloro-2-(4-fluoro-2-methylphenoxy)benzamide (I-45) preparation of

第一步：将2-氟-4,5-二氯苯甲酸(1.0g,4.8mmol),5-氨基-2-氟苯甲腈(684.0mg,5.0mmol)溶于吡啶(15.0mL)中，在0℃下缓慢滴加三氯氧磷(1.8mL，19.2mmol),控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N盐酸调节pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，浓缩析出固体得4,5-二氯-N-(3-氰基-4-氟苯基)-2-氟苯甲酰胺(45-a)(1.1g，收率74.3％)。1H-NMR(400MHz,DMSO-d6)δ:10.96(s,1H),8.21(brs,1H),8.03(d,J＝6.8Hz,1H),7.98(brs,1H),7.93(d,J＝9.6Hz,1H),7.57(t,J＝8.8Hz,1H)；MS(ESI)m/z[M+H]+＝326.9,328.9(3:1)。The first step: Dissolve 2-fluoro-4,5-dichlorobenzoic acid (1.0g, 4.8mmol), 5-amino-2-fluorobenzonitrile (684.0mg, 5.0mmol) in pyridine (15.0mL) , slowly add phosphorus oxychloride (1.8mL, 19.2mmol) dropwise at 0°C, and control the temperature below 10°C. Hydrochloric acid to adjust the pH value to about 2~3, extract with ethyl acetate, dry over anhydrous sodium sulfate, concentrate and precipitate the 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=6.8Hz, 1H), 7.98(brs, 1H), 7.93(d , J = 9.6 Hz, 1H), 7.57 (t, J = 8.8 Hz, 1 H); MS (ESI) m/z [M+H] + = 326.9, 328.9 (3:1).

第二步：将4,5-二氯-N-(3-氰基-4-氟苯基)-2-氟苯甲酰胺(45-a)(327.0mg，1.0mmol),4-氟-2甲基苯酚(132mg,1.1mmol)和碳酸铯(651.0mg,2.0mmol)加入到N,N-二甲基甲酰胺(5.0mL)中，在80℃下反应直到原料反应完全。冷却，将反应体系倒入到冰水中，用2N稀盐酸调节pH值至2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩析出大量固体，过滤 得到4,5-二氯-N-(3-氰基-4-氟苯基)-2-(4-氟-2-甲基苯氧基)苯甲酰胺(II-A-32)(220mg，收率50.8％)。1H-NMR(400MHz,DMSO-d6)δ:10.84(s,1H),8.14(brs,1H),7.98(s,1H),7.93(brs,1H),7.54(t,J＝8.8Hz,1H),7.20(d,J＝8.8Hz,1H),7.08(d,J＝6Hz,2H),6.98(s,1H),2.16(s,3H)；MS(ESI)m/z[M+H]+＝432.8,434.6(3:1)。The second step: 4,5-dichloro-N-(3-cyano-4-fluorophenyl)-2-fluorobenzamide (45-a) (327.0mg, 1.0mmol), 4-fluoro- 2-Methylphenol (132mg, 1.1mmol) and cesium carbonate (651.0mg, 2.0mmol) were added into N,N-dimethylformamide (5.0mL), and reacted at 80°C until the raw materials were 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 over anhydrous sodium sulfate, concentrate to precipitate a large amount of solid, filter Obtained 4,5-dichloro-N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (II-A-32) (220mg , yield 50.8%). 1 H-NMR (400MHz, DMSO-d 6 )δ: 10.84(s, 1H), 8.14(brs, 1H), 7.98(s, 1H), 7.93(brs, 1H), 7.54(t, J=8.8Hz ,1H),7.20(d,J=8.8Hz,1H),7.08(d,J=6Hz,2H),6.98(s,1H),2.16(s,3H); MS(ESI)m/z[M +H] + = 432.8, 434.6 (3:1).

第三步：将4,5-二氯-N-(3-氰基-4-氟苯基)-2-(4-氟-2-甲基苯氧基)苯甲酰胺(II-A-32)(200mg,0.46mmol)，无水乙醇(0.25mL)加入到盐酸-乙酸乙酯体系(10N,10.0mL)中，于室温下封管反应。待反应完全后将反应体系蒸干得Pinner盐，随后加入无水甲醇(3.0mL),氨-甲醇溶液(7N,13mL),2eq氯化铵，于回流反应直到Pinner盐反应完全。反应完全后直接浓缩得粗品。粗品用二氯甲烷:甲醇＝20：1(v/v)过硅胶柱(200～300目)得目标化合物(I-45)(15mg,收率7.2％)。1H-NMR(400MHz,DMSO-d6)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)。The third step: 4,5-dichloro-N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)benzamide (II-A- 32) (200mg, 0.46mmol), absolute ethanol (0.25mL) was added to hydrochloric acid-ethyl acetate system (10N, 10.0mL), and the reaction was sealed at room temperature. After the reaction was complete, the reaction system was evaporated to dryness to obtain Pinner's salt, then anhydrous methanol (3.0 mL), ammonia-methanol solution (7N, 13 mL), and 2 eq ammonium chloride were added, and the mixture was refluxed until the Pinner salt was completely reacted. After the reaction was complete, it was directly concentrated to obtain the crude product. The crude product was passed through a silica gel column (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 (400MHz,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).

实施例46 N-(3-氨基甲脒酰基苯基)-6-(4-氟-2-甲基苯氧基)苯并[d][1,3]二氧戊环-5-甲酰胺(I-46)的制备Example 46 N-(3-aminocarbamidinoylphenyl)-6-(4-fluoro-2-methylphenoxy)benzo[d][1,3]dioxolane-5-carboxamide Preparation of (I-46)

第一步：将6-溴苯并[d][1,3]二氧戊环-5-羧酸(46-SM1)(735.mg,3.0mmol),间氨基苯甲腈(372mg,3.2mmol)溶于吡啶(10.0mL)中，在0℃下缓慢滴加三氯氧磷(0.6mL，2.0mmol),控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N盐酸调节pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，蒸干得粗品。粗品用石油醚：乙酸乙酯＝4：1(v/v)过硅胶柱(200～300目)得化合物(46-a)(200.0mg)。1H-NMR(400MHz,DMSO-d6)δ:10.73(s,1H),8.17(s,1H),7.93(brs,1H),7.57(d,J＝7.2Hz,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)。The first step: 6-bromobenzo[d][1,3]dioxolane-5-carboxylic acid (46-SM1) (735.mg, 3.0mmol), m-aminobenzonitrile (372mg, 3.2 mmol) was dissolved in pyridine (10.0mL), and phosphorus oxychloride (0.6mL, 2.0mmol) was slowly added dropwise at 0°C, and the temperature was controlled below 10°C. The reaction system was poured into ice water, the pH value was adjusted to about 2-3 with 2N hydrochloric acid, extracted with ethyl acetate, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a crude product. The crude product was passed through a silica gel column (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=7.2Hz, 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).

第二步：将46-a(200.0mg，0.58mmol),4-氟-2-甲基苯酚(87.8mg,0.7mmol)，碘化亚铜(11.0mg,0.06mmol)和碳酸铯(377.6mg,1.2mmol)加入到甲苯(10.0mL)中，在100℃下反应。反应完全后，用2N稀盐酸调节pH值至2～3左右，乙酸乙酯萃取，无水硫酸钠干燥，浓缩得粗品。粗品用石油醚：乙酸乙酯＝10：1(v/v)过硅胶柱(200～300目)得N-(3-氰基苯基)-6-(4-氟-2-甲基苯氧基)苯并[d][1,3]二恶唑-5-甲酰胺(II-A-34)(80.0mg，收率30.6％)。1H-NMR(400MHz,DMSO-d6)δ:10.50(brs,1H),8.08(s,1H),7.50(s,1H),7.52(d,4.8Hz,2H),7.24(s,1H),7.08～7.11(dd,J＝9.2,2.8Hz,1H),6.9～7.01(td,J＝8.8,3.2Hz,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.The second step: 46-a (200.0mg, 0.58mmol), 4-fluoro-2-methylphenol (87.8mg, 0.7mmol), cuprous iodide (11.0mg, 0.06mmol) and cesium carbonate (377.6mg , 1.2mmol) was added to toluene (10.0mL) and reacted 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 a crude product. Use petroleum ether for the crude product: ethyl acetate = 10:1 (v/v) to pass through a silica gel column (200-300 mesh) to obtain N-(3-cyanophenyl)-6-(4-fluoro-2-methylbenzene Oxy)benzo[d][1,3]dioxazole-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,4.8Hz,2H),7.24(s,1H ), 7.08～7.11(dd, J＝9.2, 2.8Hz, 1H), 6.9～7.01(td, J＝8.8, 3.2Hz, 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.

第三步：将N-(3-氰基苯基)-6-(4-氟-2-甲基苯氧基)苯并[d][1,3]二恶唑-5-甲酰胺(II-A-34)(50.0mg,0.13mmol)和无水乙醇(0.2mL)加入到盐酸-乙酸乙酯体系(10N,10.0mL)中，于室温下封管反应。待反应完全后将反应体系蒸干的Pinner盐粗品，随后加入氨-甲醇溶液(7N，5.0mL),氯化铵(10.0mg,0.24mmol)，于回流反应直到Pinner盐反应完全。随后 直接浓缩得粗品。粗品用二氯甲烷：甲醇＝20～15：1(v/v)过硅胶柱(200～300目)得目标化合物(I-46)(10.0mg)。1H-NMR(600MHz,DMSO-d6)δ:10.53(s,1H),8.21(s,1H),7.86(d,J＝8.4Hz,1H),7.56(t,J＝8.4Hz,1H),7.47(d,J＝7.2Hz,1H),7.23(s,1H),7.13～7.15(dd,J＝9.0,3.0Hz,1H),7.00～7.03(td,J＝9.0,3.0Hz,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。The third step: N-(3-cyanophenyl)-6-(4-fluoro-2-methylphenoxy)benzo[d][1,3]dioxazole-5-carboxamide ( II-A-34) (50.0mg, 0.13mmol) and absolute ethanol (0.2mL) were added to hydrochloric acid-ethyl acetate system (10N, 10.0mL), and the reaction was sealed at room temperature. After the reaction was complete, evaporate the crude Pinner salt from the reaction system to dryness, then add ammonia-methanol solution (7N, 5.0 mL) and ammonium chloride (10.0 mg, 0.24 mmol), and react under reflux until the Pinner salt was completely reacted. then Concentrate directly to crude product. The crude product was passed through a 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=8.4Hz, 1H), 7.56(t, J=8.4Hz, 1H ),7.47(d,J=7.2Hz,1H),7.23(s,1H),7.13~7.15(dd,J=9.0,3.0Hz,1H),7.00~7.03(td,J=9.0,3.0Hz, 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.

实施例47 2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-6-(三氟甲基)烟酰胺(I-47)的制备Example 47 2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-6-(trifluoromethyl)nicotinamide Preparation of (I-47)

第一步：先将2-氯-6-(三氟甲基)烟酸甲酯(478.0mg,2.00mmol)，4-氟-2甲基苯酚(251.9mg,2.00mmol)，碳酸铯(1.3g,4.0mmol)和碘化亚铜(38.0mg,0.2mmol)加入到甲苯(20mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝100～50：1(v/v)过硅胶柱(200～300目)得到2-(4-氟-2-甲基苯氧基)-6-(三氟甲基)烟酸甲酯(468.0mg,收率71％)。1H-NMR(400MHz,CDCl3)δ:8.38d,J＝7.6Hz,1H),7.40(d,J＝7.6Hz,1H),7.03～7.07(q,1H),6.96(dd,J＝9.2,2.4Hz,1H),6.90(td,J＝8.4,3.2Hz,1H),3.98(s,3H),2.15(s,3H)；ESI[M+Na]+＝330.1。The first step: first 2-chloro-6-(trifluoromethyl)nicotinic acid methyl ester (478.0mg, 2.00mmol), 4-fluoro-2 methylphenol (251.9mg, 2.00mmol), cesium carbonate (1.3 g, 4.0mmol) and cuprous iodide (38.0mg, 0.2mmol) were added to toluene (20mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Use petroleum ether for the crude product: ethyl acetate = 100~50:1 (v/v) to pass through a silica gel column (200~300 mesh) to obtain 2-(4-fluoro-2-methylphenoxy)-6-(trifluoro Methyl) nicotinic acid methyl ester (468.0 mg, yield 71%). 1 H-NMR (400MHz, CDCl 3 ) δ: 8.38d, J=7.6Hz, 1H), 7.40(d, J=7.6Hz, 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.

第二步:将2-(4-氟-2-甲基苯氧基)-6-(三氟甲基)烟酸甲酯(400.0mg,1.21mmol)加入到95％乙醇(20mL)中，随后加入氢氧化钠(5N,2.43mL,12.15mmol)于回流下反应直到原料完全水解成酸，浓缩，加入水，随后用盐酸调pH值到2～3左右析出大量白色固体，过滤，干燥得到2-(4-氟-2-甲基苯氧基)-6-(三氟甲基)烟酸(329.0mg，收率85.9％)。1H-NMR(400MHz,DMSO-d6)δ:8.48(d,J＝7.6Hz,1H),7.69(d,J＝7.6Hz,1H),7.19～7.22(dd,J＝9.2,3.2Hz,1H),7.17(t,3.6Hz,1H),7.06～7.11(td,J＝8.4,3.2Hz,1H),2.07(s,3H)；MS(ESI)m/z[M+H]+＝316.1。Second step: 2-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)nicotinic acid methyl ester (400.0mg, 1.21mmol) was added in 95% ethanol (20mL), Then add sodium hydroxide (5N, 2.43mL, 12.15mmol) 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 to 3 with hydrochloric acid to precipitate a large amount of white solid, filter, and dry 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=7.6Hz, 1H), 7.69(d, J=7.6Hz, 1H), 7.19～7.22(dd, J=9.2, 3.2Hz ,1H),7.17(t,3.6Hz,1H),7.06～7.11(td,J＝8.4,3.2Hz,1H),2.07(s,3H); MS(ESI)m/z[M+H] + = 316.1.

第三步:在装有干燥管的反应瓶中，先将2-(4-氟-2-甲基苯氧基)-6-(三氟甲基)烟酸(325.0mg,1.03mmol)溶于二氯甲烷(20mL)中，加入催化量的DMF后将反应体系冷却到0℃左右，随后缓慢滴加草酰氯(0.8mL,10.31mmol)，滴加完毕后于室温下反应直到酸全部转化为酰氯。将反应体系浓缩除去多余的草酰氯和二氯甲烷，再将残留物溶于二氯甲烷中并冷却到0℃左右缓慢加入三乙胺(0.29mL,2.06mmol)，随后加入5-氨基-2-氟苯腈(140.4mg,1.03mmol)于室温下反应直到反应完全，加入水，用稀盐酸中和，静止分液得到二氯甲烷相，浓缩得粗品。石油醚：乙酸乙酯＝4：1(v/v)过硅胶柱(200～300目)得到N-(3-氰基-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-6-(三氟甲基)烟酰胺(358.0mg,收率80％)。1H-NMR(400MHz,DMSO-d6)δ:11.04(s,1H),8.40(d,J＝7.6Hz,1H),8.23～8.25(q,J＝5.6,2.8Hz,1H),7.96～8.00(m,1H),7.78(d,J＝7.6Hz,1H),7.58(t,J＝8.8Hz,1H),7.25～7.29(q,J＝8.8,5.2Hz,1H),7.20(dd,J＝9.6,3.2Hz,1H),7.08～7.13(td,J＝8.4,3.2Hz,1H),2.08(s,3H)；MS(ESI)m/z[M+H]+＝434.1。 The third step: in a reaction flask equipped with a drying tube, first dissolve 2-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)nicotinic acid (325.0mg, 1.03mmol) In dichloromethane (20mL), add a catalytic amount of DMF and cool the reaction system to about 0°C, then slowly add oxalyl chloride (0.8mL, 10.31mmol) dropwise, and react at room temperature until the acid is completely converted For acid chloride. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0°C and slowly add triethylamine (0.29mL, 2.06mmol), followed by 5-amino-2 - Fluorobenzonitrile (140.4mg, 1.03mmol) was reacted at room temperature until the reaction was complete, water was added, neutralized with dilute hydrochloric acid, static liquid separation was obtained to obtain a dichloromethane phase, and the crude product was concentrated. Petroleum ether: ethyl acetate = 4:1 (v/v) through a silica gel column (200-300 mesh) to obtain N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methyl phenoxy)-6-(trifluoromethyl)nicotinamide (358.0 mg, yield 80%). 1 H-NMR (400MHz, DMSO-d 6 ) δ: 11.04(s, 1H), 8.40(d, J=7.6Hz, 1H), 8.23～8.25(q, J=5.6, 2.8Hz, 1H), 7.96 ～8.00(m, 1H), 7.78(d, J＝7.6Hz, 1H), 7.58(t, J＝8.8Hz, 1H), 7.25～7.29(q, J＝8.8, 5.2Hz, 1H), 7.20( dd, J＝9.6, 3.2Hz, 1H), 7.08～7.13(td, J＝8.4, 3.2Hz, 1H), 2.08(s, 3H); MS(ESI) m/z[M+H] + ＝434.1 .

第四步:将N-(3-氰基-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-6-(三氟甲基)烟酰胺(100.0mg,0.23mmol)，三乙胺(140.1mg,1.38mmol)和盐酸羟胺(32.1mg,0.46mmol)加入到无水乙醇中,回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷:甲醇(v/v)＝10～20：1过柱(200～300目)得到2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-6-(三氟甲基)烟酰胺(I-47)(55.0mg,收率51％)。1H-NMR(400MHz,DMSO-d6)δ:10.75(s,1H),9.68(s,1H),8.35(d,J＝7.2Hz,1H),7.88(s,1H),7.76(d,J＝7.2Hz,2H),7.26～7.30(m,2H),7.20(d,J＝9.2Hz,1H),7.11(t,J＝8.4Hz,1H),5.85(brs,2H),2.09(s,3H)；MS(ESI)m/z[M+H]+＝467.0。The fourth step: N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-6-(trifluoromethyl)nicotinamide (100.0mg, 0.23mmol), triethylamine (140.1mg, 1.38mmol) and hydroxylamine hydrochloride (32.1mg, 0.46mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain a crude product, which was then passed through a column (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 H-NMR (400MHz, DMSO-d 6 ) δ: 10.75(s, 1H), 9.68(s, 1H), 8.35(d, J=7.2Hz, 1H), 7.88(s, 1H), 7.76(d ,J＝7.2Hz, 2H), 7.26～7.30(m, 2H), 7.20(d, J＝9.2Hz, 1H), 7.11(t, J＝8.4Hz, 1H), 5.85(brs, 2H), 2.09 (s,3H); MS (ESI) m/z [M+H] + = 467.0.

实施例48 2-氟-6-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-甲氧基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-48)的制备Example 48 2-fluoro-6-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-methoxycarbamoyl)phenyl)-3-(tri Preparation of fluoromethyl)benzamide (I-48)

第一步：先将6-溴-2-氟-3-(三氟甲基)苯甲酸(2.00g,6.97mmol)，4-氟-2-甲基苯酚(1-SM2)(1.05g,8.36mmol)，碳酸铯(4.54g,13.94mmol)和碘化亚铜(265.4mg,1.39mmol)，加入到甲苯(50mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝2：1(v/v)过硅胶柱(200～300目)得到2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酸(2.3g,收率64.8％)，直接下一步，MS(ESI)m/z[M+H]+＝332.9。The first step: 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.00g, 6.97mmol), 4-fluoro-2-methylphenol (1-SM2) (1.05g, 8.36mmol), cesium carbonate (4.54g, 13.94mmol) and cuprous iodide (265.4mg, 1.39mmol), were added to toluene (50mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Petroleum ether: ethyl acetate = 2:1 (v/v) was used to pass the crude product through a silica gel column (200-300 mesh) to obtain 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-( Trifluoromethyl)benzoic acid (2.3 g, yield 64.8%), directly to the next step, MS (ESI) m/z [M+H] + =332.9.

第二步:将2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酸(210.0mg,1.00mmol)和5-氨基-2-氟苯腈(143.6mg,1.06mmol)溶于无水吡啶(4mL,49.71mmol)中，冷却到0℃左右缓慢滴加三氯氧磷(0.2mL,2.01mmol)，控制温度在10℃以下，滴加完毕，继续反应直到原料反应完全，随后将反应体系倒入到冰水中，用2N盐酸调节pH值至2～3左右，用乙酸乙酯萃取，无水硫酸钠干燥，蒸干得粗品。粗品用石油醚：乙酸乙酯＝10：1(v/v))过硅胶柱(200～300目)得到N-(3-氰基-4-氟苯基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酰胺(150.0mg,收率33％)。1H-NMR(400MHz,DMSO-d6)δ:11.30(s,1H),8.19(s,1H),7.92～7.96(m,1H),7.82(t,J＝8.8Hz,1H),7.57(t,J＝9.2Hz,1H),7.26(dd,J＝9.2,2.8Hz,1H),7.13～7.22(m,2H),6.63(d,J＝9.2Hz,1H),2.13(s,3H)；MS(ESI)m/z[M+H]+＝450.9The second step: 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzoic acid (210.0mg, 1.00mmol) and 5-amino-2-fluoro Dissolve benzonitrile (143.6mg, 1.06mmol) in anhydrous pyridine (4mL, 49.71mmol), cool to about 0°C and slowly add phosphorus oxychloride (0.2mL, 2.01mmol) dropwise, control the temperature below 10°C, drop 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 a crude product. The crude product was passed through a silica gel column (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 H-NMR (400MHz, DMSO-d 6 )δ: 11.30(s, 1H), 8.19(s, 1H), 7.92～7.96(m, 1H), 7.82(t, J＝8.8Hz, 1H), 7.57 (t, J=9.2Hz, 1H), 7.26(dd, J=9.2, 2.8Hz, 1H), 7.13～7.22(m, 2H), 6.63(d, J=9.2Hz, 1H), 2.13(s, 3H); MS (ESI) m/z [M+H] + = 450.9

第三步:将N-(3-氰基-4-氟苯基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酰胺(250.0mg,0.55mmol)，无水乙醇(0.16mL,2.8mmol)和氯化氢-乙酸乙酯体系(10N,50.0mL)加入到封管反应瓶中于室温下反应直到原料完全转化为中间体Pinner盐，随后浓缩除去溶剂得粗品中间体Pinner盐，随后溶于无水乙醇中，随后加入三乙胺(1.54mL,11.10mmol)和甲氧基胺盐酸盐(463.6mg,5.55mmol)于回流下反应知道Pinner盐转化完全，随后再加入加入氨甲醇体系(7N,4.2mL)于回流下反应得到目标产物，随后浓缩得到粗品，随后用石油醚:乙酸乙酯＝10:1～4:1(v/v)过硅胶柱(200～300目)得到2-氟-6-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-甲氧基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-48)(31.0mg,收率11.0％)。1H-NMR (400MHz,DMSO-d6)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。The third step: N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzyl Amide (250.0mg, 0.55mmol), absolute ethanol (0.16mL, 2.8mmol) and hydrogen chloride-ethyl acetate system (10N, 50.0mL) were added to a sealed reaction flask and reacted at room temperature until the raw material was completely converted into an intermediate Pinner salt, then concentrated to remove the solvent to give the crude product intermediate Pinner salt, then dissolved in absolute ethanol, then added triethylamine (1.54mL, 11.10mmol) and methoxylamine hydrochloride (463.6mg, 5.55mmol) in Reaction under reflux until Pinner salt conversion is complete, then add ammonia methanol system (7N, 4.2mL) to react under reflux to obtain the target product, then concentrate to obtain the crude product, then use petroleum ether:ethyl acetate=10:1～4: 1 (v/v) through a silica gel column (200-300 mesh) to obtain 2-fluoro-6-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-methoxy (carbamoyl)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.

实施例49 2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)-6-(2-(三氟甲基)苯氧基)苯甲酰胺(I-49)的制备Example 49 2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)-6-(2-(trifluoromethyl)phenoxy Base) the preparation of benzamide (I-49)

第一步:先将6-溴-2-氟-3-(三氟甲基)苯甲酸(287.0mg,1.0mmol)，2-(三氟甲基)苯酚(194.5mg,1.20mmol)，碳酸铯(651.6mg,2.00mmol)和碘化亚铜(38.1mg,0.2mmol)，加入到甲苯(50.00mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝2：1(v/v)过硅胶柱(200～300目)得到2-氟-3-(三氟甲基)-6-(2-(三氟乙基)苯氧基)苯甲酸(110.0mg,收率27％)。1H-NMR(400MHz,DMSO-d6)δ:7.80(d,J＝7.6Hz,1H),7.68(t,J＝7.6Hz,1H),7.60(t,J＝8.4Hz,1H),7.38(t,J＝7.6Hz,1H),7.15(d,J＝8.4Hz,1H),6.72(d,J＝8.4Hz,1H)；MS(ESI)m/z[M+H]+＝269.0。The first step: first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (287.0mg, 1.0mmol), 2-(trifluoromethyl)phenol (194.5mg, 1.20mmol), carbonic acid Cesium (651.6mg, 2.00mmol) and cuprous iodide (38.1mg, 0.2mmol) were added into toluene (50.00mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Petroleum ether: ethyl acetate = 2:1 (v/v) for the crude product to pass through a silica gel column (200-300 mesh) 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=7.6Hz, 1H), 7.68(t, J=7.6Hz, 1H), 7.60(t, J=8.4Hz, 1H), 7.38(t, J=7.6Hz, 1H), 7.15(d, J=8.4Hz, 1H), 6.72(d, J=8.4Hz, 1H); MS(ESI) m/z[M+H] + = 269.0.

第二步:在装有干燥管的反应瓶中，先将2-氟-3-(三氟甲基)-6-(2-(三氟乙基)苯氧基)苯甲酸(95.0mg,0.26mmol)溶于二氯甲烷(10mL)中，加入催化量的DMF后将反应体系冷却到0℃左右，随后缓慢滴加草酰氯(327.5mg,2.58mmol)，滴加完毕后于室温下反应直到酸全部转化为酰氯。将反应体系浓缩除去多余的草酰氯和二氯甲烷，再将残留物溶于二氯甲烷中并冷却到0℃左右缓慢加入三乙胺(52.2mg,0.52mmol)，随后加入5-氨基-2-氟苯腈(38.6mg,0.28mmol)于室温下反应直到反应完全，加入水，用稀盐酸中和，静止分液得到二氯甲烷相，浓缩得粗品。粗品用石油醚：乙酸乙酯＝8～4：1(v/v)过硅胶柱(200～300目)得N-(3-氰基-4-氟苯基)-2-氟-3-(三氟甲基)-6-(2-(三氟乙基)苯氧基)苯甲酰胺(74.0mg,收率58.9％)。1H-NMR(400MHz,DMSO-d6)δ:11.30(s,1H),8.12～8.14(q,1H),7.88～7.91(m,2H),7.84(d,J＝8.0Hz,1H),7.78(t,J＝8.0Hz,1H),7.56(t,J＝9.2Hz,1H),7.67(t,J＝8.0Hz,1H),7.36(d,J＝8.4Hz,1H),6.94(d,J＝9.2Hz,1H)；MS(ESI)m/z[M+H]+＝487.1。The second step: in the reaction flask equipped with a drying tube, first 2-fluoro-3-(trifluoromethyl)-6-(2-(trifluoroethyl)phenoxy)benzoic acid (95.0mg, 0.26mmol) was dissolved in dichloromethane (10mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then slowly added dropwise oxalyl chloride (327.5mg, 2.58mmol), and reacted at room temperature after the dropwise addition until the acid is completely converted to acid chloride. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0°C and slowly add triethylamine (52.2 mg, 0.52 mmol), followed by 5-amino-2 - Fluorobenzonitrile (38.6mg, 0.28mmol) was reacted at room temperature until the reaction was complete, water was added, neutralized with dilute hydrochloric acid, static separation was obtained to obtain the dichloromethane phase, and the crude product was obtained by concentration. Use petroleum ether for the crude product: ethyl acetate = 8 ~ 4: 1 (v/v) through a silica gel column (200 ~ 300 mesh) 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＝8.0Hz, 1H) ,7.78(t,J=8.0Hz,1H),7.56(t,J=9.2Hz,1H),7.67(t,J=8.0Hz,1H),7.36(d,J=8.4Hz,1H),6.94 (d, J = 9.2 Hz, 1H); MS (ESI) m/z [M+H] + = 487.1.

第三步:将N-(3-氰基-4-氟苯基)-2-氟-3-(三氟甲基)-6-(2-(三氟乙基)苯氧基)苯甲酰胺(70.0mg,0.14mmol)，三乙胺(145.65mg,1.44mmol)和盐酸羟胺(40.0mg,0.58mmol)加入到无水乙醇中,回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷：甲醇＝40～20：1(v/v)过层析硅胶柱(200～300目)得到2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)-6-(2-(三氟甲基)苯氧基)苯甲酰胺(44.0mg,58.8％)。1H-NMR(400MHz,DMSO-d6)δ:10.96(s,1H),9.68(s,1H),7.88(t,J＝8.4Hz,1H),7.84～7.75(m,3H),7.65(m,1H),7.46(t,J＝7.6Hz,1H),7.36(d,J＝8.4Hz,1H),7.24(t,J＝9.6Hz,1H),6.92(d,J＝9.2Hz,1H),5.86(brs,2H)；MS(ESI)m/z[M+H]+＝520.1。The third step: N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)-6-(2-(trifluoroethyl)phenoxy)benzyl Amide (70.0mg, 0.14mmol), triethylamine (145.65mg, 1.44mmol) and hydroxylamine hydrochloride (40.0mg, 0.58mmol) were added to absolute ethanol, and reacted 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 a crude product, which was then passed through a chromatographic 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 (400MHz, DMSO-d 6 ) δ: 10.96(s, 1H), 9.68(s, 1H), 7.88(t, J=8.4Hz, 1H), 7.84～7.75(m, 3H), 7.65 (m,1H),7.46(t,J=7.6Hz,1H),7.36(d,J=8.4Hz,1H),7.24(t,J=9.6Hz,1H),6.92(d,J=9.2Hz , 1H), 5.86 (brs, 2H); MS (ESI) m/z [M+H] + = 520.1.

实施例50 2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-5-(三氟甲基)烟酰胺 (I-50)的制备Example 50 2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-5-(trifluoromethyl)nicotinamide Preparation of (I-50)

第一步:先将2-氯-5-(三氟甲基)烟酸甲酯(586.0mg,2.45mmol)，4-氟-2-甲基苯酚(1-SM2)(308.8mg,2.45mmol)，碳酸铯(1.6g,4.89mmol)和碘化亚铜(46.6mg,0.24mmol)加入到甲苯(20ml)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝100～50：1(v/v)过硅胶柱(200～300目)得到2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)烟酸甲酯(667.0mg,收率82.8％)。1H-NMR(400MHz,CDCl3)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。The first step: first 2-chloro-5-(trifluoromethyl)nicotinic acid methyl ester (586.0mg, 2.45mmol), 4-fluoro-2-methylphenol (1-SM2) (308.8mg, 2.45mmol ), cesium carbonate (1.6g, 4.89mmol) and cuprous iodide (46.6mg, 0.24mmol) were added to toluene (20ml), replaced by nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Use petroleum ether for the crude product: ethyl acetate = 100~50:1 (v/v) to pass through a silica gel column (200~300 mesh) to obtain 2-(4-fluoro-2-methylphenoxy)-5-(trifluoro Methyl) nicotinic acid methyl ester (667.0mg, 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.

第二步:将2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)烟酸甲酯(500.0mg,1.52mmol)加入到95％乙醇(20mL)中，随后加入氢氧化钠(5N,607.4mg,15.2mmol)于回流下反应直到原料完全水解成酸，浓缩，加入水，随后用盐酸调pH值到2～3左右析出大量白色固体，过滤，干燥得到2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)烟酸(440.0mg,收率91.9％)。MS(ESI)m/z[M+H]+＝(316.1)。The second step: 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)nicotinic acid methyl ester (500.0mg, 1.52mmol) was added in 95% ethanol (20mL), Then add sodium hydroxide (5N, 607.4mg, 15.2mmol) and react under reflux until the raw material is completely hydrolyzed into an acid, concentrate, add water, and then adjust the pH value to about 2 to 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).

第三步:在装有干燥管的反应瓶中，先将2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)烟酸(315.0mg,1.0mmol)溶于二氯甲烷(10mL)中，加入催化量的DMF后将反应体系冷却到0℃左右，随后缓慢滴加草酰氯(1.27g,10.00mmol)，滴加完毕后于室温下反应直到酸全部转化为酰氯。将反应体系浓缩除去多余的草酰氯和二氯甲烷，再将残留物溶于二氯甲烷中并冷却到0℃左右缓慢加入三乙胺(202.2mg,2.00mmol)，随后加入5-氨基-2-氟苯腈(136.0mg,1.0mmol)于室温下反应直到反应完全，加入水，用稀盐酸中和，静止分液得到二氯甲烷相，浓缩得粗品。粗品用石油醚：乙酸乙酯＝10～5：1(v/v)过硅胶柱(200～300目)N-(3-氰基-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)烟酰胺(230.0mg,收率53％)。1H-NMR(400MHz,DMSO-d6)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。The third step: in a reaction flask equipped with a drying tube, first dissolve 2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)nicotinic acid (315.0mg, 1.0mmol) In dichloromethane (10mL), add a catalytic amount of DMF and cool the reaction system to about 0°C, then slowly add oxalyl chloride (1.27g, 10.00mmol) dropwise, and react at room temperature until the acid is completely converted For acid chloride. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0°C and slowly add triethylamine (202.2mg, 2.00mmol), followed by 5-amino-2 - Fluorobenzonitrile (136.0mg, 1.0mmol) was reacted at room temperature until the reaction was complete, water was added, neutralized with dilute hydrochloric acid, static separation was obtained to obtain a dichloromethane phase, and the crude product was concentrated. Petroleum ether for crude product: Ethyl acetate = 10～5:1 (v/v) through silica gel column (200～300 mesh) 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.

第四步:将N-(3-氰基-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-5-(三氟甲基)烟酰胺(185.0mg,0.43mmol)，三乙胺(432.0mg,4.27mmol)和盐酸羟胺(118.7mg,1.71mmol)加入到无水乙醇中,回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷:甲醇＝40～20:1过柱(200～300目)得到2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-5-(三氟甲基)烟酰胺(120.0mg,收率60％)。1H-NMR(400MHz,DMSO-d6)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＝9.2Hz,1H),7.11(t,J＝8.0Hz,1H),5.84(s,1H),2.09(s,3H)；MS(ESI)m/z[M+H]+＝467.1。The fourth step: N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-5-(trifluoromethyl)nicotinamide (185.0mg, 0.43mmol), triethylamine (432.0mg, 4.27mmol) and hydroxylamine hydrochloride (118.7mg, 1.71mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain a crude product, which was then passed through a column (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＝9.2Hz,1H),7.11(t,J＝8.0Hz,1H),5.84(s,1H),2.09(s, 3H); MS (ESI) m/z [M+H] + = 467.1.

实施例51 2-氟-6-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲 酰胺(I-51)的制备Example 51 2-fluoro-6-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoroform Base) Benzene Preparation of Amide (I-51)

将N-(3-氰基-4-氟苯基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酰胺(112.0mg,0.25mmol)[见实施例48步骤2]，三乙胺(151.0mg,1.49mmol)和盐酸羟胺(34.6mg,0.50mmol)加入到无水乙醇中,回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷:甲醇＝40～20:1(v/v)过柱(200～300目)得到2-氟-6-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-51)(80.0mg,收率66.5％)。1H-NMR(400MHz,DMSO-d6)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＝8.8Hz,1H),5.84(brs,2H),2.13(s,3H)；MS(ESI)m/z[M+H]+＝483.9。N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide (112.0mg , 0.25mmol) [see step 2 of Example 48], triethylamine (151.0mg, 1.49mmol) and hydroxylamine hydrochloride (34.6mg, 0.50mmol) were added to absolute ethanol, and reacted 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 a crude product, which was then passed through a column (200-300 mesh) with dichloromethane:methanol=40-20:1 (v/v) to obtain 2-fluoro-6-(4-fluoro-2-methyl Phenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-51) (80.0mg, yield 66.5% ). 1 H-NMR (400MHz,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=8.8Hz, 1H), 5.84(brs, 2H), 2.13(s, 3H); MS (ESI) m/z [M+H] + = 483.9.

实施例52 2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-6-(2-甲基-4-(三氟甲氧基)苯氧基)-3-(三氟甲基)苯甲酰胺(I-52)的制备Example 52 2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-6-(2-methyl-4-(trifluoromethoxy)phenoxy)- Preparation of 3-(trifluoromethyl)benzamide (I-52)

第一步:先将6-溴-2-氟-3-(三氟甲基)苯甲酸(340.0mg,1.2mmol)，2-甲基-4-(三氟甲氧基)苯酚(230.6mg,1.2mmol)，碳酸铯(771.9mg,2.4mmol)和碘化亚铜(45.1mg,0.24mmol)，加入到甲苯(20mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚:乙酸乙酯＝2：1(v/v)过硅胶柱(200～300目)得到2-氟-6-(2-甲基-4-(三氟甲氧基)苯氧基)-3-(三氟甲基)苯甲酸(320.0mg,收率67.8％)。1H-NMR(400MHz,DMSO-d6)δ:7.79(t,J＝8.8Hz,1H),7.44(s,1H),7.29(d,J＝8.8Hz,1H),7.22(d,J＝8.8Hz,1H),6.68(d,J＝8.8Hz,1H),2.18(s,3H)；MS(ESI)m/z[M+H]+＝399.1。The first step: first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (340.0mg, 1.2mmol), 2-methyl-4-(trifluoromethoxy)phenol (230.6mg , 1.2mmol), cesium carbonate (771.9mg, 2.4mmol) and cuprous iodide (45.1mg, 0.24mmol), were added to toluene (20mL), replaced by nitrogen, and then heated to 100 ° C until the reaction of the raw materials was complete. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Use petroleum ether:ethyl acetate=2:1 (v/v) to pass the crude product through a silica gel column (200-300 mesh) to obtain 2-fluoro-6-(2-methyl-4-(trifluoromethoxy)phenoxy base)-3-(trifluoromethyl)benzoic acid (320.0 mg, yield 67.8%). 1 H-NMR (400MHz, DMSO-d 6 )δ: 7.79(t, J=8.8Hz, 1H), 7.44(s, 1H), 7.29(d, J=8.8Hz, 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.

第二步:在装有干燥管的反应瓶中，先将2-氟-6-(2-甲基-4-(三氟甲氧基)苯氧基)-3-(三氟甲基)苯甲酸(289.0mg,0.73mmol)溶于二氯甲烷(10mL)中，加入催化量的DMF后将反应体系冷却到0℃左右，随后缓慢滴加草酰氯(921.1mg,7.26mmol)，滴加完毕后于室温下反应直到酸全部转化为酰氯。将反应体系浓缩除去多余的草酰氯和二氯甲烷，再将残留物溶于二氯甲烷中并冷却到0℃左右缓慢加入三乙胺(146.9mg,1.45mmol)，随后加入5-氨基-2-氟苯腈(108.7mg,0.80mmol)于室温下反应直到反应完全，加入水，用稀盐酸中和，静止分液得到二氯甲烷相，浓缩得粗品。粗品用石油醚：乙酸乙酯＝10～4：1(v/v)过硅胶柱(200～300目)得到N-(3-氰基-4-氟苯基)-2-氟-6-(2-甲基-4-三氟甲氧基)苯氧基)-3-(三氟甲基)苯甲酰胺(280mg,收率74％)。1H-NMR(600MHz,DMSO-d6)δ:11.30(s,1H),8.16(q,J＝12.0,3.0Hz,1H),7.91～7.94(m,1H),7.85(t,J＝9.0Hz,1H),7.56(t,J＝9.6Hz,1H),7.42(s,1H),7.31(d,J＝10.8Hz,1H),7.26(d,J＝8.4Hz,1H),6.74(d,J＝9.0Hz,1H),2.18(s,3H)；MS(ESI)m/z[M+H]+＝517.1。The second step: in the reaction bottle equipped with a drying tube, first 2-fluoro-6-(2-methyl-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl) Benzoic acid (289.0mg, 0.73mmol) was dissolved in dichloromethane (10mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, and then oxalyl chloride (921.1mg, 7.26mmol) was slowly added dropwise. After completion, react at room temperature until all the acids are converted into acid chlorides. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0°C and slowly add triethylamine (146.9 mg, 1.45 mmol), followed by 5-amino-2 - Fluorobenzonitrile (108.7mg, 0.80mmol) was reacted at room temperature until the reaction was complete, water was added, neutralized with dilute hydrochloric acid, static separation was obtained to obtain a dichloromethane phase, and the crude product was concentrated. Petroleum ether: ethyl acetate = 10-4:1 (v/v) for the crude product to pass through a silica gel column (200-300 mesh) 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, 3.0Hz, 1H), 7.91～7.94(m, 1H), 7.85(t, J= 9.0Hz, 1H), 7.56(t, J=9.6Hz, 1H), 7.42(s, 1H), 7.31(d, J=10.8Hz, 1H), 7.26(d, J=8.4Hz, 1H), 6.74 (d, J = 9.0 Hz, 1H), 2.18 (s, 3H); MS (ESI) m/z [M+H] + = 517.1.

第三步:将N-(3-氰基-4-氟苯基)-2-氟-6-(2-甲基-4-三氟甲氧基)苯氧基)-3-(三氟甲基)苯甲酰胺(143.0mg,0.28mmol)，三乙胺(168.1mg,1.66mmol)和盐酸羟胺(38.5mg,0.55mmol)加 入到无水乙醇中,回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷：甲醇(v/v)＝40～20：1过柱(200～300目)，得到2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-6-(2-甲基-4-(三氟甲氧基)苯氧基)-3-(三氟甲基)苯甲酰胺(I-52)(66.0mg,收率43.4％)。1H-NMR(400MHz,DMSO-d6)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＝8.8Hz,1H),5.83(brs,2H),2.18(s,3H)；MS(ESI)m/z[M+H]+＝550.1。The third step: N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(2-methyl-4-trifluoromethoxy)phenoxy)-3-(trifluoro Methyl) benzamide (143.0mg, 0.28mmol), triethylamine (168.1mg, 1.66mmol) and hydroxylamine hydrochloride (38.5mg, 0.55mmol) were added Pour into absolute ethanol, and react under reflux until the reaction of raw materials is complete. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain a crude product, which was then passed through 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-methyl-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzamide (I-52)( 66.0mg, yield 43.4%). 1 H-NMR (400MHz, 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＝8.8Hz,1H),5.83(brs,2H),2.18(s,3H); MS(ESI)m/z[M+H] + = 550.1.

实施例53 2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-6-(2-甲氧基-4-(三氟甲氧基)苯氧基)-3-(三氟甲基)苯甲酰胺(I-53)的制备Example 53 2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-6-(2-methoxy-4-(trifluoromethoxy)phenoxy) - Preparation of 3-(trifluoromethyl)benzamide (I-53)

第一步:先将6-溴-2-氟-3-(三氟甲基)苯甲酸(345.0mg,1.20mmol)，2-甲氧基-4-(三氟甲氧基)苯酚(249.7mg,1.20mmol)，碳酸铯(783.3mg,2.40mmol)和碘化亚铜(45.8mg,0.24mmol)，加入到甲苯(20.0mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝10～2：1(v/v)过硅胶柱(200～300目)得到2-氟-6-(2-甲氧基-4-(三氟甲氧基)苯氧基)-3-(三氟甲基)苯甲酸(342.0mg,收率68.7％)。1H-NMR(400MHz,DMSO-d6)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。The first step: first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (345.0mg, 1.20mmol), 2-methoxy-4-(trifluoromethoxy)phenol (249.7 mg, 1.20mmol), cesium carbonate (783.3mg, 2.40mmol) and cuprous iodide (45.8mg, 0.24mmol), were added to toluene (20.0mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted . The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Use petroleum ether for the crude product: ethyl acetate = 10～2:1 (v/v) to pass through a silica gel column (200～300 mesh) 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 = 8.8 Hz, 1H), 6.61 (d, J = 8.8 Hz, 1 H), 3.79 (s, 3H); MS (ESI) m/z [M+H] + = 415.1.

第二步:在装有干燥管的反应瓶中，先将2-氟-6-(2-甲氧基-4-(三氟甲氧基)苯氧基)-3-(三氟甲基)苯甲酸(324.0mg,0.78mmol)溶于二氯甲烷(20mL)中，加入催化量的DMF后将反应体系冷却到0℃左右，随后缓慢滴加草酰氯(0.6mL,7.82mmol)，滴加完毕后于室温下反应直到酸全部转化为酰氯。将反应体系浓缩除去多余的草酰氯和二氯甲烷，再将残留物溶于二氯甲烷中并冷却到0℃左右缓慢加入三乙胺(158.3mg,1.56mmol)，随后加入5-氨基-2-氟苯腈(117.1mg,0.86mmol)于室温下反应直到反应完全，加入水，用稀盐酸中和，静止分液得到二氯甲烷相，浓缩得粗品。粗品用石油醚：乙酸乙酯＝10～2：1(v/v)过硅胶柱(200～300目)得到N-(3-氰基-4-氟苯基)-2-氟-6-(2-甲氧基-4-三氟甲氧基)苯氧基)-3-(三氟甲基)苯甲酰胺(334.0mg,收率82.6％)。1H-NMR(400MHz,CDCl3)δ:8.42(s,1H),7.92～7.94(m,1H),7.81～7.85(q,1H),7.55(t,J＝8.4Hz,1H),7.19～7.26(q,J＝8.4Hz,2H),6.96(d,2H),6.56(d,J＝8.8Hz,1H),3.87(s,3H)；MS(ESI)m/z[M+H]+＝533.1。The second step: in a reaction flask equipped with a drying tube, first 2-fluoro-6-(2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl ) benzoic acid (324.0mg, 0.78mmol) was dissolved in dichloromethane (20mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then slowly added dropwise oxalyl chloride (0.6mL, 7.82mmol), dropwise After the addition was complete, it was reacted at room temperature until all the acids were converted to acid chlorides. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0°C and slowly add triethylamine (158.3mg, 1.56mmol), followed by 5-amino-2 - Fluorobenzonitrile (117.1mg, 0.86mmol) was reacted at room temperature until the reaction was complete, water was added, neutralized with dilute hydrochloric acid, static liquid separation was obtained to obtain a dichloromethane phase, and the crude product was concentrated. Use petroleum ether for the crude product: ethyl acetate = 10～2:1 (v/v) to pass through a silica gel column (200～300 mesh) 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＝8.4Hz, 1H), 7.19 ~7.26(q,J=8.4Hz,2H),6.96(d,2H),6.56(d,J=8.8Hz,1H),3.87(s,3H); MS(ESI)m/z[M+H ] + = 533.1.

第三步:将N-(3-氰基-4-氟苯基)-2-氟-6-(2-甲氧基-4-三氟甲氧基)苯氧基)-3-(三氟甲基)苯甲酰胺(188.0mg,0.35mmol)，三乙胺(107.2mg,1.06mmol)和盐酸羟胺(49.1mg,0.70mmol)加入到无水乙醇中,回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷：甲醇(v/v)＝40～20：1过柱(200～300目)得到2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-6-(2-甲氧基-4-(三氟甲氧基)苯氧基)-3-(三氟甲基)苯甲酰胺(I-53)(77.0mg,收率38.6％)。1H-NMR(400MHz,DMSO-d6)δ:10.85(s,1H),9.66(s, 1H),7.86(dd,J＝6.4,2.8Hz,1H),7.77(t,J＝8.4Hz,1H),7.70～7.74(m,1H),7.35(d,J＝8.8Hz,1H),7.27(s,1H),7.25(t,J＝9.2Hz,1H),7.05(d,J＝10.4Hz,1H),6.64(d,J＝9.2Hz,1H),5.83(brs,2H),3.80(s,3H)；MS(ESI)m/z[M+H]+＝566.1。The third step: N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(2-methoxy-4-trifluoromethoxy)phenoxy)-3-(tri Fluoromethyl)benzamide (188.0mg, 0.35mmol), triethylamine (107.2mg, 1.06mmol) and hydroxylamine hydrochloride (49.1mg, 0.70mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain a crude product, which was then passed through 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)( 77.0mg, yield 38.6%). 1 H-NMR (400MHz, DMSO-d 6 ) δ: 10.85(s, 1H), 9.66(s, 1H), 7.86(dd, J＝6.4, 2.8Hz, 1H), 7.77(t, J＝8.4Hz, 1H), 7.70～7.74(m, 1H), 7.35(d, J＝8.8Hz, 1H), 7.27(s,1H),7.25(t,J=9.2Hz,1H),7.05(d,J=10.4Hz,1H),6.64(d,J=9.2Hz,1H),5.83(brs,2H), 3.80 (s,3H); MS (ESI) m/z [M+H] + = 566.1.

实施例54 6-(4-溴-2-(三氟甲基)苯氧基)-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-54)的制备Example 54 6-(4-bromo-2-(trifluoromethyl)phenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3- Preparation of (trifluoromethyl)benzamide (I-54)

第一步:先将6-溴-2-氟-3-(三氟甲基))苯甲酸(287.0mg,1.0mmol)，4-溴-2-(三氟甲基)苯酚(289.2mg,1.20mmol)，碳酸铯(651.6mg,2.00mmol)和碘化亚铜(38.1mg,0.2mmol)，加入到甲苯(20mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝4～2：1(v/v)过硅胶柱(200～300目)得到6-(4-溴-2-(三氟甲基)苯氧基)-2-氟-3-(三氟甲基)苯甲酸(244.0mg,收率53.7％)。1H-NMR(400MHz,DMSO-d6)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)。The first step: first 6-bromo-2-fluoro-3-(trifluoromethyl))benzoic acid (287.0mg, 1.0mmol), 4-bromo-2-(trifluoromethyl)phenol (289.2mg, 1.20mmol), cesium carbonate (651.6mg, 2.00mmol) and cuprous iodide (38.1mg, 0.2mmol), were added to toluene (20mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Petroleum ether: ethyl acetate = 4-2:1 (v/v) for the crude product was passed through a silica gel column (200-300 mesh) 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 = 8.8 Hz, 1H); MS (ESI) m/z [M+H] + = 447.0, 448.9 (1:1).

第二步:在装有干燥管的反应瓶中，先将6-(4-溴-2-(三氟甲基)苯氧基)-2-氟-3-(三氟甲基)苯甲酸(199.0mg,0.46mmol)溶于二氯甲烷(10mL)中，加入催化量的DMF后将反应体系冷却到0℃左右，随后缓慢滴加草酰氯(564.9mg,4.45mmol)，滴加完毕后于室温下反应直到酸全部转化为酰氯。将反应体系浓缩除去多余的草酰氯和二氯甲烷，再将残留物溶于二氯甲烷中并冷却到0℃左右缓慢加入三乙胺(90.1mg,0.89mmol)，随后加入5-氨基-2-氟苯腈(66.6mg,0.49mmol)于室温下反应直到反应完全，加入水，用稀盐酸中和，静止分液得到二氯甲烷相，浓缩得粗品。粗品用石油醚：乙酸乙酯＝10～4：1(v/v)过硅胶柱(200～300目)得到6-(4-溴-2-(三氟甲基)苯氧基)-N-(3-氰基-4-氟苯基)-2-氟-3-(三氟甲基)苯甲酰胺(163.0mg,收率64.8％)。1H-NMR(400MHz,CDCl3)δ:8.00～8.02(q,J＝8.4Hz,1H),7.93(s,1H),7.87(s,J＝2.4Hz,1H),7.72～7.78(m,2H),7.64(t,J＝8.4Hz,1H),7.22(t,J＝8.8Hz,1H),7.05(d,J＝8.8Hz,1H),6.68(d,J＝8.4Hz,1H)；MS(ESI)m/z[M+H]+＝565.0,567.0(1:1)。The second step: in a reaction flask equipped with a drying tube, first 6-(4-bromo-2-(trifluoromethyl)phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (199.0mg, 0.46mmol) was dissolved in dichloromethane (10mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, and then oxalyl chloride (564.9mg, 4.45mmol) was slowly added dropwise. React at room temperature until all the acid is converted to acid chloride. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0°C and slowly add triethylamine (90.1mg, 0.89mmol), followed by 5-amino-2 - Fluorobenzonitrile (66.6mg, 0.49mmol) was reacted at room temperature until the reaction was complete, water was added, neutralized with dilute hydrochloric acid, static separation was obtained to obtain a dichloromethane phase, and the crude product was concentrated. Petroleum ether: ethyl acetate = 10-4:1 (v/v) for the crude product was passed through a silica gel column (200-300 mesh) 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＝8.4Hz, 1H), 7.93(s, 1H), 7.87(s, J＝2.4Hz, 1H), 7.72～7.78(m ,2H),7.64(t,J=8.4Hz,1H),7.22(t,J=8.8Hz,1H),7.05(d,J=8.8Hz,1H),6.68(d,J=8.4Hz,1H ); MS (ESI) m/z [M+H] + = 565.0, 567.0 (1:1).

第三步:将6-(4-溴-2-(三氟甲基)苯氧基)-N-(3-氰基-4-氟苯基)-2-氟-3-(三氟甲基)苯甲酰胺(130.0mg,0.23mmol)，三乙胺(69.8mg,0.69mmol)和盐酸羟胺(32.0mg,0.46mmol)加入到无水乙醇中,回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷：甲醇(v/v)＝40～20：1过柱(200～300目)得到6-(4-溴-2-(三氟甲基)苯氧基)-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-54)(61.0mg,收率44.3％)。1H-NMR(400MHz,DMSO-d6)δ:10.96(s,1H),9.66(s,1H),8.00(s,1H),7.96(dd,J＝9.2,2.0Hz,1H),7.89(t,J＝8.4Hz,1H),7.79(dd,J＝6.0,2.4Hz,1H),7.61～7.66(m,1H),7.30(d,J＝8.8Hz,1H),7.24(t,J＝9.2Hz,1H),7.04(d,J＝9.2Hz,1H),5.83(brs,1H)；MS(ESI)m/z[M+H]+＝598.0,600.0(1:1)。 The third step: 6-(4-bromo-2-(trifluoromethyl)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl Base) benzamide (130.0mg, 0.23mmol), triethylamine (69.8mg, 0.69mmol) and hydroxylamine hydrochloride (32.0mg, 0.46mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. 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 the column (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) (61.0mg, Yield 44.3%). 1 H-NMR (400MHz,DMSO-d 6 )δ:10.96(s,1H),9.66(s,1H),8.00(s,1H),7.96(dd,J=9.2,2.0Hz,1H),7.89 (t, J=8.4Hz, 1H), 7.79(dd, J=6.0, 2.4Hz, 1H), 7.61～7.66(m, 1H), 7.30(d, J=8.8Hz, 1H), 7.24(t, J = 9.2Hz, 1H), 7.04 (d, J = 9.2Hz, 1H), 5.83 (brs, 1H); MS (ESI) m/z [M+H] + = 598.0, 600.0 (1:1).

实施例55 2-氟-6-(4-氟-2-甲氧基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺的制备Example 55 2-fluoro-6-(4-fluoro-2-methoxyphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoro The preparation of methyl) benzamide

第一步:先将6-溴-2-氟-3-(三氟甲基)苯甲酸(287.0mg,1.0mmol)，4-氟-2-甲氧基苯酚(170.6mg,1.20mmol)，碳酸铯(651.6mg,2.00mmol)和碘化亚铜(38.1mg,0.2mmol)，加入到甲苯(20.0mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝2：1(v/v)过硅胶柱(200～300目)得到2-氟-6-(4-氟-2-甲氧基苯氧基)-3-(三氟甲基)苯甲酸(190.0mg,收率54.5％)。1H-NMR(600MHz,DMSO-d6)δ:7.71(t,J＝9.0Hz,1H),7.24(dd,J＝9.0,6.0Hz,1H),7.19(dd,J＝10.2,2.4Hz,1H),6.86(td,J＝3.0,8.4Hz,1H),6.54(d,J＝9.0Hz,1H),3.76(s,3H)；MS(ESI)m/z[M+H]+＝349.1。The first step: first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (287.0mg, 1.0mmol), 4-fluoro-2-methoxyphenol (170.6mg, 1.20mmol), Cesium carbonate (651.6mg, 2.00mmol) and cuprous iodide (38.1mg, 0.2mmol) were added into toluene (20.0mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Petroleum ether: ethyl acetate = 2:1 (v/v) for the crude product to pass through a silica gel column (200-300 mesh) 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=9.0Hz, 1H), 7.24(dd, J=9.0, 6.0Hz, 1H), 7.19(dd, J=10.2, 2.4Hz ,1H),6.86(td,J=3.0,8.4Hz,1H),6.54(d,J=9.0Hz,1H),3.76(s,3H); MS(ESI)m/z[M+H] + = 349.1.

第二步:在装有干燥管的反应瓶中，先将2-氟-6-(4-氟-2-甲氧基苯氧基)-3-(三氟甲基)苯甲酸(172.0mg,0.49mmol)溶于二氯甲烷(20mL)中，加入催化量的DMF后将反应体系冷却到0℃左右，随后缓慢滴加草酰氯(626.9mg,4.94mmol)，滴加完毕后于室温下反应直到酸全部转化为酰氯。将反应体系浓缩除去多余的草酰氯和二氯甲烷，再将残留物溶于二氯甲烷中并冷却到0℃左右缓慢加入三乙胺(99.97mg,0.99mmol)，随后加入5-氨基-2-氟苯腈(74.0mg,0.54mmol)于室温下反应直到反应完全，加入水，用稀盐酸中和，静止分液得到二氯甲烷相，浓缩得粗品。粗品用石油醚：乙酸乙酯＝10～2：1(v/v)过硅胶柱(200～300目)得到N-(3-氰基-4-氟苯基)-2-氟-6-(4-氟-2-甲氧基苯氧基)-3-(三氟甲基)苯甲酰胺(106.0mg,收率46.0％)。1H-NMR(400MHz,CDCl3)δ:8.50(s,1H),7.91～7.93(q,J＝8.0Hz,1H),7.82～7.86(m,1H),7.53(t,J＝8.4Hz,1H),7.22(d,J＝9.2Hz,1H),7.19(t,J＝5.6Hz,1H),6.82～6.85(dd,J＝9.6,2.8Hz,1H),6.76～6.80(td,J＝8.4,2.8Hz,1H),6.55(d,J＝9.2Hz,1H),3.85(s,3H)；MS(ESI)m/z[M+H]+＝467.1。The second step: in the reaction flask equipped with a drying tube, first 2-fluoro-6-(4-fluoro-2-methoxyphenoxy)-3-(trifluoromethyl)benzoic acid (172.0mg , 0.49mmol) was dissolved in dichloromethane (20mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then slowly added dropwise oxalyl chloride (626.9mg, 4.94mmol), and after the dropwise addition was completed, the React until all the acid is converted to acid 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 (99.97mg, 0.99mmol), and then add 5-amino-2 - Fluorobenzonitrile (74.0mg, 0.54mmol) was reacted at room temperature until the reaction was complete, water was added, neutralized with dilute hydrochloric acid, static liquid separation was obtained to obtain a dichloromethane phase, and concentrated to obtain a crude product. Use petroleum ether for the crude product: ethyl acetate = 10～2:1 (v/v) to pass through a silica gel column (200～300 mesh) 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＝8.0Hz, 1H), 7.82～7.86(m, 1H), 7.53(t, J＝8.4Hz ,1H),7.22(d,J=9.2Hz,1H),7.19(t,J=5.6Hz,1H),6.82~6.85(dd,J=9.6,2.8Hz,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.

第三步:将N-(3-氰基-4-氟苯基)-2-氟-6-(4-氟-2-甲氧基苯氧基)-3-(三氟甲基)苯甲酰胺(100.0mg,0.21mmol)，三乙胺(65.1mg,0.63mmol)和盐酸羟胺(29.8mg,0.42mmol)加入到无水乙醇中，回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷：甲醇(v/v)＝40～20：1过柱(200～300目)得到2-氟-6-(4-氟-2-甲氧基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-55)(44.0mg,收率41.1％)。1H-NMR(400MHz,DMSO-d6)δ:10.93(s,1H),9.66(s,1H),7.86(dd,J＝2.8,6.4Hz,1H),7.71～7.78(m,2H),7.23～7.29(m,2H),7.18(dd,J＝10.4,3.2Hz,1H),6.84～6.90(td,J＝8.4,2.8Hz,1H),6.59(d,J＝9.2Hz,1H),5.84(brs,1H),3.77(s,3H)；MS(ESI)m/z[M+H]+＝500.7。The third step: N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methoxyphenoxy)-3-(trifluoromethyl)benzene Formamide (100.0mg, 0.21mmol), triethylamine (65.1mg, 0.63mmol) and hydroxylamine hydrochloride (29.8mg, 0.42mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain a crude product, which was then passed through a column (200-300 mesh) with dichloromethane:methanol (v/v)=40-20:1 to obtain 2-fluoro-6-(4-fluoro-2-methoxy phenyloxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-55) (44.0mg, yield 41.1 %). 1 H-NMR (400MHz, DMSO-d 6 )δ: 10.93(s, 1H), 9.66(s, 1H), 7.86(dd, J=2.8, 6.4Hz, 1H), 7.71～7.78(m, 2H) ,7.23～7.29(m,2H),7.18(dd,J＝10.4,3.2Hz,1H),6.84～6.90(td,J＝8.4,2.8Hz,1H),6.59(d,J＝9.2Hz,1H ), 5.84 (brs, 1H), 3.77 (s, 3H); MS (ESI) m/z [M+H] + = 500.7.

实施例56 6-(3-氯-2-氟-5-(三氟甲基)苯氧基)-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-56)的制备 Example 56 6-(3-Chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl )-3-(trifluoromethyl)benzamide (I-56) preparation

第一步:先将6-溴-2-氟-3-(三氟甲基)苯甲酸(340.0mg,1.2mmol)，3-氯-2-氟-5-(三氟甲基)苯酚(250.0mg,1.2mmol)，碳酸铯(772.0mg,2.4mmol)和碘化亚铜(45.1mg,0.24mmol)，加入到甲苯(20mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝10～2：1(v/v)过硅胶柱(200～300目)得到6-(3-氯-2-氟-5-(三氟甲基)苯氧基)-2-氟-3-(三氟甲基)苯甲酸(72.0mg,收率14.5％)。1H-NMR(600MHz,DMSO-d6)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。The first step: earlier 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (340.0mg, 1.2mmol), 3-chloro-2-fluoro-5-(trifluoromethyl)phenol ( 250.0mg, 1.2mmol), cesium carbonate (772.0mg, 2.4mmol) and cuprous iodide (45.1mg, 0.24mmol), added to toluene (20mL), replaced by nitrogen, then heated to 100 ° C until the reaction of the raw materials was complete . The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Use petroleum ether for the crude product: ethyl acetate = 10～2:1 (v/v) to pass through a silica gel column (200～300 mesh) to obtain 6-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy (yl)-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 = 9.0 Hz, 1H); MS (ESI) m/z [M+H] + = 421.1.

第二步:在装有干燥管的反应瓶中，先将6-(3-氯-2-氟-5-(三氟甲基)苯氧基)-2-氟-3-(三氟甲基)苯甲酸(70.0mg,0.17mmol)溶于二氯甲烷(10mL)中，加入催化量的DMF后将反应体系冷却到0℃左右，随后缓慢滴加草酰氯(211.2mg,1.66mmol)，滴加完毕后于室温下反应直到酸全部转化为酰氯。将反应体系浓缩除去多余的草酰氯和二氯甲烷，再将残留物溶于二氯甲烷中并冷却到0℃左右缓慢加入三乙胺(33.68mg,0.32mmol)，随后加入5-氨基-2-氟苯腈(24.9mg,0.18mmol)于室温下反应直到反应完全，加入水，用稀盐酸中和，静止分液得到二氯甲烷相，浓缩得粗品。粗品用石油醚：乙酸乙酯＝10～4：1(v/v)过硅胶柱(200～300目)得到6-(3-氯-2-氟-5-(三氟甲基)苯氧基)-N-(3-氰基-4-氟苯基)-2-氟-3-(三氟甲基)苯甲酰胺(50.0mg,收率55.7％)。1H-NMR(400MHz in CDCl3)δ:8.01(sq,1H),7.97(d,J＝8.0Hz,1H),7.83(sq,1H),7.67(t,J＝8.8Hz,1H),7.62(d,J＝6.8Hz,1H),7.42(d,J＝8.8Hz,1H),7.23(t,1H),6.71(d,J＝8.8Hz,1H)；MS(ESI)m/z[M+H]+＝539.0。The second step: in a reaction flask equipped with a drying tube, first 6-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-2-fluoro-3-(trifluoromethyl Base) benzoic acid (70.0mg, 0.17mmol) was dissolved in dichloromethane (10mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, and then oxalyl chloride (211.2mg, 1.66mmol) was slowly added dropwise, After the dropwise addition, react at room temperature until the acid is completely converted into acid 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 (33.68mg, 0.32mmol), and then add 5-amino-2 - Fluorobenzonitrile (24.9mg, 0.18mmol) was reacted at room temperature until the reaction was complete, water was added, neutralized with dilute hydrochloric acid, static liquid separation was obtained to obtain a dichloromethane phase, and the crude product was concentrated. Petroleum ether: ethyl acetate = 10-4:1 (v/v) for the crude product to pass through a silica gel column (200-300 mesh) to obtain 6-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy yl)-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=8.0Hz, 1H), 7.83(sq, 1H), 7.67(t, J=8.8Hz, 1H), 7.62(d, J=6.8Hz, 1H), 7.42(d, J=8.8Hz, 1H), 7.23(t, 1H), 6.71(d, J=8.8Hz, 1H); MS(ESI) m/z [M+H] + = 539.0.

第三步:将6-(3-氯-2-氟-5-(三氟甲基)苯氧基)-N-(3-氰基-4-氟苯基)-2-氟-3-(三氟甲基)苯甲酰胺(50.0mg,0.09mmol)，三乙胺(28.2mg,0.28mmol)和盐酸羟胺(12.9mg,0.18mmol)加入到无水乙醇中,回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷：甲醇(v/v)＝40～20：1过柱(200～300目)得到6-(3-氯-2-氟-5-(三氟甲基)苯氧基)-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-56)(30.0mg,收率56.5％)。1H-NMR(400MHz,DMSO-d6)δ:11.00(s,1H),9.67(s,1H),8.05(d,J＝8.4Hz,1H),7.89(t,J＝8.8Hz,1H),7.78～7.84(m,2H),7.64～7.66(m,1H),7.24(t,J＝9.2Hz,1H),7.15(d,J＝8.4Hz,1H),5.83(brs,1H)；MS(ESI)m/z[M+H]+＝572.1,574.1(3:1)。The third step: 6-(3-chloro-2-fluoro-5-(trifluoromethyl)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3- (Trifluoromethyl)benzamide (50.0mg, 0.09mmol), triethylamine (28.2mg, 0.28mmol) and hydroxylamine hydrochloride (12.9mg, 0.18mmol) were added to absolute ethanol, and reacted under reflux until the raw material reacted completely. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain a crude product, which was then passed through a column (200-300 mesh) with dichloromethane:methanol (v/v)=40-20:1 to obtain 6-(3-chloro-2-fluoro-5-(tri Fluoromethyl)phenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-56) (30.0 mg, yield 56.5%). 1 H-NMR (400MHz, DMSO-d 6 ) δ: 11.00(s, 1H), 9.67(s, 1H), 8.05(d, J=8.4Hz, 1H), 7.89(t, J=8.8Hz, 1H ),7.78～7.84(m,2H),7.64～7.66(m,1H),7.24(t,J＝9.2Hz,1H),7.15(d,J＝8.4Hz,1H),5.83(brs,1H) ; MS (ESI) m/z [M+H] + = 572.1, 574.1 (3:1).

实施例57 2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)-6-(4-(三氟甲基)苯氧基)苯甲酰胺(I-57)的制备Example 57 2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)-6-(4-(trifluoromethyl)phenoxy Base) the preparation of benzamide (I-57)

第一步:先将6-溴-2-氟-3-(三氟甲基)苯甲酸(287.0mg,1.0mmol)，4-(三氟甲基)苯酚(194.5mg,1.2mmol)，碳酸铯(651.6mg,2.0mmol)和碘化亚铜(38.1mg,0.2mmol)加入到甲苯(50mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝4～2：1(v/v) 过硅胶柱(200～300目)得到2-氟-3-(三氟甲基)-6-(4-(三氟甲基)苯氧基)苯甲酸(183.0mg,收率49.7％)。1H-NMR(400MHz,DMSO-d6)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。The first step: first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (287.0mg, 1.0mmol), 4-(trifluoromethyl)phenol (194.5mg, 1.2mmol), carbonic acid Cesium (651.6mg, 2.0mmol) and cuprous iodide (38.1mg, 0.2mmol) were added to toluene (50mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Petroleum ether for crude product: ethyl acetate = 4 ~ 2: 1 (v/v) Pass through a silica gel column (200-300 mesh) 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 = 8.8 Hz, 1H); MS (ESI) m/z [M+H] + = 368.9.

第二步:在装有干燥管的反应瓶中，先将2-氟-3-(三氟甲基)-6-(4-(三氟乙基)苯氧基)苯甲酸(67.0mg,0.18mmol)溶于二氯甲烷(10mL)中，加入催化量的DMF后将反应体系冷却到0℃左右，随后缓慢滴加草酰氯(231.0mg,1.82mmol)，滴加完毕后于室温下反应直到酸全部转化为酰氯。将反应体系浓缩除去多余的草酰氯和二氯甲烷，再将残留物溶于二氯甲烷中并冷却到0℃左右缓慢加入三乙胺(36.8mg,0.26mmol)，随后加入5-氨基-2-氟苯腈(27.3mg,0.2mmol)于室温下反应直到反应完全，加入水，用稀盐酸中和，静止分液得到二氯甲烷相，浓缩得粗品。粗品用石油醚：乙酸乙酯＝20～10：1(v/v)过硅胶柱(200～300目)得到N-(3-氰基-4-氟苯基)-2-氟-3-(三氟甲基)-6-(4-(三氟甲基)苯氧基)苯甲酰胺(20.0mg,收率22％)。1H-NMR(400MHz,DMSO-d6)δ:8.12(s,1H),7.96(dd,J＝5.4,2.7Hz,1H),7.77(ddd,J＝9.1,4.6,2.8Hz,1H),7.70～7.59(m,3H),7.22～7.16(m,3H),6.79(d,J＝8.8Hz,1H)；MS(ESI)m/z[M+H]+＝487.1。The second step: in the reaction flask equipped with a drying tube, first 2-fluoro-3-(trifluoromethyl)-6-(4-(trifluoroethyl)phenoxy)benzoic acid (67.0mg, 0.18mmol) was dissolved in dichloromethane (10mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, and then oxalyl chloride (231.0mg, 1.82mmol) was slowly added dropwise, and reacted at room temperature after the dropwise addition until the acid is completely converted to acid chloride. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0°C and slowly add triethylamine (36.8 mg, 0.26 mmol), followed by 5-amino-2 - Fluorobenzonitrile (27.3mg, 0.2mmol) was reacted at room temperature until the reaction was complete, water was added, neutralized with dilute hydrochloric acid, static separation was obtained to obtain the dichloromethane phase, and the crude product was obtained by concentration. Use petroleum ether for the crude product: ethyl acetate = 20-10:1 (v/v) to pass through a silica gel column (200-300 mesh) 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, 2.7Hz, 1H), 7.77(ddd, J=9.1, 4.6, 2.8Hz, 1H) , 7.70 ~ 7.59 (m, 3H), 7.22 ~ 7.16 (m, 3H), 6.79 (d, J = 8.8Hz, 1H); MS (ESI) m/z [M+H] + = 487.1.

第三步：将N-(3-氰基-4-氟苯基)-2-氟-3-(三氟甲基)-6-(4-(三氟甲基)苯氧基)苯甲酰胺(20.0mg,0.041mmol)，三乙胺(12.48mg,0.12mmol)和盐酸羟胺(5.7mg,0.082mmol)加入到无水乙醇中,回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷：甲醇(v/v)＝40～20：1过柱(200～300目)得到2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)-6-(4-(三氟甲基)苯氧基)苯甲酰胺(I-57)(10.0mg,收率46％)。1H-NMR(400MHz,DMSO-d6)δ:11.00(s,1H),9.66(s,1H),7.89(t,J＝8.8Hz,1H),7.79～7.84(q,3H),7.62～7.66(m,1H),7.38(d,J＝8.4Hz,2H),7.23(t,J＝8.8Hz,1H),7.02(d,J＝8.8Hz,1H),5.83(brs,2H)；MS(ESI)m/z[M+H]+＝520.1。The third step: N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl)-6-(4-(trifluoromethyl)phenoxy)benzyl Amide (20.0mg, 0.041mmol), triethylamine (12.48mg, 0.12mmol) and hydroxylamine hydrochloride (5.7mg, 0.082mmol) were added to absolute ethanol, and reacted 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 a crude product, which was then passed through a column (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) (10.0mg, yield 46% ). 1 H-NMR (400MHz, DMSO-d 6 ) δ: 11.00(s, 1H), 9.66(s, 1H), 7.89(t, J=8.8Hz, 1H), 7.79～7.84(q, 3H), 7.62 ~7.66(m,1H),7.38(d,J=8.4Hz,2H),7.23(t,J=8.8Hz,1H),7.02(d,J=8.8Hz,1H),5.83(brs,2H) ; MS (ESI) m/z [M+H] + = 520.1.

实施例58 6-(2,4-二甲基苯氧基)-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-58)的制备Example 58 6-(2,4-Dimethylphenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl ) preparation of benzamide (I-58)

第一步:先将6-溴-2-氟-3-(三氟甲基)苯甲酸(287.0mg,1.0mmol)，2,4-二甲基苯酚(146.6mg,1.2mmol)，碳酸铯(651.6mg,2.00mmol)和碘化亚铜(38.1mg,0.2mmol)，加入到甲苯(20.0mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝4～2：1(v/v)过硅胶柱(200～300目)得到6-(2,4-二甲基苯氧基)-2-氟-3-(三氟甲基)苯甲酸(160.0mg,收率48.7％)，直接下一步。MS(ESI)m/z[M+H]+＝329.1。The first step: first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (287.0mg, 1.0mmol), 2,4-dimethylphenol (146.6mg, 1.2mmol), cesium carbonate (651.6mg, 2.00mmol) and cuprous iodide (38.1mg, 0.2mmol), were added to toluene (20.0mL), replaced with nitrogen, and then heated to 100°C to react until the reaction of the raw materials was complete. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Petroleum ether: ethyl acetate = 4～2:1 (v/v) for the crude product to pass through a silica gel column (200～300 mesh) to obtain 6-(2,4-dimethylphenoxy)-2-fluoro-3- (Trifluoromethyl)benzoic acid (160.0 mg, yield 48.7%), directly to the next step. MS (ESI) m/z [M+H] + = 329.1.

第二步:在装有干燥管的反应瓶中，先将6-(2,4-二甲基苯氧基)-2-氟-3-(三氟甲基)苯甲酸(100.0mg,0.3mmol)溶于二氯甲烷(10mL)中，加入催化量的DMF后将反应体系冷却到0℃左右，随后缓慢滴加草酰氯(386.6mg,3.0mmol)，滴加完毕后于室温下反应直到酸全部转化 为酰氯。将反应体系浓缩除去多余的草酰氯和二氯甲烷，再将残留物溶于二氯甲烷中并冷却到0℃左右缓慢加入三乙胺(61.7mg,0.61mmol)，随后加入5-氨基-2-氟苯腈(49.7mg,0.36mmol)于室温下反应直到反应完全，加入水，用稀盐酸中和，静止分液得到二氯甲烷相，浓缩得粗品。粗品用石油醚：乙酸乙酯＝20～4：1(v/v)过硅胶柱(200～300目)得到N-(3-氰基-4-氟苯基)-6-(2,4-二甲基苯氧基)-2-氟-3-(三氟甲基)苯甲酰胺(69.0mg,收率50.7％)。1H-NMR(400MHz in CDCl3)δ:8.34(s,1H),7.99(s,1H),7.80～7.84(m,1H),7.49(t,J＝8.4Hz,1H),7.18(t,J＝8.4Hz,1H),7.09(s,1H),7.03(d,J＝8.4Hz,1H),6.90(d,J＝8.0Hz,1H),6.50(d,J＝8.8Hz,1H),2.33(s,3H),2.13(s,3H)；MS(ESI)m/z[M+H]+＝447.2。The second step: in a reaction flask equipped with a drying tube, first add 6-(2,4-dimethylphenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (100.0mg, 0.3 mmol) was dissolved in dichloromethane (10mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then slowly added dropwise oxalyl chloride (386.6mg, 3.0mmol), and reacted at room temperature until full conversion of acid For acid chloride. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0°C and slowly add triethylamine (61.7mg, 0.61mmol), followed by 5-amino-2 - Fluorobenzonitrile (49.7mg, 0.36mmol) was reacted at room temperature until the reaction was complete, water was added, neutralized with dilute hydrochloric acid, static separation was obtained to obtain a dichloromethane phase, and the crude product was concentrated. Petroleum ether: ethyl acetate = 20-4:1 (v/v) for the crude product to pass through a silica gel column (200-300 mesh) 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(400MHz in CDCl 3 )δ:8.34(s,1H),7.99(s,1H),7.80～7.84(m,1H),7.49(t,J＝8.4Hz,1H),7.18(t ,J=8.4Hz,1H),7.09(s,1H),7.03(d,J=8.4Hz,1H),6.90(d,J=8.0Hz,1H),6.50(d,J=8.8Hz,1H ), 2.33 (s, 3H), 2.13 (s, 3H); MS (ESI) m/z [M+H] + = 447.2.

第三步:将N-(3-氰基-4-氟苯基)-6-(2,4-二甲基苯氧基)-2-氟-3-(三氟甲基)苯甲酰胺(69.0mg,0.15mmol)，三乙胺(46.9mg,0.46mmol)和盐酸羟胺(21.5mg,0.31mmol)加入到无水乙醇中,回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷：甲醇(v/v)＝100～20：1过柱(200～300目)得到6-(2,4-二甲基苯氧基)-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-58)(38.0mg,51.3％)。1H-NMR(400MHz,DMSO-d6)δ:10.97(s,1H),9.66(s,1H),7.85～7.88(dd,J＝6.4,2.8Hz,1H),7.77(t,J＝8.4Hz,1H),7.68～7.73(m,1H),7.25(t,J＝9.6Hz,1H),7.18(s,1H),7.12(d,J＝8.0Hz,1H),7.03(d,J＝8.4Hz,1H),6.55(d,J＝9.2Hz,1H),5.83(brs,2H),2.29(s,3H),2.09(s,3H)；MS(ESI)m/z[M+H]+＝480.1。The third step: N-(3-cyano-4-fluorophenyl)-6-(2,4-dimethylphenoxy)-2-fluoro-3-(trifluoromethyl)benzamide (69.0mg, 0.15mmol), triethylamine (46.9mg, 0.46mmol) and hydroxylamine hydrochloride (21.5mg, 0.31mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. 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 the column (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, 2.8Hz, 1H), 7.77(t, J= 8.4Hz, 1H), 7.68～7.73(m, 1H), 7.25(t, J=9.6Hz, 1H), 7.18(s, 1H), 7.12(d, J=8.0Hz, 1H), 7.03(d, J=8.4Hz,1H),6.55(d,J=9.2Hz,1H),5.83(brs,2H),2.29(s,3H),2.09(s,3H); MS(ESI)m/z[M +H] + = 480.1.

实施例59 N-(3-(N-氰基氨基甲酰)-4-氟苯基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酰胺(I-59)的制备Example 59 N-(3-(N-cyanocarbamoyl)-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoro Preparation of methyl) benzamide (I-59)

称取由实施例48制备的N-(3-氰基-4-氟苯基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酰胺(450.0mg,1.0mmol)，无水乙醇(0.2mL)加入到盐酸-乙酸乙酯体系(10N,10.0mL)中，于室温下封管反应。待反应完全生成中间体后将反应体系蒸干的残留物，将残留物溶于乙醇中，随后加入50％氰胺水溶液(840.18mg,10.0mmol)反应回流直到中间体反应完全，随后加入氨-甲醇溶液(4N,10.0mL),继续于回流反应。反应完全后浓缩得粗品。粗品用二氯甲烷：甲醇(v/v)＝40～20：1过柱(200～300目)得到N-(3-(N-氰基氨基甲酰)-4-氟苯基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酰胺(I-59)(60.0mg,收率12.2％)。1H-NMR(600MHz,DMSO-d6)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。Weigh N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl) prepared in Example 48 ) benzamide (450.0mg, 1.0mmol), absolute ethanol (0.2mL) were added to hydrochloric acid-ethyl acetate system (10N, 10.0mL), and the reaction was sealed at room temperature. After the reaction is complete to generate the intermediate, evaporate the residue from the reaction system to dryness, dissolve the residue in ethanol, then add 50% aqueous cyanamide solution (840.18mg, 10.0mmol) and reflux until the intermediate is completely reacted, then add ammonia- Methanol solution (4N, 10.0mL), continue the reaction at reflux. After the reaction was complete, it was concentrated to obtain a crude product. The crude product was passed through the column (200-300 mesh) with dichloromethane:methanol (v/v)=40-20:1 to obtain N-(3-(N-cyanocarbamoyl)-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 = 9.0 Hz, 1H), 2.14 (s, 3H); MS (ESI) m/z [M+H] + = 493.1.

实施例60 2-氟-6-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲氧基)苯甲酰胺(I-60)的制备Example 60 2-fluoro-6-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoroform Preparation of oxy)benzamide (I-60)

第一步:先将6-溴-2-氟-3-(三氟甲氧基)苯甲酸(250.0mg,0.83mmol)，4-氟-2-甲基苯酚(156.1mg,1.24mmol)，碳酸铯(537.6mg,1.65mmol)和碘化亚铜(157.1mg,0.83mmol)，加入到 甲苯(20.0mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用二氯甲烷：甲醇(v/v)＝100～10：1过柱(200～300目)得到2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲氧基)苯甲酸(150mg,收率52％)。1H-NMR(400MHz,DMSO-d6)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。The first step: first 6-bromo-2-fluoro-3-(trifluoromethoxy)benzoic acid (250.0mg, 0.83mmol), 4-fluoro-2-methylphenol (156.1mg, 1.24mmol), Cesium carbonate (537.6mg, 1.65mmol) and cuprous iodide (157.1mg, 0.83mmol) were added to Nitrogen was replaced in toluene (20.0 mL), and then the temperature was raised to 100° C. to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. The crude product was passed through 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 = 9.2 Hz, 1H), 2.13 (s, 3H); MS (ESI) m/z [M+H] + = 348.9.

第二步:在装有干燥管的反应瓶中，先将2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲氧基)苯甲酸(140.0mg,0.4mmol)溶于二氯甲烷(20mL)中，加入催化量的DMF后将反应体系冷却到0℃左右，随后缓慢滴加草酰氯(510.3mg,4.02mmol)，滴加完毕后于室温下反应直到酸全部转化为酰氯。将反应体系浓缩除去多余的草酰氯和二氯甲烷，再将残留物溶于二氯甲烷中并冷却到0℃左右缓慢加入三乙胺(81.4mg,1.12mmol)，随后加入5-氨基-2-氟苯腈(54.7mg,0.4mmol)于室温下反应直到反应完全，加入水，用稀盐酸中和，静止分液得到二氯甲烷相，浓缩得粗品。粗品用石油醚：乙酸乙酯＝10～4：1(v/v)过硅胶柱(200～300目)得到N-(3-氰基-4-氟苯基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲氧基)苯甲酰胺(110.0mg,收率58％)。1H-NMR(400MHz,DMSO-d6)δ:8.17(d,J＝5.6Hz,1H),7.91～7.95(q,1H),7.63(t,J＝8.8Hz,1H),7.57(t,J＝8.8Hz,1H),7.22(dd,J＝2.4,9.2Hz,1H),7.11～7.15(q,2H),6.60(dd,J＝1.2,9.2Hz,1H),2.14(s,3H)；MS(ESI)m/z[M+H]+＝466.9。The second step: in the reaction flask equipped with a drying tube, first 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethoxy)benzoic acid (140.0mg ,0.4mmol) was dissolved in dichloromethane (20mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then slowly added dropwise oxalyl chloride (510.3mg, 4.02mmol), and after the dropwise addition, the React until all the acid is converted to acid chloride. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0°C and slowly add triethylamine (81.4mg, 1.12mmol), followed by 5-amino-2 - Fluorobenzonitrile (54.7mg, 0.4mmol) was reacted at room temperature until the reaction was complete, water was added, neutralized with dilute hydrochloric acid, static liquid separation was obtained to obtain a dichloromethane phase, and concentrated to obtain a crude product. Petroleum ether: ethyl acetate = 10-4:1 (v/v) for the crude product to pass through a silica gel column (200-300 mesh) 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=5.6Hz, 1H), 7.91～7.95(q, 1H), 7.63(t, J=8.8Hz, 1H), 7.57(t ,J=8.8Hz,1H),7.22(dd,J=2.4,9.2Hz,1H),7.11～7.15(q,2H),6.60(dd,J=1.2,9.2Hz,1H),2.14(s, 3H); MS (ESI) m/z [M+H] + = 466.9.

第三步:将N-(3-氰基-4-氟苯基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲氧基)苯甲酰胺(100.0mg,0.22mmol)，三乙胺(130.2mg,1.29mmol)和盐酸羟胺(29.8mg,0.43mmol)加入到无水乙醇中，回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷：甲醇(v/v)＝100～20：1过柱(200～300目)得到2-氟-6-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲氧基)苯甲酰胺(I-60)(68.0mg,收率63.5％)。1H-NMR(400MHz,DMSO-d6)δ:10.96(s,1H),9.67(s,1H),7.85(dd,J＝6.4,2.8Hz,1H),7.68～7.72(m,1H),7.60(t,J＝9.2Hz,1H),7.21～7.27(m,2H),7.09～7.17(q,2H),6.58(d,J＝8.8Hz,1H),5.83(brs,2H),2.15(s,3H)；MS(ESI)m/z[M+H]+＝499.9。The third step: N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethoxy)benzene Formamide (100.0mg, 0.22mmol), triethylamine (130.2mg, 1.29mmol) and hydroxylamine hydrochloride (29.8mg, 0.43mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain a crude product, which was then passed through a column (200-300 mesh) with dichloromethane:methanol (v/v)=100-20:1 to obtain 2-fluoro-6-(4-fluoro-2-methyl Phenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethoxy)benzamide (I-60) (68.0mg, yield 63.5 %). 1 H-NMR (400MHz,DMSO-d 6 )δ:10.96(s,1H),9.67(s,1H),7.85(dd,J＝6.4,2.8Hz,1H),7.68～7.72(m,1H) ,7.60(t,J＝9.2Hz,1H),7.21～7.27(m,2H),7.09～7.17(q,2H),6.58(d,J＝8.8Hz,1H),5.83(brs,2H), 2.15 (s,3H); MS (ESI) m/z [M+H] + = 499.9.

实施例61 5-氯-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-4-(三氟甲基)苯甲酰胺(I-61)的制备Example 61 5-chloro-2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-4-(trifluoroform base) preparation of benzamide (I-61)

第一步:在装有干燥管的反应瓶中，先将5-氯-2-氟-4-(三氟甲基)苯甲酸(968.0mg,4.0mmol)溶于二氯甲烷(20mL)中，加入催化量的DMF后将反应体系冷却到0℃左右，随后缓慢滴加草酰氯(3.8mL,40.0mmol)，滴加完毕后于室温下反应直到酸全部转化为酰氯。将反应体系浓缩除去多余的草酰氯和二氯甲烷，再将残留物溶于二氯甲烷中并冷却到0℃左右缓慢加入三乙胺(807.7mg,8.0mmol)，随后加入5-氨基-2-氟苯腈(570.4mg,4.2mmol)于室温下反应直到反应完全，加入水，用稀盐酸中和，静止分液得到二氯甲烷相，浓缩得粗品。粗品石油醚：乙酸乙酯＝20～4：1(v/v)过硅胶柱(200～300目)得到5-氯-N-(3-氰基-4-氟苯基)-2- 氟-4-(三氟甲基)苯甲酰胺(1.1g,收率76.4％)。1H-NMR(400MHz,DMSO-d6)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。The first step: in a reaction flask equipped with a drying tube, first dissolve 5-chloro-2-fluoro-4-(trifluoromethyl)benzoic acid (968.0mg, 4.0mmol) in dichloromethane (20mL) , after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then oxalyl chloride (3.8mL, 40.0mmol) was slowly added dropwise, and reacted at room temperature after the addition was completed until the acid was completely converted into acid chloride. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0°C and slowly add triethylamine (807.7mg, 8.0mmol), followed by 5-amino-2 - Fluorobenzonitrile (570.4mg, 4.2mmol) was reacted at room temperature until the reaction was complete, water was added, neutralized with dilute hydrochloric acid, static liquid separation was obtained to obtain a dichloromethane phase, and concentrated to obtain a crude product. Crude petroleum ether: ethyl acetate = 20~4:1 (v/v) through a silica gel column (200~300 mesh) 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 = 7.6 Hz, 1H), 7.59 (t, J = 8.8 Hz, 1H); MS (ESI) m/z [M+H] + = 360.9.

第二步:先将5-氯-N-(3-氰基-4-氟苯基)-2-氟-4-(三氟甲基)苯甲酰胺(360.00mg,1.0mmol)，4-氟-2-甲基苯酚(138.49mg,1.10mmol)，碳酸铯(650.43mg,2.00mmol)和碘化亚铜(38mg,0.2mmol)加入到甲苯(20mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝10：1(v/v)过硅胶柱(200～300目)得到5-氯-N-(3-氰基-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(218.0mg,收率68％)。1H-NMR(400MHz,DMSO-d6)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＝9.2Hz,1H),7.21(d,J＝8.8Hz,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)。The second step: first 5-chloro-N-(3-cyano-4-fluorophenyl)-2-fluoro-4-(trifluoromethyl)benzamide (360.00mg, 1.0mmol), 4- Fluorine-2-methylphenol (138.49mg, 1.10mmol), cesium carbonate (650.43mg, 2.00mmol) and cuprous iodide (38mg, 0.2mmol) were added in toluene (20mL), replaced by nitrogen, and then heated to 100 °C to react until the raw materials are completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Petroleum ether: ethyl acetate = 10:1 (v/v) was used to pass the crude product through a silica gel column (200-300 mesh) 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＝9.2Hz, 1H), 7.21(d, J＝8.8Hz, 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).

第三步:将5-氯-N-(3-氰基-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(638.0mg,1.37mmol)，三乙胺(276.6mg,2.73mmol)和盐酸羟胺(189.9mg,2.73mmol)加入到无水乙醇中,回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷：甲醇＝100～40：1(v/v)过柱(200～300目)得到5-氯-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-4-(三氟甲基)苯甲酰胺(I-61)(360.0mg,收率52.7％)。1H-NMR(400MHz,DMSO-d6)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＝10.0Hz,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)。The third step: 5-chloro-N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzene Amide (638.0mg, 1.37mmol), triethylamine (276.6mg, 2.73mmol) and hydroxylamine hydrochloride (189.9mg, 2.73mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain a crude product, which was then passed through a column (200-300 mesh) with dichloromethane:methanol=100-40:1 (v/v) to obtain 5-chloro-2-(4-fluoro-2-methyl Phenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-4-(trifluoromethyl)benzamide (I-61) (360.0mg, yield 52.7% ). 1 H-NMR (400MHz,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=10.0Hz, 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).

实施例62 N-(4-氯-3-(N-羟基氨基甲酰)苯基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酰胺(I-62)的制备Example 62 N-(4-chloro-3-(N-hydroxycarbamoyl)phenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoroform Base) the preparation of benzamide (I-62)

第一步:称取由实施例48制备的2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酸(150.0mg,0.45mmol)置于圆底烧瓶中，加入N,N-二甲基甲酰胺(5mL)作溶剂，再加入HATU(206.0mg,0.54mmol)，室温下搅拌15min,再加入3-氰基-4-氯苯胺(75.6mg,0.50mmol)和N,N-二异丙基乙胺(129.25mg,1.36mmol)，室温下继续搅拌5h。TLC监测反应。反应完成后，将反应液倒入乙酸乙酯中，用水洗去溶剂N,N-二甲基甲酰胺，正己烷：乙酸乙酯＝8：1(v/v)过柱(200～300目)纯化得N-(4-氯-3-氰基苯基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酰胺(130mg，收率60％)。1H-NMR(400MHz,CDCl3)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。The first step: Weigh 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzoic acid (150.0mg, 0.45mmol) prepared by Example 48 In a round bottom flask, add N,N-dimethylformamide (5mL) as a solvent, then add HATU (206.0mg, 0.54mmol), stir at room temperature for 15min, then add 3-cyano-4-chloroaniline ( 75.6mg, 0.50mmol) and N,N-diisopropylethylamine (129.25mg, 1.36mmol), and continued stirring at room temperature for 5h. The reaction was monitored by TLC. After the reaction is completed, pour the reaction liquid into ethyl acetate, wash the solvent N,N-dimethylformamide with water, and pass through the column (200-300 mesh ) was purified to obtain N-(4-chloro-3-cyanophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzamide ( 130mg, 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.

第二步:称取N-(4-氯-3-氰基苯基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酰胺 (140.0mg,0.3mmol)和盐酸羟胺(104.3mg,1.5mmol)置于封管中，加入5mL无水乙醇，再加入三乙胺(151.8mg,1.5mmol)，在氮气氛围下80℃反应过夜。反应完全后，蒸干反应液，加入水，用二氯甲烷萃取，收集有机相，柱层析纯化，二氯甲烷：甲醇＝100～50：1(v/v)过柱(200～300目)，得到N-(4-氯-3-(N-羟基氨基甲酰)苯基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酰胺(I-62)(105mg，收率70％)。1H-NMR(400MHz in Methanol-d4)δ:7.81～7.78(m,2H),7.68(t,J＝8.5Hz,1H),7.47～7.44(m,1H),7.13～7.10(m,1H),7.10～7.07(m,1H),7.01(td,J＝8.4,3.1Hz,1H),6.60(d,J＝8.9Hz,1H),2.18(s,3H)；MS(ESI)m/z[M+H]+＝500.0。The second step: weigh N-(4-chloro-3-cyanophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzene Formamide (140.0mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, 5mL of absolute ethanol was added, and triethylamine (151.8mg, 1.5mmol) was added, and reacted overnight at 80°C under a nitrogen atmosphere . After the reaction is complete, evaporate the reaction liquid to dryness, add water, extract with dichloromethane, collect the organic phase, and purify by column chromatography, dichloromethane:methanol=100～50:1 (v/v) through the column (200～300 mesh ), to give N-(4-chloro-3-(N-hydroxycarbamoyl)phenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethane yl) 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＝8.5Hz, 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, 3.1Hz, 1H), 6.60(d, J＝8.9Hz, 1H), 2.18(s, 3H); MS(ESI)m /z[M+H] + = 500.0.

实施例63 2-氟-6-(4-氟-2-甲基苯氧基)-N-(3-(N-羟基氨基甲酰)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(I-63)的制备Example 63 2-fluoro-6-(4-fluoro-2-methylphenoxy)-N-(3-(N-hydroxycarbamoyl)-4-methylphenyl)-3-(trifluoro The preparation of methyl) benzamide (I-63)

第一步:称取由实施例48制备的2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酸(150.0mg,0.45mmol)置于圆底烧瓶中，加入N,N-二甲基甲酰胺(5mL)作溶剂，再加入HATU(206.0mg,0.54mmol)，室温下搅拌15min,再加入5-氨基-2-甲基苯甲腈(65.6mg,0.50mmol)和N,N-二异丙基乙胺(129.25mg,1.36mmol)，室温下继续搅拌5h。TLC监测反应。反应完成后，将反应液倒入乙酸乙酯中，用水洗去溶剂N,N-二甲基甲酰胺，正己烷：乙酸乙酯＝8：1(v/v)过柱(200～300目)层析纯化得N-(3-氰基-4-甲基苯基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酰胺(121mg，收率60％)。1H-NMR(400MHz,CDCl3)δ:8.18(s,1H),7.93(d,J＝2.3Hz,1H),7.71(dd,J＝8.4,2.4Hz,1H),7.51(t,J＝8.4Hz,1H),7.29(d,J＝8.4Hz,1H),7.00(dt,J＝7.5,3.7Hz,2H),6.93(td,J＝8.2,3.0Hz,1H),6.47(d,J＝8.9Hz,1H),2.49(s,3H),2.17(s,3H)；MS(ESI)m/z[M+H]+＝446.8。The first step: Weigh 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzoic acid (150.0mg, 0.45mmol) prepared by Example 48 In a round bottom flask, add N,N-dimethylformamide (5mL) as solvent, then add HATU (206.0mg, 0.54mmol), stir at room temperature for 15min, then add 5-amino-2-methylbenzyl Nitrile (65.6mg, 0.50mmol) and N,N-diisopropylethylamine (129.25mg, 1.36mmol), continued stirring at room temperature for 5h. The reaction was monitored by TLC. After the reaction is completed, pour the reaction liquid into ethyl acetate, wash the solvent N,N-dimethylformamide with water, and pass through the column (200-300 mesh ) chromatographic purification to obtain N-(3-cyano-4-methylphenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzene Formamide (121 mg, yield 60%). 1 H-NMR (400MHz, CDCl 3 ) δ: 8.18(s, 1H), 7.93(d, J=2.3Hz, 1H), 7.71(dd, J=8.4, 2.4Hz, 1H), 7.51(t, J =8.4Hz,1H),7.29(d,J=8.4Hz,1H),7.00(dt,J=7.5,3.7Hz,2H),6.93(td,J=8.2,3.0Hz,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.

第二步:称取N-(3-氰基-4-甲基苯基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酰胺(133.8mg,0.3mmol)和盐酸羟胺(104.3mg,1.5mmol)置于封管中，加入5mL无水乙醇，再加入三乙胺(151.8mg,1.5mmol)，在氮气氛围下80℃反应过夜。反应完全后，蒸干反应液，加入水，用二氯甲烷萃取，收集有机相，用二氯甲烷：甲醇＝100～50：1(v/v)过硅胶柱(200～300目)，得到2-氟-6-(4-氟-2-甲基苯氧基)-N-(3-(N-羟基氨基甲酰)-4-甲基苯基)-3-(三氟甲基)苯甲酰胺(I-63)(100.6mg，收率70％)。1H-NMR(400MHz in Methanol-d4)δ:7.73～7.66(m,3H),7.28(d,J＝8.9Hz,1H),7.13(m,2H),7.05(dt,J＝9.0,4.5Hz,1H),6.62(d,J＝8.9Hz,1H),2.42(s,3H),2.22(s,3H)；MS(ESI)m/z[M+H]+＝480.0。The second step: weigh N-(3-cyano-4-methylphenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl) Benzamide (133.8mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, 5mL of absolute ethanol was added, and then triethylamine (151.8mg, 1.5mmol) was added, under nitrogen atmosphere for 80 °C overnight. 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-6-(4-fluoro-2-methylphenoxy)-N-(3-(N-hydroxycarbamoyl)-4-methylphenyl)-3-(trifluoromethyl) Benzamide (I-63) (100.6 mg, yield 70%). 1 H-NMR (400MHz in Methanol-d 4 )δ: 7.73～7.66(m,3H),7.28(d,J＝8.9Hz,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.

实施例64 2-氟-6-(4-氟-2-甲基苯氧基)-N-(2-(N-羟胺基)吡啶-4-基)-3-(三氟甲基)苯甲酰胺(I-64)的制备Example 64 2-fluoro-6-(4-fluoro-2-methylphenoxy)-N-(2-(N-hydroxylamino)pyridin-4-yl)-3-(trifluoromethyl)benzene Preparation of formamide (I-64)

第一步:称取由实施例48制备的2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酸(150.0mg,0.45mmol)置于圆底烧瓶中，加入二氯甲烷(15mL)作溶剂，在冰水浴下搅拌10min，再加入草酰氯(171.4mg,1.35mmol)和催化量N,N-二甲基甲酰胺，滴加完毕后于室温下反应直到酸全部转化为酰氯。将反应体系浓缩除去多余的草酰氯和二氯甲烷，再将残留物溶于 二氯甲烷中并冷却到0℃左右缓慢加入三乙胺(91.0mg,0.9mmol)，随后加入4-氨基-2-氰基吡啶(54.0mg,0.45mmol)于室温下反应直到反应完全，加入水，用稀盐酸中和，静止分液得到二氯甲烷相，用石油醚：乙酸乙酯＝8：1(v/v)过硅胶柱(200～300目)纯化得N-(2-氰基吡啶-4-基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酰胺(117mg，收率60％)。1H-NMR(400MHz,DMSO-d6)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。The first step: Weigh 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzoic acid (150.0mg, 0.45mmol) prepared by Example 48 In a round bottom flask, add dichloromethane (15mL) as a solvent, stir in an ice-water bath for 10min, then add oxalyl chloride (171.4mg, 1.35mmol) and a catalytic amount of N,N-dimethylformamide, dropwise Then react at room temperature until the acid is completely converted to acid chloride. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, then dissolve the residue in Add triethylamine (91.0mg, 0.9mmol) slowly to dichloromethane and cool to about 0°C, then add 4-amino-2-cyanopyridine (54.0mg, 0.45mmol) and react at room temperature until the reaction is complete, add Water, neutralized with dilute hydrochloric acid, static liquid separation to obtain the dichloromethane phase, purified by silica gel column (200-300 mesh) with petroleum ether: ethyl acetate = 8:1 (v/v) to obtain N-(2-cyano (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= 8.9 Hz, 1H), 2.13(s, 3H); MS (ESI) m/z [M+H] + = 433.8.

第二步:称取N-(2-氰基吡啶-4-基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酰胺(130.0mg,0.3mmol)和盐酸羟胺(104.3mg,1.5mmol)置于封管中，加入5mL无水乙醇，再加入三乙胺(151.8mg,1.5mmol)，在氮气氛围下80℃反应过夜。反应完全后，蒸干反应液，加入水，用二氯甲烷萃取，收集有机相，用二氯甲烷：甲醇＝100～50：1(v/v)过硅胶柱(200～300目)，得到2-氟-6-(4-氟-2-甲基苯氧基)-N-(2-(N-羟胺基)吡啶-4-基)-3-(三氟甲基)苯甲酰胺(I-64)(98mg，收率70％)。1H-NMR(400MHz,DMSO-d6)δ:11.35(s,1H),9.94(s,1H),8.49(d,J＝5.6Hz,1H),8.28(d,J＝2.0Hz,1H),7.81(t,J＝8.7Hz,1H),7.63(dd,J＝5.6,2.1Hz,1H),7.29～7.19(m,2H),7.15(td,J＝8.5,3.1Hz,1H),6.63(d,J＝8.9Hz,1H),5.83(s,2H),2.13(s,3H)；MS(ESI)m/z[M+H]+＝466.9。The second step: weigh N-(2-cyanopyridin-4-yl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzene Add amide (130.0mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) in a sealed tube, add 5mL of absolute ethanol, then add triethylamine (151.8mg, 1.5mmol), and react at 80°C under nitrogen atmosphere overnight. 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-6-(4-fluoro-2-methylphenoxy)-N-(2-(N-hydroxylamino)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=5.6Hz, 1H), 8.28(d, J=2.0Hz, 1H ), 7.81(t, J＝8.7Hz, 1H), 7.63(dd, J＝5.6, 2.1Hz, 1H), 7.29～7.19(m, 2H), 7.15(td, J＝8.5, 3.1Hz, 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.

实施例65 2-氟-6-(4-氟-2-甲基苯氧基)-N-(3-(N-羟基氨基甲酰胺基)-4-甲氧基苯基)-3-(三氟甲基)苯甲酰胺(I-65)的制备Example 65 2-fluoro-6-(4-fluoro-2-methylphenoxy)-N-(3-(N-hydroxycarbamoyl)-4-methoxyphenyl)-3-( Preparation of trifluoromethyl)benzamide (I-65)

第一步:称取由实施例48制备的2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酸(150.0mg,0.45mmol)置于圆底烧瓶中，加入N,N-二甲基甲酰胺(5mL)作溶剂，再加入HATU(206.0mg,0.54mmol)，室温下搅拌15min,再加入5-氨基-2-甲氧基苯甲腈(73.6mg,0.50mmol)和N,N-二异丙基乙胺(129.25mg,1.36mmol)，室温下继续搅拌5h。TLC监测反应。反应完成后，将反应液倒入乙酸乙酯中，用水洗去溶剂N,N-二甲基甲酰胺，石油醚：乙酸乙酯＝8：1(v/v)过硅胶柱(200～300目)层析纯化得N-(3-氰基-4-甲氧基苯基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酰胺(125mg，收率60％)。1H-NMR(400MHz,CDCl3)δ:8.12(s,1H),7.83(dd,J＝9.0,2.7Hz,1H),7.80(d,J＝2.6Hz,1H),7.50(t,J＝8.4Hz,1H),7.01～6.91(m,4H),6.46(d,J＝8.9Hz,1H),3.92(s,3H),2.17(s,3H)；MS(ESI)m/z[M+H]+＝462.8。The first step: Weigh 2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl)benzoic acid (150.0mg, 0.45mmol) prepared by Example 48 In a round bottom flask, add N,N-dimethylformamide (5mL) as solvent, then add HATU (206.0mg, 0.54mmol), stir at room temperature for 15min, then add 5-amino-2-methoxybenzene Formonitrile (73.6mg, 0.50mmol) and N,N-diisopropylethylamine (129.25mg, 1.36mmol) were stirred at room temperature for 5h. The reaction was monitored by TLC. After the reaction is completed, pour the reaction solution into ethyl acetate, wash off the solvent N,N-dimethylformamide with water, and pass petroleum ether: ethyl acetate = 8:1 (v/v) through a silica gel column (200-300 Purification by chromatography to obtain N-(3-cyano-4-methoxyphenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl ) benzamide (125 mg, yield 60%). 1 H-NMR (400MHz, CDCl 3 ) δ: 8.12(s, 1H), 7.83(dd, J=9.0, 2.7Hz, 1H), 7.80(d, J=2.6Hz, 1H), 7.50(t, J =8.4Hz,1H),7.01～6.91(m,4H),6.46(d,J=8.9Hz,1H),3.92(s,3H),2.17(s,3H); MS(ESI)m/z[ M+H] + = 462.8.

第二步:称取N-(3-氰基-4-甲氧基苯基)-2-氟-6-(4-氟-2-甲基苯氧基)-3-(三氟甲基)苯甲酰胺(138.6mg,0.3mmol)和盐酸羟胺(104.3mg,1.5mmol)置于封管中，加入5mL无水乙醇，再加入三乙胺(151.8mg,1.5mmol)，在氮气氛围下80℃反应过夜。反应完全后，蒸干反应液，加入水，用二氯甲烷萃取，收集有机相，用二氯甲烷：甲醇＝100～50：(v/v)过硅胶柱(200～300目)得到2-氟-6-(4-氟-2-甲基苯氧基)-N-(3-(N-羟基氨基甲酰胺基)-4-甲氧基苯基)-3-(三氟甲基)苯甲酰胺(I-65)(103.9mg，收率70％)。1H-NMR(400MHz in Methanol-d4)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。The second step: weigh N-(3-cyano-4-methoxyphenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)-3-(trifluoromethyl ) benzamide (138.6mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, 5mL of absolute ethanol was added, then triethylamine (151.8mg, 1.5mmol) was added, under nitrogen atmosphere React overnight at 80°C. After the reaction is complete, evaporate the reaction solution to dryness, add water, extract with dichloromethane, collect the organic phase, and use dichloromethane:methanol=100~50:(v/v) to pass through a silica gel column (200~300 mesh) to obtain 2- Fluoro-6-(4-fluoro-2-methylphenoxy)-N-(3-(N-hydroxycarbamoyl)-4-methoxyphenyl)-3-(trifluoromethyl) Benzamide (I-65) (103.9 mg, yield 70%). 1 H-NMR (400MHz in Methanol-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.

实施例66 6-氯-5-氟-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)烟酰胺(I-66)的制备Example 66 6-chloro-5-fluoro-2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)nicotinamide ( I-66) Preparation

第一步:先将2,6-二氯-5-氟烟酸(1.46g,6.97mmol)，4-氟-2-甲基苯酚(1-SM2)(1.05g,8.36mmol)，碳酸铯(4.54g,13.94mmol)和碘化亚铜(265.43mg,1.39mmol)，加入到甲苯(50mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚:乙酸乙酯＝2:1(v/v)过硅胶柱(200～300目)得到6-氯-5-氟-2-(4-氟-2-甲基苯氧基)烟酸(1.35g,收率64.8％)。1H-NMR(400MHz,DMSO-d6)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。The first step: first 2,6-dichloro-5-fluoronicotinic acid (1.46g, 6.97mmol), 4-fluoro-2-methylphenol (1-SM2) (1.05g, 8.36mmol), cesium carbonate (4.54g, 13.94mmol) and cuprous iodide (265.43mg, 1.39mmol), were added to toluene (50mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Use petroleum ether:ethyl acetate=2:1 (v/v) to pass the crude product through a silica gel column (200-300 mesh) to obtain 6-chloro-5-fluoro-2-(4-fluoro-2-methylphenoxy) Nicotinic acid (1.35g, 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.

第二步:称取6-氯-5-氟-2-(4-氟-2-甲基苯氧基)烟酸(135.0mg,0.45mmol)置于圆底烧瓶中，加入N,N-二甲基甲酰胺(5mL)作溶剂，再加入HATU(206.0mg,0.54mmol)，室温下搅拌15min,再加入3-氰基-4-氟苯胺(68mg,0.50mmol)和N,N-二异丙基乙胺(129.2mg,1.36mmol)，室温下继续搅拌5h。TLC监测反应。反应完成后，将反应液倒入乙酸乙酯中，用水洗去溶剂N,N-二甲基甲酰胺，石油醚：乙酸乙酯＝8：1(v/v)过柱(200～300目)纯化得6-氯-N-(3-氰基-4-氟苯基)-5-氟-2-(4-氟-2-甲基苯氧基)烟酰胺(113mg，收率60％)。1H-NMR(400MHz,DMSO-d6)δ:11.00(s,1H),8.37(d,J＝9.4Hz,1H),8.18(dd,J＝5.8,2.7Hz,1H),7.93(ddd,J＝9.2,4.9,2.7Hz,1H),7.56(t,J＝9.1Hz,1H),7.30～7.22(m,2H),7.14(td,J＝8.5,3.1Hz,1H),2.14(s,3H)；MS(ESI)m/z[M+H]+＝417.8。The second step: Weigh 6-chloro-5-fluoro-2-(4-fluoro-2-methylphenoxy) nicotinic acid (135.0mg, 0.45mmol) into a round bottom flask, add N,N- Dimethylformamide (5mL) was used as solvent, then HATU (206.0mg, 0.54mmol) was added, stirred at room temperature for 15min, then 3-cyano-4-fluoroaniline (68mg, 0.50mmol) and N,N-di Isopropylethylamine (129.2mg, 1.36mmol), continued stirring at room temperature for 5h. The reaction was monitored by TLC. After the reaction is completed, pour the reaction solution into ethyl acetate, wash the solvent N,N-dimethylformamide with water, and pass petroleum ether: ethyl acetate = 8:1 (v/v) through the column (200-300 mesh ) was purified to obtain 6-chloro-N-(3-cyano-4-fluorophenyl)-5-fluoro-2-(4-fluoro-2-methylphenoxy)nicotinamide (113mg, yield 60% ). 1 H-NMR (400MHz, DMSO-d 6 ) δ: 11.00(s, 1H), 8.37(d, J=9.4Hz, 1H), 8.18(dd, J=5.8, 2.7Hz, 1H), 7.93(ddd ,J=9.2,4.9,2.7Hz,1H),7.56(t,J=9.1Hz,1H),7.30~7.22(m,2H),7.14(td,J=8.5,3.1Hz,1H),2.14( s, 3H); MS (ESI) m/z [M+H] + = 417.8.

第三步:称取6-氯-N-(3-氰基-4-氟苯基)-5-氟-2-(4-氟-2-甲基苯氧基)烟酰胺(125.1mg,0.3mmol)和盐酸羟胺(104.3mg,1.5mmol)置于封管中，加入5mL无水乙醇，再加入三乙胺(151.8mg,1.5mmol)，在氮气氛围下80℃反应过夜。反应完全后，蒸干反应液，加入水，用二氯甲烷萃取，收集有机相，柱层析纯化，二氯甲烷：甲醇＝100～50：1(v/v)过柱(200～300目)，得到6-氯-5-氟-2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)烟酰胺(I-66)(95mg，收率70％)。1H-NMR(400MHz,DMSO-d6)δ:10.74(s,1H),9.70s,1H),8.39(d,J＝9.4Hz,1H),7.88(dd,J＝6.5,2.7Hz,1H),7.73(dt,J＝7.8,3.8Hz,1H),7.34～7.24(m,3H),7.18(td,J＝8.5,3.1Hz,1H),5.87(s,2H),2.18(s,3H)；MS(ESI)m/z[M+H]+＝450.8。The third step: weigh 6-chloro-N-(3-cyano-4-fluorophenyl)-5-fluoro-2-(4-fluoro-2-methylphenoxy)nicotinamide (125.1mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, 5mL of absolute ethanol was added, and then triethylamine (151.8mg, 1.5mmol) was added, and reacted overnight at 80°C under a nitrogen atmosphere. After the reaction is complete, evaporate the reaction liquid to dryness, add water, extract with dichloromethane, collect the organic phase, and purify by column chromatography, dichloromethane:methanol=100～50:1 (v/v) through the column (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 (400MHz, DMSO-d 6 )δ: 10.74(s, 1H), 9.70s, 1H), 8.39(d, J=9.4Hz, 1H), 7.88(dd, J=6.5, 2.7Hz, 1H), 7.73(dt, J＝7.8, 3.8Hz, 1H), 7.34～7.24(m, 3H), 7.18(td, J＝8.5, 3.1Hz, 1H), 5.87(s, 2H), 2.18(s ,3H); MS (ESI) m/z [M+H] + = 450.8.

实施例67 2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-6-(4-氟-3-(三氟甲基)苯氧基)-3-(三氟甲基)苯甲酰胺(I-67)的制备Example 67 2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-6-(4-fluoro-3-(trifluoromethyl)phenoxy)-3- Preparation of (Trifluoromethyl)benzamide (I-67)

第一步:先将6-溴-2-氟-3-(三氟甲基)苯甲酸(2.0g,6.97mmol)，4-氟-3-(三氟甲基)苯酚(1.5g,8.36mmol)，碳酸铯(4.54g,13.94mmol)和碘化亚铜(265.4mg,1.4mmol)，加入到甲苯(50mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中， 随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝2：1(v/v)过硅胶柱(200～300目)得到2-氟-6-(4-氟-3-三氟甲基苯氧基)-3-(三氟甲基)苯甲酸(1.75g,收率64.8％)，直接下一步。MS(ESI)m/z[M+H]+＝386.8。The first step: first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.0g, 6.97mmol), 4-fluoro-3-(trifluoromethyl)phenol (1.5g, 8.36 mmol), cesium carbonate (4.54g, 13.94mmol) and cuprous iodide (265.4mg, 1.4mmol), were added to toluene (50mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. Pour the reaction system into ice water, Subsequent extraction with ethyl acetate, the organic phase was dried and concentrated to give the crude product. Petroleum ether: ethyl acetate = 2:1 (v/v) for the crude product to pass through a silica gel column (200-300 mesh) to obtain 2-fluoro-6-(4-fluoro-3-trifluoromethylphenoxy)-3 -(Trifluoromethyl)benzoic acid (1.75g, yield 64.8%), directly to the next step. MS (ESI) m/z [M+H] + = 386.8.

第二步:称取2-氟-6-(4-氟-3-三氟甲基苯氧基)-3-(三氟甲基)苯甲酸(173.7mg,0.45mmol)置于圆底烧瓶中，加入N,N-二甲基甲酰胺(5mL)作溶剂，再加入HATU(206.0mg,0.54mmol)，室温下搅拌15min,再加入3-氰基-4-氟苯胺(68.0mg,0.50mmol)和N,N-二异丙基乙胺(129.3mg,1.36mmol)，室温下继续搅拌5h。反应完成后，将反应液倒入乙酸乙酯中，用水洗去溶剂N,N-二甲基甲酰胺，石油醚：乙酸乙酯＝8：1(v/v)过硅胶柱(200～300目)纯化得N-(3-氰基-4-氟苯基)-2-氟-6-(4-氟-3-三氟甲基苯氧基)-3-(三氟甲基)苯甲酰胺(136mg，收率约60％)。1H-NMR(400MHz,DMSO-d6)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。The second step: Weigh 2-fluoro-6-(4-fluoro-3-trifluoromethylphenoxy)-3-(trifluoromethyl)benzoic acid (173.7mg, 0.45mmol) and place it in a round bottom flask Add N,N-dimethylformamide (5mL) as solvent, then add HATU (206.0mg, 0.54mmol), stir at room temperature for 15min, then add 3-cyano-4-fluoroaniline (68.0mg, 0.50 mmol) and N,N-diisopropylethylamine (129.3mg, 1.36mmol), stirring was continued at room temperature for 5h. After the reaction is completed, pour the reaction solution into ethyl acetate, wash off the solvent N,N-dimethylformamide with water, and pass petroleum ether: ethyl acetate = 8:1 (v/v) through a silica gel column (200-300 Mesh) Purified N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-3-trifluoromethylphenoxy)-3-(trifluoromethyl)benzene Formamide (136 mg, about 60% yield). 1 H-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.

第三步:称取N-(3-氰基-4-氟苯基)-2-氟-6-(4-氟-3-三氟甲基苯氧基)-3-(三氟甲基)苯甲酰胺(151.2mg,0.3mmol)和盐酸羟胺(104.3mg,1.5mmol)置于封管中，加入5mL无水乙醇，再加入三乙胺(151.8mg,1.5mmol)，在氮气氛围下80℃反应过夜。反应完全后，蒸干反应液，加入水，用二氯甲烷萃取，收集有机相，用二氯甲烷：甲醇＝100～50：1(v/v)过硅胶柱(200～300目)得到2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-6-(4-氟-3-(三氟甲基)苯氧基)-3-(三氟甲基)苯甲酰胺(I-67)(112.8mg，收率约70％)。1H-NMR(400MHz in Methanol-d4)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。The third step: weigh N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-3-trifluoromethylphenoxy)-3-(trifluoromethyl ) benzamide (151.2mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, 5mL of absolute ethanol was added, then triethylamine (151.8mg, 1.5mmol) was added, under nitrogen atmosphere React overnight at 80°C. 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 base) benzamide (I-67) (112.8mg, yield about 70%). 1 H-NMR (400MHz in Methanol-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, 8.7 Hz, 1H), 6.89 (d, J = 8.8 Hz, 1H); MS (ESI) m/z [M+H] + = 537.8.

实施例68 6-(2,3-二氟苯氧基)-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-68)的制备Example 68 6-(2,3-difluorophenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl) Preparation of benzamide (I-68)

第一步:先将6-溴-2-氟-3-(三氟甲基)苯甲酸(2.0g,6.97mmol)，2,3-二氟苯酚(1.09g,8.36mmol)，碳酸铯(4.5g,14.0mmol)和碘化亚铜(265.43mg,1.4mmol)，加入到甲苯(50mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚:乙酸乙酯＝2:1(v/v)过硅胶柱(200～300目)得到6-(2,3-二氟苯氧基)-2-氟-3-(三氟甲基)苯甲酸(1.52g,收率64.8％)，直接下一步，MS(ESI)m/z[M+H]+＝336.8。The first step: earlier 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.0g, 6.97mmol), 2,3-difluorophenol (1.09g, 8.36mmol), cesium carbonate ( 4.5g, 14.0mmol) and cuprous iodide (265.43mg, 1.4mmol), were added to toluene (50mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Use petroleum ether: ethyl acetate = 2:1 (v/v) to pass the crude product through a silica gel column (200-300 mesh) to obtain 6-(2,3-difluorophenoxy)-2-fluoro-3-(trifluorophenoxy) Methyl)benzoic acid (1.52 g, yield 64.8%), directly to the next step, MS (ESI) m/z [M+H] + =336.8.

第二步:称取6-(2,3-二氟苯氧基)-2-氟-3-(三氟甲基)苯甲酸(151.2mg,0.45mmol)置于圆底烧瓶中，加入N,N-二甲基甲酰胺(5mL)作溶剂和HATU(206.0mg,0.54mmol)，于室温下搅拌15min,再加入3-氰基-4-氟苯胺(68.0mg,0.50mmol)和N,N-二异丙基乙胺(129.25mg,1.36mmol)，室温下继续搅拌5h。反应完成后，将反应液倒入乙酸乙酯中，用水洗去溶剂N,N-二甲基甲酰胺，用石油醚：乙酸乙酯＝8：1(v/v)过硅胶柱柱(200～300目)纯化得N-(3- 氰基-4-氟苯基)-6-(2,3-二氟苯氧基)-2-氟-3-(三氟甲基)苯甲酰胺(122.58mg，收率60％)。1H-NMR(400MHz,DMSO-d6)δ:11.35(s,1H),8.18(dd,J＝5.7,2.7Hz,1H),7.93(ddd,J＝9.2,4.8,2.7Hz,1H),7.88(t,J＝8.6Hz,1H),7.55(t,J＝9.1Hz,1H),7.40(dddd,J＝10.3,8.6,6.9,1.7Hz,1H),7.31(tdd,J＝8.3,5.8,1.8Hz,1H),7.20(ddt,J＝8.4,6.7,1.7Hz,1H),6.99(d,J＝8.9Hz,1H)；MS(ESI)m/z[M+H]+＝455.1。The second step: take 6-(2,3-difluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (151.2mg, 0.45mmol) and place it in a round bottom flask, add N , N-dimethylformamide (5mL) as solvent and HATU (206.0mg, 0.54mmol), stirred at room temperature for 15min, then added 3-cyano-4-fluoroaniline (68.0mg, 0.50mmol) and N, N-Diisopropylethylamine (129.25mg, 1.36mmol), continued stirring at room temperature for 5h. After the reaction is completed, pour the reaction solution into ethyl acetate, wash the solvent N,N-dimethylformamide with water, and pass through a silica gel column (200 ~300 mesh) 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, 2.7Hz, 1H), 7.93 (ddd, J=9.2, 4.8, 2.7Hz, 1H) ,7.88(t,J=8.6Hz,1H),7.55(t,J=9.1Hz,1H),7.40(dddd,J=10.3,8.6,6.9,1.7Hz,1H),7.31(tdd,J=8.3 ,5.8,1.8Hz,1H),7.20(ddt,J＝8.4,6.7,1.7Hz,1H),6.99(d,J＝8.9Hz,1H); MS(ESI)m/z[M+H] + = 455.1.

第三步:称取N-(3-氰基-4-氟苯基)-6-(2,3-二氟苯氧基)-2-氟-3-(三氟甲基)苯甲酰胺(136.2mg,0.3mmol)和盐酸羟胺(104.3mg,1.5mmol)置于封管中，加入5mL无水乙醇，再加入三乙胺(151.8mg,1.5mmol)，在氮气氛围下80℃反应过夜。反应完全后，蒸干反应液，加入水，用二氯甲烷萃取，收集有机相，用二氯甲烷：甲醇＝100～50：1(v/v)过硅胶柱(200～300目)，得到6-(2,3-二氟苯氧基)-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-68)(102.3mg，收率70％)。1H-NMR(400MHz,DMSO-d6)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。The third step: weigh N-(3-cyano-4-fluorophenyl)-6-(2,3-difluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzamide (136.2mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, 5mL of absolute ethanol was added, and then triethylamine (151.8mg, 1.5mmol) was added, and reacted 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 = 8.8 Hz, 1H), 5.83 (s, 2H); MS (ESI) m/z [M+H] + = 487.8.

实施例69 6-(4-溴-2-氟-6-(三氟甲基)苯氧基)-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-69)的制备Example 69 6-(4-bromo-2-fluoro-6-(trifluoromethyl)phenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl )-3-(trifluoromethyl)benzamide (I-69) preparation

第一步:先将6-溴-2-氟-3-(三氟甲基)苯甲酸(2.0g,6.97mmol)，4-溴-2-氟-6-(三氟甲基)苯酚(2.2g,8.36mmol)，碳酸铯(4.54g,13.94mmol)和碘化亚铜(265.43mg,1.39mmol)，加入到甲苯(50mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝2：1(v/v)过硅胶柱(200～300目)得到6-(4-溴-2-氟-6-(三氟甲基)苯氧基)-2-氟-3-(三氟甲基)苯甲酸(2.10g,收率64.8％)，直接下一步，MS(ESI)m/z[M+H]+＝465.0。The first step: earlier 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.0g, 6.97mmol), 4-bromo-2-fluoro-6-(trifluoromethyl)phenol ( 2.2g, 8.36mmol), cesium carbonate (4.54g, 13.94mmol) and cuprous iodide (265.43mg, 1.39mmol), were added to toluene (50mL), replaced by nitrogen, and then heated to 100 ° C until the reaction of the raw materials was complete . The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Petroleum ether: ethyl acetate = 2:1 (v/v) for the crude product to pass through a silica gel column (200-300 mesh) to obtain 6-(4-bromo-2-fluoro-6-(trifluoromethyl)phenoxy) -2-Fluoro-3-(trifluoromethyl)benzoic acid (2.10 g, yield 64.8%), directly to the next step, MS (ESI) m/z[M+H] + =465.0.

第二步:称取6-(4-溴-2-氟-6-(三氟甲基)苯氧基)-2-氟-3-(三氟甲基)苯甲酸(208.8mg,0.45mmol)置于圆底烧瓶中，加入N,N-二甲基甲酰胺(5mL)作溶剂，再加入HATU(206mg,0.54mmol)，室温下搅拌15min,再加入3-氰基-4-氟苯胺(68.0mg,0.50mmol)和N,N-二异丙基乙胺(129.25mg,1.36mmol)，室温下继续搅拌5h。反应完成后，将反应液倒入乙酸乙酯中，用水洗去溶剂N,N-二甲基甲酰胺，用石油醚：乙酸乙酯＝8：1(v/v)过层析柱(200～300目)纯化得6-(4-溴-2-氟-6-(三氟甲基)苯氧基)-N-(3-氰基-4-氟苯基)-2-氟-3-(三氟甲基)苯甲酰胺(157.14mg，收率60％)。1H-NMR(400MHz,DMSO-d6)δ:11.34(s,1H),8.27(dd,J＝9.9,2.3Hz,1H),8.18(dd,J＝5.7,2.7Hz,1H),7.99～7.91(m,2H),7.84(t,J＝8.6Hz,1H),7.57(t,J＝9.1Hz,1H),6.99(d,J＝8.9Hz,1H)；MS(ESI)m/z[M+H]+＝582.9。The second step: weigh 6-(4-bromo-2-fluoro-6-(trifluoromethyl)phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (208.8mg, 0.45mmol ) in a round bottom flask, add N,N-dimethylformamide (5mL) as solvent, then add HATU (206mg, 0.54mmol), stir at room temperature for 15min, then add 3-cyano-4-fluoroaniline (68.0mg, 0.50mmol) and N,N-diisopropylethylamine (129.25mg, 1.36mmol), and continued stirring at room temperature for 5h. After the reaction is completed, pour the reaction solution into ethyl acetate, wash the solvent N,N-dimethylformamide with water, and pass through the chromatography column with petroleum ether:ethyl acetate=8:1 (v/v) (200 ~300 mesh) 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 (400MHz, DMSO-d 6 )δ: 11.34(s, 1H), 8.27(dd, J=9.9, 2.3Hz, 1H), 8.18(dd, J=5.7, 2.7Hz, 1H), 7.99 ~7.91(m,2H),7.84(t,J=8.6Hz,1H),7.57(t,J=9.1Hz,1H),6.99(d,J=8.9Hz,1H); MS(ESI)m/ z[M+H] + = 582.9.

第三步:称取6-(4-溴-2-氟-6-(三氟甲基)苯氧基)-N-(3-氰基-4-氟苯基)-2-氟-3-(三氟甲基)苯甲酰胺(174.6mg,0.3mmol)和盐酸羟胺(104.3mg,1.5mmol)置于封管中，加入5mL无水乙 醇，再加入三乙胺(151.8mg,1.5mmol)，在氮气氛围下80℃反应过夜。反应完全后，蒸干反应液，加入水，用二氯甲烷萃取，收集有机相，用二氯甲烷：甲醇＝100～50：1(v/v)过层析柱(200～300目)，得到6-(4-溴-2-氟-6-(三氟甲基)苯氧基)-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-69)(129.2mg，收率70％)。1H-NMR(400MHz,DMSO-d6)δ:10.49(s,1H),9.15(s,1H),7.76(dd,J＝9.9,2.3Hz,1H),7.46(d,J＝2.1Hz,1H),7.37～7.27(m,2H),7.18(ddd,J＝8.9,4.4,2.8Hz,1H),6.74(dd,J＝10.2,9.0Hz,1H),6.44(d,J＝8.9Hz,1H),5.32(s,2H)；MS(ESI)m/z[M+H]+＝615.9。The third step: weigh 6-(4-bromo-2-fluoro-6-(trifluoromethyl)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3 -(Trifluoromethyl)benzamide (174.6mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, and 5mL of anhydrous ethyl alcohol was added Alcohol, then added triethylamine (151.8mg, 1.5mmol), and reacted 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 use dichloromethane:methanol=100~50:1 (v/v) to pass through the chromatography column (200~300 mesh), 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 (400MHz, DMSO-d 6 )δ: 10.49(s, 1H), 9.15(s, 1H), 7.76(dd, J=9.9, 2.3Hz, 1H), 7.46(d, J=2.1Hz ,1H),7.37～7.27(m,2H),7.18(ddd,J＝8.9,4.4,2.8Hz,1H),6.74(dd,J＝10.2,9.0Hz,1H),6.44(d,J＝8.9 Hz, 1H), 5.32 (s, 2H); MS (ESI) m/z [M+H] + = 615.9.

实施例70 2,3,4-三氟-6-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)苯甲酰胺(I-70)的制备Example 70 2,3,4-Trifluoro-6-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)benzene Preparation of Amide (I-70)

第一步:先将6-溴-2,3,4-三氟苯甲酸(1.77g,6.97mmol)，4-氟-2-甲基苯酚(1-SM2)(1.05g,8.36mmol)，碳酸铯(4.54g,13.94mmol)和碘化亚铜(265.43mg,1.39mmol)加入到甲苯(50mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝2：1(v/v)过硅胶柱(200～300目)得到2,3,4-三氟-6-(4-氟-2-甲基苯氧基)苯甲酸(1.35g,收率64.8％)，直接下一步，MS(ESI)m/z[M+H]+＝300.8。The first step: first 6-bromo-2,3,4-trifluorobenzoic acid (1.77g, 6.97mmol), 4-fluoro-2-methylphenol (1-SM2) (1.05g, 8.36mmol), Cesium carbonate (4.54g, 13.94mmol) and cuprous iodide (265.43mg, 1.39mmol) were added to toluene (50mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Use petroleum ether: ethyl acetate = 2:1 (v/v) to pass the crude product through a silica gel column (200-300 mesh) to obtain 2,3,4-trifluoro-6-(4-fluoro-2-methylphenoxy ) Benzoic acid (1.35g, yield 64.8%), directly to the next step, MS (ESI) m/z [M+H] + =300.8.

第二步:称取2,3,4-三氟-6-(4-氟-2-甲基苯氧基)苯甲酸(135.0mg,0.45mmol)置于圆底烧瓶中，加入N,N-二甲基甲酰胺(5mL)作溶剂，再加入HATU(206.0mg,0.54mmol)，室温下搅拌15min,再加入3-氰基-4-氟苯胺(68.0mg,0.50mmol)和N,N-二异丙基乙胺(129.3mg,1.36mmol)，室温下继续搅拌5h。反应完成后，将反应液倒入乙酸乙酯中，用水洗去溶剂N,N-二甲基甲酰胺，用石油醚：乙酸乙酯＝8：1(v/v)过层析柱(200～300目)纯化得N-(3-氰基-4-氟苯基)-2,3,4-三氟-6-(4-氟-2-甲基苯氧基)苯甲酰胺(112.9mg，收率60％)。1H-NMR(400MHz,DMSO-d6)δ:11.24(s,1H),8.14(dd,J＝5.8,2.7Hz,1H),7.89(ddd,J＝9.2,4.8,2.7Hz,1H),7.54(t,J＝9.1Hz,1H),7.18(dd,J＝8.9,1.9Hz,1H),7.09(d,J＝1.7Hz,1H),7.07(d,J＝2.3Hz,1H),6.79(ddd,J＝11.7,6.0,2.0Hz,1H),2.14(s,3H)；MS(ESI)m/z[M+H]+＝419.1。Second step: Weigh 2,3,4-trifluoro-6-(4-fluoro-2-methylphenoxy)benzoic acid (135.0mg, 0.45mmol) into a round bottom flask, add N,N -Dimethylformamide (5mL) was used as solvent, then HATU (206.0mg, 0.54mmol) was added, stirred at room temperature for 15min, then 3-cyano-4-fluoroaniline (68.0mg, 0.50mmol) and N,N -Diisopropylethylamine (129.3mg, 1.36mmol), stirring was continued at room temperature for 5h. After the reaction is completed, pour the reaction solution into ethyl acetate, wash the solvent N,N-dimethylformamide with water, and pass through the chromatography column with petroleum ether:ethyl acetate=8:1 (v/v) (200 ~300 mesh) to obtain N-(3-cyano-4-fluorophenyl)-2,3,4-trifluoro-6-(4-fluoro-2-methylphenoxy)benzamide (112.9 mg, yield 60%). 1 H-NMR (400MHz, DMSO-d 6 ) δ: 11.24(s, 1H), 8.14(dd, J=5.8, 2.7Hz, 1H), 7.89(ddd, J=9.2, 4.8, 2.7Hz, 1H) ,7.54(t,J=9.1Hz,1H),7.18(dd,J=8.9,1.9Hz,1H),7.09(d,J=1.7Hz,1H),7.07(d,J=2.3Hz,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.

第三步:称取N-(3-氰基-4-氟苯基)-2,3,4-三氟-6-(4-氟-2-甲基苯氧基)苯甲酰胺(125.4mg,0.3mmol)和盐酸羟胺(104.3mg,1.5mmol)置于封管中，加入无水乙醇(5mL)，再加入三乙胺(151.8mg,1.5mmol)，在氮气氛围下80℃反应过夜。反应完全后，蒸干反应液，加入水，用二氯甲烷萃取，收集有机相，用二氯甲烷：甲醇＝100～50：1(v/v)过层析柱(200～300目)得到2,3,4-三氟-6-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)苯甲酰胺(I-70)(94.7mg，收率70％)。1H-NMR(400MHz,DMSO-d6)δ:10.93(s,1H),9.67(s,1H),7.82(dd,J＝6.4,2.7Hz,1H),7.67(ddd,J＝8.9,4.3,2.7Hz,1H),7.29～7.18(m,2H),7.10(d,J＝1.8Hz,1H),7.08(d,J＝2.2Hz,1H),6.76(ddd,J＝11.7,5.9,2.1Hz,1H),5.83(s,2H),2.15(s,3H)；MS(ESI)m/z[M+H]+＝451.8。 The third step: weigh N-(3-cyano-4-fluorophenyl)-2,3,4-trifluoro-6-(4-fluoro-2-methylphenoxy)benzamide (125.4 mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, added absolute ethanol (5mL), then added triethylamine (151.8mg, 1.5mmol), and reacted 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 use dichloromethane:methanol=100~50:1 (v/v) to pass through a chromatography column (200~300 mesh) 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, 2.7Hz, 1H), 7.67(ddd, J=8.9, 4.3,2.7Hz,1H),7.29～7.18(m,2H),7.10(d,J=1.8Hz,1H),7.08(d,J=2.2Hz,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.

实施例71 6-(2-乙基-4-氟苯氧基)-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-71)的制备Example 71 6-(2-Ethyl-4-fluorophenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoroform base) preparation of benzamide (I-71)

第一步:先将6-溴-2-氟-3-(三氟甲基)苯甲酸(2.0g,6.97mmol)，2-乙基-4-氟苯酚(1.2g,8.36mmol)，碳酸铯(4.54g,13.94mmol)和碘化亚铜(265.43mg,1.39mmol)加入到甲苯(50mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝2：1(v/v)过硅胶柱(200～300目)得到6-(2-乙基-4-氟苯氧基)-2-氟-3-(三氟甲基)苯甲酸(1.57g,收率64.8％)，直接下一步，MS(ESI)m/z[M+H]+＝347.0。The first step: first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.0g, 6.97mmol), 2-ethyl-4-fluorophenol (1.2g, 8.36mmol), carbonic acid Cesium (4.54g, 13.94mmol) and cuprous iodide (265.43mg, 1.39mmol) were added to toluene (50mL), replaced by nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Petroleum ether: ethyl acetate = 2:1 (v/v) was used to pass the crude product through a silica gel column (200-300 mesh) to obtain 6-(2-ethyl-4-fluorophenoxy)-2-fluoro-3-( Trifluoromethyl)benzoic acid (1.57 g, yield 64.8%), directly to the next step, MS (ESI) m/z [M+H] + =347.0.

第二步:称取6-(2-乙基-4-氟苯氧基)-2-氟-3-(三氟甲基)苯甲酸(155.7mg,0.45mmol)置于圆底烧瓶中，加入N,N-二甲基甲酰胺(5mL)作溶剂，再加入HATU(206mg,0.54mmol)，室温下搅拌15min,再加入3-氰基-4-氟苯胺(68mg,0.50mmol)和N,N-二异丙基乙胺(129.3mg,1.36mmol)，室温下继续搅拌5h。反应完成后，将反应液倒入乙酸乙酯中，用水洗去溶剂N,N-二甲基甲酰胺，用石油醚：乙酸乙酯＝8：1(v/v)过层析柱(200～300目)纯化得N-(3-氰基-4-氟苯基)-6-(2-乙基-4-氟苯氧基)-2-氟-3-(三氟甲基)苯甲酰胺(125.3mg，收率60％)。1H-NMR(400MHz,DMSO-d6)δ:11.34(s,1H),8.20(dd,J＝5.7,2.7Hz,1H),7.95(ddd,J＝9.3,4.9,2.7Hz,1H),7.81(t,J＝8.7Hz,1H),7.56(t,J＝9.1Hz,1H),7.25(dd,J＝9.5,3.0Hz,1H),7.23～7.14(m,2H),6.65(d,J＝8.9Hz,1H),2.56～2.44(m,2H),1.05(t,J＝7.6Hz,3H)；MS(ESI)m/z[M+H]+＝465.1。The second step: take 6-(2-ethyl-4-fluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (155.7mg, 0.45mmol) and place it in a round bottom flask, Add N,N-dimethylformamide (5mL) as solvent, then add HATU (206mg, 0.54mmol), stir at room temperature for 15min, then add 3-cyano-4-fluoroaniline (68mg, 0.50mmol) and N , N-diisopropylethylamine (129.3mg, 1.36mmol), continued stirring at room temperature for 5h. After the reaction is completed, pour the reaction solution into ethyl acetate, wash the solvent N,N-dimethylformamide with water, and pass through the chromatography column with petroleum ether:ethyl acetate=8:1 (v/v) (200 ~300 mesh) to obtain N-(3-cyano-4-fluorophenyl)-6-(2-ethyl-4-fluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzene Formamide (125.3 mg, yield 60%). 1 H-NMR (400MHz, DMSO-d 6 ) δ: 11.34 (s, 1H), 8.20 (dd, J=5.7, 2.7Hz, 1H), 7.95 (ddd, J=9.3, 4.9, 2.7Hz, 1H) ,7.81(t,J=8.7Hz,1H),7.56(t,J=9.1Hz,1H),7.25(dd,J=9.5,3.0Hz,1H),7.23～7.14(m,2H),6.65( d, J=8.9Hz, 1H), 2.56~2.44(m, 2H), 1.05(t, J=7.6Hz, 3H); MS (ESI) m/z[M+H] + =465.1.

第三步:称取N-(3-氰基-4-氟苯基)-6-(2-乙基-4-氟苯氧基)-2-氟-3-(三氟甲基)苯甲酰胺(139.2mg,0.3mmol)和盐酸羟胺(104.3mg,1.5mmol)置于封管中，加入无水乙醇(5mL)，再加入三乙胺(151.8mg,1.5mmol)，在氮气氛围下80℃反应过夜。反应完全后，蒸干反应液，加入水，用二氯甲烷萃取，收集有机相，用二氯甲烷：甲醇＝100～50：1(v/v)过层析柱(200～300目)得到6-(2-乙基-4-氟苯氧基)-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-71)(104.4mg，收率70％)。1H-NMR(400MHz,DMSO-d6)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。The third step: weigh N-(3-cyano-4-fluorophenyl)-6-(2-ethyl-4-fluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzene Formamide (139.2mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, added absolute ethanol (5mL), then added triethylamine (151.8mg, 1.5mmol), under nitrogen atmosphere React overnight at 80°C. After the reaction is complete, evaporate the reaction solution to dryness, add water, extract with dichloromethane, collect the organic phase, and use dichloromethane:methanol=100~50:1 (v/v) to pass through a chromatography column (200~300 mesh) to obtain 6-(2-Ethyl-4-fluorophenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzene Formamide (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 = 7.5 Hz, 2H), 1.10 (t, J = 7.5 Hz, 3H); MS (ESI) m/z [M+H] + = 497.9.

实施例72 6-(2-环丙基-4-氟苯氧基)-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-72)的制备Example 72 6-(2-cyclopropyl-4-fluorophenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoro Preparation of methyl) benzamide (I-72)

第一步:先将6-溴-2-氟-3-(三氟甲基)苯甲酸(2.0g,6.97mmol)，2-环丙基-4-氟苯酚(38-a)(1.27g,8.36mmol)，碳酸铯(4.54g,13.94mmol)和碘化亚铜(265.43mg,1.39mmol)加入到甲苯(50mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝2： 1(v/v)过硅胶柱(200～300目)得到6-(2-环丙基-4-氟苯氧基)-2-氟-3-(三氟甲基)苯甲酸(1.62g,收率64.8％)，直接下一步，MS(ESI)m/z[M+H]+＝359.1。The first step: first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.0g, 6.97mmol), 2-cyclopropyl-4-fluorophenol (38-a) (1.27g , 8.36mmol), cesium carbonate (4.54g, 13.94mmol) and cuprous iodide (265.43mg, 1.39mmol) were added to toluene (50mL), replaced with nitrogen, and then heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Petroleum ether for crude product: ethyl acetate = 2: 1 (v/v) passed through a silica gel column (200-300 mesh) to obtain 6-(2-cyclopropyl-4-fluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (1.62g , yield 64.8%), directly to the next step, MS (ESI) m/z [M+H] + =359.1.

第二步:称取6-(2-环丙基-4-氟苯氧基)-2-氟-3-(三氟甲基)苯甲酸(161.1mg,0.45mmol)置于圆底烧瓶中，加入N,N-二甲基甲酰胺(5mL)作溶剂，再加入HATU(206mg,0.54mmol)，室温下搅拌15min，再加入3-氰基-4-氟苯胺(68.0mg,0.50mmol)和N,N-二异丙基乙胺(129.2mg,1.36mmol)，室温下继续搅拌5h。反应完成后，将反应液倒入乙酸乙酯中，用水洗去溶剂N,N-二甲基甲酰胺，用石油醚：乙酸乙酯＝8：1(v/v)过层析柱(200～300目)纯化得N-(3-氰基-4-氟苯基)-6-(2-环丙基-4-氟苯氧基)-2-氟-3-(三氟甲基)苯甲酰胺(128.5mg，收率60％)。1H-NMR(400MHz,DMSO-d6)δ:11.37(s,1H),8.22(dd,J＝5.7,2.7Hz,1H),8.00～7.92(m,1H),7.82(t,J＝8.7Hz,1H),7.56(t,J＝9.1Hz,1H),7.21(dd,J＝8.9,5.0Hz,1H),7.08(td,J＝8.4,3.0Hz,1H),6.88(dd,J＝10.0,3.1Hz,1H),6.64(d,J＝8.9Hz,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。The second step: Weigh 6-(2-cyclopropyl-4-fluorophenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (161.1mg, 0.45mmol) and place it in a round bottom flask , add N,N-dimethylformamide (5mL) as solvent, then add HATU (206mg, 0.54mmol), stir at room temperature for 15min, then add 3-cyano-4-fluoroaniline (68.0mg, 0.50mmol) And N,N-diisopropylethylamine (129.2mg, 1.36mmol), stirring was continued at room temperature for 5h. After the reaction is completed, pour the reaction solution into ethyl acetate, wash the solvent N,N-dimethylformamide with water, and pass through the chromatography column with petroleum ether:ethyl acetate=8:1 (v/v) (200 ~300 mesh) to obtain N-(3-cyano-4-fluorophenyl)-6-(2-cyclopropyl-4-fluorophenoxy)-2-fluoro-3-(trifluoromethyl) Benzamide (128.5 mg, yield 60%). 1 H-NMR (400MHz, DMSO-d 6 ) δ: 11.37(s, 1H), 8.22(dd, J=5.7, 2.7Hz, 1H), 8.00～7.92(m, 1H), 7.82(t, J= 8.7Hz, 1H), 7.56(t, J=9.1Hz, 1H), 7.21(dd, J=8.9, 5.0Hz, 1H), 7.08(td, J=8.4, 3.0Hz, 1H), 6.88(dd, MS (ESI) m/z [M+H] + = 476.9.

第三步:称取N-(3-氰基-4-氟苯基)-6-(2-环丙基-4-氟苯氧基)-2-氟-3-(三氟甲基)苯甲酰胺(142.8mg,0.3mmol)和盐酸羟胺(104.3mg,1.5mmol)置于封管中，加入无水乙醇(5mL)，再加入三乙胺(151.8mg,1.5mmol)，在氮气氛围下80℃反应过夜。反应完全后，蒸干反应液，加入水，用二氯甲烷萃取，收集有机相，用二氯甲烷：甲醇＝100～50：1(v/v)过层析柱(200～300目)，得到6-(2-环丙基-4-氟苯氧基)-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-72)(106.9mg，收率70％)。1H-NMR(400MHz,DMSO-d6)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。The third step: weigh N-(3-cyano-4-fluorophenyl)-6-(2-cyclopropyl-4-fluorophenoxy)-2-fluoro-3-(trifluoromethyl) Benzamide (142.8mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, and absolute ethanol (5mL) was added, followed by triethylamine (151.8mg, 1.5mmol). React overnight at 80°C. After the reaction is complete, evaporate the reaction solution to dryness, add water, extract with dichloromethane, collect the organic phase, and use dichloromethane:methanol=100~50:1 (v/v) to pass through the chromatography column (200~300 mesh), 6-(2-Cyclopropyl-4-fluorophenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl ) benzamide (I-72) (106.9 mg, yield 70%). 1 H-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.

实施例73 2-氟-6-(3-氟-2-甲氧基-4-(三氟甲氧基)苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-73)的制备Example 73 2-fluoro-6-(3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl ) phenyl) -3- (trifluoromethyl) benzamide (I-73) preparation

第一步:先将6-溴-2-氟-3-(三氟甲基)苯甲酸(2.00g,6.97mmol)，3-氟-2-甲氧基-4-(三氟甲氧基)苯酚(1.89g,8.36mmol)，碳酸铯(4.54g,13.94mmol)和碘化亚铜(265.43mg,1.39mmol)加入到甲苯(50mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝2：1(v/v)过硅胶柱(200～300目)得到2-氟-6-(3-氟-2-甲氧基-4-(三氟甲氧基)苯氧基)-3-(三氟甲基)苯甲酸(1.96g,收率64.8％)，直接下一步；MS(ESI)m/z[M+H]+＝433.1。The first step: first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (2.00g, 6.97mmol), 3-fluoro-2-methoxy-4-(trifluoromethoxy ) phenol (1.89g, 8.36mmol), cesium carbonate (4.54g, 13.94mmol) and cuprous iodide (265.43mg, 1.39mmol) were added in toluene (50mL), replaced by nitrogen, and then heated to 100 ° C to react until the raw material The response is complete. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Use petroleum ether:ethyl acetate=2:1 (v/v) to pass the crude product through a silica gel column (200-300 mesh) to obtain 2-fluoro-6-(3-fluoro-2-methoxy-4-(trifluoroform Oxy)phenoxy)-3-(trifluoromethyl)benzoic acid (1.96 g, yield 64.8%), directly to the next step; MS (ESI) m/z [M+H] + =433.1.

第二步:称取2-氟-6-(3-氟-2-甲氧基-4-(三氟甲氧基)苯氧基)-3-(三氟甲基)苯甲酸(194.8mg,0.45mmol)置于圆底烧瓶中，加入N,N-二甲基甲酰胺(5mL)作溶剂，再加入HATU(206mg,0.54mmol)，室温下搅拌15min,再加入3-氰基-4-氟苯胺(68mg,0.50mmol)和N,N-二异丙基乙胺(129.25mg,1.36mmol)，室温下继续搅拌5h。反应完成后，将反应液倒入 乙酸乙酯中，用水洗去溶剂N,N-二甲基甲酰胺，用石油醚：乙酸乙酯＝8：1(v/v)过层析柱(200～300目)纯化得N-(3-氰基-4-氟苯基)-2-氟-6-(3-氟-2-甲氧基-4-(三氟甲氧基)苯氧基)-3-(三氟甲基)苯甲酰胺(148.8mg，收率60％)。1H-NMR(400MHz,DMSO-d6)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。The second step: weigh 2-fluoro-6-(3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy)-3-(trifluoromethyl)benzoic acid (194.8mg , 0.45mmol) in a round bottom flask, add N,N-dimethylformamide (5mL) as solvent, then add HATU (206mg, 0.54mmol), stir at room temperature for 15min, then add 3-cyano-4 -Fluoroaniline (68mg, 0.50mmol) and N,N-diisopropylethylamine (129.25mg, 1.36mmol), continued stirring at room temperature for 5h. After the reaction is complete, pour the reaction solution into In ethyl acetate, wash the solvent N,N-dimethylformamide with water, and use petroleum ether:ethyl acetate=8:1 (v/v) to purify through a chromatographic column (200-300 mesh) 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=9.3,2.1 Hz, 1H), 6.91 (d, J = 8.9 Hz, 1H), 3.86 (s, 3H); MS (ESI) m/z [M+H] + = 551.0.

第三步:称取N-(3-氰基-4-氟苯基)-2-氟-6-(3-氟-2-甲氧基-4-(三氟甲氧基)苯氧基)-3-(三氟甲基)苯甲酰胺(165.0mg,0.3mmol)和盐酸羟胺(104.3mg,1.5mmol)置于封管中，加入无水乙醇(5mL)，再加入三乙胺(151.8mg,1.5mmol)，在氮气氛围下80℃反应过夜。反应完全后，蒸干反应液，加入水，用二氯甲烷萃取，收集有机相，用二氯甲烷：甲醇＝100～50：1(v/v)过层析柱(200～300目)，得到2-氟-6-(3-氟-2-甲氧基-4-(三氟甲氧基)苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-73)(122.4mg，收率70％)。1H-NMR(400MHz,DMSO-d6)δ:11.03(s,1H),9.68(s,1H),7.86(dt,J＝6.0,2.9Hz,1H),7.81(d,J＝8.6Hz,1H),7.71(ddd,J＝8.9,4.3,2.8Hz,1H),7.41(ddd,J＝9.3,8.0,1.3Hz,1H),7.30～7.19(m,2H),6.88(d,J＝8.8Hz,1H),5.85(s,2H),3.87(s,3H)；MS(ESI)m/z[M+H]+＝583.9。The third step: weigh N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy )-3-(trifluoromethyl)benzamide (165.0mg, 0.3mmol) and hydroxylamine hydrochloride (104.3mg, 1.5mmol) were placed in a sealed tube, added absolute ethanol (5mL), and then added triethylamine ( 151.8mg, 1.5mmol), react overnight at 80°C under nitrogen atmosphere. After the reaction is complete, evaporate the reaction solution to dryness, add water, extract with dichloromethane, collect the organic phase, and use dichloromethane:methanol=100~50:1 (v/v) to pass through the chromatography column (200~300 mesh), 2-Fluoro-6-(3-fluoro-2-methoxy-4-(trifluoromethoxy)phenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)benzene is obtained yl)-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, 2.9Hz, 1H), 7.81(d, J=8.6Hz ,1H),7.71(ddd,J＝8.9,4.3,2.8Hz,1H),7.41(ddd,J＝9.3,8.0,1.3Hz,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.

实施例74 5-氯-2-(4-氟-2-甲基苯氧基)-N-(3-(N-羟基氨基甲酰)苯基)-4-(三氟甲基)苯甲酰胺(I-74)的制备Example 74 5-Chloro-2-(4-fluoro-2-methylphenoxy)-N-(3-(N-hydroxycarbamoyl)phenyl)-4-(trifluoromethyl)benzene Preparation of Amide (I-74)

将实施例34得到的5-氯-N-(3-氰基苯基)-2-(4-氟-3-甲氧基苯氧基)-4-(三氟甲基)苯甲酰胺(II-A-26)(141.00mg,0.32mmol)，三乙胺(190.75mg,1.89mmol)和盐酸羟胺(43.66mg,0.64mmol)加入到无水乙醇中，回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷：甲醇(v/v)＝100～20：1过层析柱(200～300目)得到5-氯-2-(4-氟-2-甲基苯氧基)-N-(3-(N-羟基氨基甲酰)苯基)-4-(三氟甲基)苯甲酰胺(I-74)(80.0mg,收率52.8％)。1H-NMR(400MHz,DMSO-d6)δ:10.64(s,1H),9.66(s,1H),8.03(s,1H),8.01(s,1H),7.65(d,J＝7.6Hz,1H),7.35～7.40(q,2H),7.21(dd,J＝1.6,9.6Hz,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。5-Chloro-N-(3-cyanophenyl)-2-(4-fluoro-3-methoxyphenoxy)-4-(trifluoromethyl)benzamide obtained in Example 34 ( II-A-26) (141.00mg, 0.32mmol), triethylamine (190.75mg, 1.89mmol) and hydroxylamine hydrochloride (43.66mg, 0.64mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain a crude product, which was then passed through a chromatographic 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 H-NMR (400MHz,DMSO-d 6 )δ:10.64(s,1H),9.66(s,1H),8.03(s,1H),8.01(s,1H),7.65(d,J＝7.6Hz ,1H),7.35～7.40(q,2H),7.21(dd,J＝1.6,9.6Hz,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.

实施例75 2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-4-(三氟甲基)苯甲酰胺(I-75)的制备Example 75 2-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-4-(trifluoromethyl)benzene Preparation of Amide (I-75)

第一步:在装有干燥管的反应瓶中，将实施例1得到的2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酸(1-b)(628.0mg,2.00mmol)溶于二氯甲烷(20mL)中，加入催化量的DMF后将反应体系冷却到0℃左右，随后缓慢滴加草酰氯(1.7mL,20.00mmol)，滴加完毕后于室温下反应直到酸全部转化为酰氯。将反应体系浓缩除去多余的草酰氯和二氯甲烷，再将残留物溶于二氯甲烷中并冷却到0℃左右缓慢加入三乙胺(404.5mg,4.00mmol)，随后加入5-氨基-2-氟苯腈(285.7mg,2.10mmol)于室温下反应直到反应完全，加入水，用稀盐酸中和，静止分液 得到二氯甲烷相，浓缩得粗品。粗品用石油醚：乙酸乙酯＝10～2：1(v/v)过硅胶柱(200～300目)得到N-(3-氰基-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(437.0mg,收率50.4％)。1H-NMR(400MHz,DMSO-d6)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。The first step: in the reaction bottle that drying tube is housed, the 2-(4-fluoro-2-methylphenoxy group)-4-(trifluoromethyl)benzoic acid (1-b that embodiment 1 obtains ) (628.0mg, 2.00mmol) was dissolved in dichloromethane (20mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, and then oxalyl chloride (1.7mL, 20.00mmol) was slowly added dropwise, and the addition was completed Then react at room temperature until the acid is completely converted to acid 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 (404.5mg, 4.00mmol), and then add 5-amino-2 - Fluorobenzonitrile (285.7mg, 2.10mmol) was reacted at room temperature until the reaction was complete, water was added, neutralized with dilute hydrochloric acid, static liquid separation The dichloromethane phase was obtained, which was concentrated to give the crude product. Use petroleum ether for the crude product: ethyl acetate = 10～2:1 (v/v) to pass through a silica gel column (200～300 mesh) to obtain N-(3-cyano-4-fluorophenyl)-2-(4-fluorophenyl) -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.

第二步:将N-(3-氰基-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(43.00mg,0.1mmol)，三乙胺(20.13mg,0.2mmol)和盐酸羟胺(13.82mg,0.2mmol)加入到无水乙醇中,回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷：甲醇(v/v)＝100～20：1过硅胶柱(200～300目)得到2-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-4-(三氟甲基)苯甲酰胺(I-75)(25.0mg,收率54.0％)。1H-NMR(600MHz,DMSO-d6)δ:10.98(s,1H),8.06(s,1H),7.89(d,J＝5.4Hz,1H),7.84(s,1H),7.60(d,J＝5.4Hz,1H),7.48(s,1H),7.23(d,J＝5.4Hz,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。The second step: N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (43.00mg , 0.1mmol), triethylamine (20.13mg, 0.2mmol) and hydroxylamine hydrochloride (13.82mg, 0.2mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. 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 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=5.4Hz, 1H), 7.84(s, 1H), 7.60(d ,J=5.4Hz,1H),7.48(s,1H),7.23(d,J=5.4Hz,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.

实施例76 4-溴-2-氟-6-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)苯甲酰胺(I-76)的制备Example 76 4-Bromo-2-fluoro-6-(4-fluoro-2-methylphenoxy)-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)benzamide Preparation of (I-76)

第一步:先将4-溴-2,6-二氟苯甲酸甲酯(474.0mg,1.89mmol)，4-氟-2-甲基苯酚(262.0mg,2.08mmol)，碳酸铯(1.23g,3.78mmol)加入到N,N-二甲基甲酰胺(20.0mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝20：1(v/v)过硅胶柱(200～300目)得到4-溴-2-氟-6-(4-氟-2-甲基苯氧基)苯甲酸甲酯(420.0mg,收率62.8％)。1H-NMR(400MHz in CDCl3)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)。The first step: first methyl 4-bromo-2,6-difluorobenzoate (474.0mg, 1.89mmol), 4-fluoro-2-methylphenol (262.0mg, 2.08mmol), cesium carbonate (1.23g , 3.78mmol) was added into N,N-dimethylformamide (20.0mL), replaced with nitrogen, and then the temperature was raised to 100°C to react until the reaction of the raw materials was complete. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Petroleum ether: ethyl acetate = 20:1 (v/v) for the crude product to pass through a silica gel column (200-300 mesh) to obtain 4-bromo-2-fluoro-6-(4-fluoro-2-methylphenoxy) Methyl benzoate (420.0 mg, yield 62.8%). 1 H-NMR (400MHz 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).

将4-溴-2-氟-6-(4-氟-2-甲基苯氧基)苯甲酸甲酯(350.0mg,0.98mmol)加入到95％乙醇(20mL)中，随后加入氢氧化钠(10.00M,391.96mg,9.80mmol)于回流下反应直到原料完全水解成酸，浓缩，加入水，随后用盐酸调pH值到2～3左右析出大量白色固体，过滤，干燥得到4-溴-2-氟-6-(4-氟-2-甲基苯氧基)苯甲酸(300.0mg,收率94％)，直接下一步。Add methyl 4-bromo-2-fluoro-6-(4-fluoro-2-methylphenoxy)benzoate (350.0 mg, 0.98 mmol) to 95% ethanol (20 mL) followed by sodium hydroxide (10.00M, 391.96mg, 9.80mmol) was reacted under reflux until the raw material was completely hydrolyzed into an acid, concentrated, added water, and then adjusted the pH value to about 2 to 3 with hydrochloric acid to precipitate a large amount of white solid, which was filtered and dried to obtain 4-bromo- 2-Fluoro-6-(4-fluoro-2-methylphenoxy)benzoic acid (300.0 mg, yield 94%), directly to the next step.

第二步:在装有干燥管的反应瓶中，先将4-溴-2-氟-6-(4-氟-2-甲基苯氧基)苯甲酸(350.0mg,1.0mmol)溶于二氯甲烷(20mL)中，加入催化量的DMF后将反应体系冷却到0℃左右，随后缓慢滴加草酰氯(1.3g,10.2mmol)，滴加完毕后于室温下反应直到酸全部转化为酰氯。将反应体系浓缩除去多余的草酰氯和二氯甲烷，再将残留物溶于二氯甲烷中并冷却到0℃左右缓慢加入三乙胺(206.4mg,2.0mmol)，随后加入5-氨基-2-氟苯腈(138.9mg,1.0mmol)于室温下反应直到反应完全，加入水，用稀盐酸中和，静止分液得到二氯甲烷相，浓缩得粗品。粗品用石油醚：乙酸乙酯＝20～4：1(v/v)过硅胶柱(200～300目)得到4-溴-N-(3- 氰基-4-氟苯基)-2-氟-6-(4-氟-2-甲基苯氧基)苯甲酰胺(200.0mg,收率42.5％)。1H-NMR(600MHz,DMSO-d6)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)。The second step: in the reaction flask equipped with a drying tube, first dissolve 4-bromo-2-fluoro-6-(4-fluoro-2-methylphenoxy)benzoic acid (350.0mg, 1.0mmol) in In dichloromethane (20mL), add a catalytic amount of DMF and cool the reaction system to about 0°C, then slowly add oxalyl chloride (1.3g, 10.2mmol) dropwise, and react at room temperature until the acid is completely converted to acid chloride. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0°C and slowly add triethylamine (206.4mg, 2.0mmol), followed by 5-amino-2 - Fluorobenzonitrile (138.9mg, 1.0mmol) was reacted at room temperature until the reaction was complete, water was added, neutralized with dilute hydrochloric acid, static liquid separation was obtained to obtain a dichloromethane phase, and the crude product was concentrated. Use petroleum ether:ethyl acetate=20～4:1 (v/v) to pass the crude product through a silica gel column (200～300 mesh) 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).

第三步:将4-溴-N-(3-氰基-4-氟苯基)-2-氟-6-(4-氟-2-甲基苯氧基)苯甲酰胺(112.00mg,0.24mmol)，三乙胺(147.43mg,1.5mmol)和盐酸羟胺(33.75mg,0.48mmol)加入到无水乙醇中,回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷：甲醇(v/v)＝100～20：1过柱(200～300目)得到4-溴-2-氟-6-(4-氟-2-甲基苯氧基)-N-(4-氟-3-(N-羟基氨基甲酰)苯基)苯甲酰胺(I-76)(52.0mg,收率43.3％)。1H-NMR(400MHz,DMSO-d6)δ:10.88(brs,1H),9.68(brs,1H),7.83(brs,1H),7.69(brs,1H),7.49(d,J＝5.2Hz,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)。The third step: 4-bromo-N-(3-cyano-4-fluorophenyl)-2-fluoro-6-(4-fluoro-2-methylphenoxy)benzamide (112.00mg, 0.24mmol), triethylamine (147.43mg, 1.5mmol) and hydroxylamine hydrochloride (33.75mg, 0.48mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain a crude product, which was then passed through a column (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=5.2Hz ,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).

实施例77 2-氟-6-(4-氟-2-甲基苯氧基)-N-(3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-77)的制备Example 77 2-fluoro-6-(4-fluoro-2-methylphenoxy)-N-(3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzene Preparation of Amide (I-77)

第一步:在装有干燥管的反应瓶中，将按照实施例48制备的2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酸(471.0mg,1.5mmol)溶于二氯甲烷(20mL)中，加入催化量的DMF后将反应体系冷却到0℃左右，随后缓慢滴加草酰氯(1.27mL,14.99mmol)，滴加完毕后于室温下反应直到酸全部转化为酰氯。将反应体系浓缩除去多余的草酰氯和二氯甲烷，再将残留物溶于二氯甲烷中并冷却到0℃左右缓慢加入三乙胺(303.4mg,3.0mmol)，随后加入5-氨基-2-氟苯腈(214.2mg,1.6mmol)于室温下反应直到反应完全，加入水，用稀盐酸中和，静止分液得到二氯甲烷相，浓缩得粗品。粗品用石油醚：二氯甲烷＝1：1(v/v)过硅胶柱(200～300目)得到N-(3-氰基-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(437.0mg,收率67％)。MS(ESI)m/z[M+H]+＝433.0。The first step: in the reaction flask equipped with a drying tube, 2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzoic acid (471.0mg) prepared according to Example 48 , 1.5mmol) was dissolved in dichloromethane (20mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then slowly added dropwise oxalyl chloride (1.27mL, 14.99mmol), and after the dropwise addition, the React until all the acid is converted to acid chloride. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0°C and slowly add triethylamine (303.4mg, 3.0mmol), followed by 5-amino-2 - Fluorobenzonitrile (214.2mg, 1.6mmol) was reacted at room temperature until the reaction was complete, water was added, neutralized with dilute hydrochloric acid, static liquid separation was obtained to obtain a dichloromethane phase, and the crude product was concentrated. Use petroleum ether for the crude product: dichloromethane = 1:1 (v/v) to pass through a silica gel column (200-300 mesh) 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.

第二步:将N-(3-氰基-4-氟苯基)-2-(4-氟-2-甲基苯氧基)-4-(三氟甲基)苯甲酰胺(43.0mg,0.1mmol)，三乙胺(20.1mg,0.2mmol)和盐酸羟胺(13.8mg,0.2mmol)加入到无水乙醇中,回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷：甲醇(v/v)＝100～20：1过柱(200～300目)得到2-氟-6-(4-氟-2-甲基苯氧基)-N-(3-(N-羟基氨基甲酰)苯基)-3-(三氟甲基)苯甲酰胺(I-77)(25.0mg,收率54％)。1H-NMR(600MHz,DMSO-d6)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＝2.4,8Hz,2H),6.99(s,1H),2.15(s,3H)；MS(ESI)m/z[M+H]+＝466.1。The second step: N-(3-cyano-4-fluorophenyl)-2-(4-fluoro-2-methylphenoxy)-4-(trifluoromethyl)benzamide (43.0mg , 0.1mmol), triethylamine (20.1mg, 0.2mmol) and hydroxylamine hydrochloride (13.8mg, 0.2mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain a crude product, which was then passed through a column (200-300 mesh) with dichloromethane:methanol (v/v)=100-20:1 to obtain 2-fluoro-6-(4-fluoro-2-methyl Phenoxy)-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＝8.0Hz,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=2.4,8Hz,2H),6.99( s,1H), 2.15(s,3H); MS (ESI) m/z [M+H] + = 466.1.

实施例78 6-(4-氯-2-三氟甲基)苯氧基-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-三氟甲基苯甲酰胺(I-78)的制备 Example 78 6-(4-Chloro-2-trifluoromethyl)phenoxy-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-trifluoro Preparation of methyl benzamide (I-78)

第一步:先将6-溴-2-氟-3-三氟甲基苯甲酸(1.0g,3.5mmol)，4-氯-2-三氟甲基苯酚(720.0mg,3.7mmol)，碳酸铯(2.3g,7.0mmol)和碘化亚铜(130.0mg,0.7mmol)，加入到甲苯(50mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝10～2：1(v/v)过硅胶柱(200～300目)得到6-(4-氯-2-三氟甲基)苯氧基-2-氟-3-三氟甲基苯甲酸(990.0mg,收率70.6％)。1H-NMR(400MHz,DMSO-d6)δ:7.94(s,1H),7.87(t,J＝8.4Hz,1H),7.80(dd,J＝2.4,8.8Hz,1H),7.32(d,J＝8.8Hz,1H),7.10(d,J＝8.8Hz,1H)；MS(ESI)m/z[M+H]+＝425.1,427.1(3:1)。The first step: first 6-bromo-2-fluoro-3-trifluoromethylbenzoic acid (1.0g, 3.5mmol), 4-chloro-2-trifluoromethylphenol (720.0mg, 3.7mmol), carbonic acid Cesium (2.3g, 7.0mmol) and cuprous iodide (130.0mg, 0.7mmol) were added into toluene (50mL), replaced with nitrogen, and then heated to 100°C to react until the reaction of the raw materials was complete. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Use petroleum ether for the crude product: ethyl acetate = 10～2:1 (v/v) to pass through a silica gel column (200～300 mesh) 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=8.4Hz, 1H), 7.80(dd, J=2.4, 8.8Hz, 1H), 7.32(d , J=8.8Hz, 1H), 7.10 (d, J=8.8Hz, 1H); MS (ESI) m/z [M+H] + =425.1, 427.1 (3:1).

第二步:装有干燥管的反应瓶中，将6-(4-氯-2-三氟甲基)苯氧基-2-氟-3-三氟甲基苯甲酸(776.0mg,2.0mmol)溶于二氯甲烷(20mL)中，加入催化量的DMF后将反应体系冷却到0℃左右，随后缓慢滴加草酰氯(1.63mL,20.0mmol)，滴加完毕后于室温下反应直到酸全部转化为酰氯。将反应体系浓缩除去多余的草酰氯和二氯甲烷，再将残留物溶于二氯甲烷中并冷却到0℃左右缓慢加入三乙胺(0.84mL,5.8mmol)，随后加入5-氨基-2-氟苯腈(275.5mg,2.0mmol)于室温下反应直到反应完全，加入水，用稀盐酸中和，静止分液得到二氯甲烷相，浓缩得粗品。粗品用石油醚：二氯甲烷＝20～4：1(v/v)过硅胶柱(200～300目)得到6-(4-氯-2-三氟甲基)苯氧基-N-(3-氰基-4-氟苯基)-2-氟-3-三氟甲基苯甲酰胺(320.0mg,收率32％)。1H-NMR(400MHz,DMSO-d6)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＝8.8,2.4Hz,1H),7.56(t,J＝9.2Hz,1H),7.38(d,J＝8.8Hz,1H),7.07(d,J＝8.8Hz,1H)；MS(ESI)m/z[M+H]+＝521.0,523.0(3:1)。The second step: in the reaction flask equipped with a drying tube, 6-(4-chloro-2-trifluoromethyl)phenoxy-2-fluoro-3-trifluoromethylbenzoic acid (776.0mg, 2.0mmol ) was dissolved in dichloromethane (20mL), and after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then slowly added dropwise oxalyl chloride (1.63mL, 20.0mmol), and reacted at room temperature until the acid All were converted to acid chlorides. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0°C and slowly add triethylamine (0.84mL, 5.8mmol), followed by 5-amino-2 - Fluorobenzonitrile (275.5mg, 2.0mmol) was reacted at room temperature until the reaction was complete, water was added, neutralized with dilute hydrochloric acid, static separation was obtained to obtain a dichloromethane phase, and the crude product was concentrated. Use petroleum ether for the crude product: dichloromethane=20～4:1 (v/v) to pass through a silica gel column (200～300 mesh) to obtain 6-(4-chloro-2-trifluoromethyl)phenoxy-N-( 3-cyano-4-fluorophenyl)-2-fluoro-3-trifluoromethylbenzamide (320.0 mg, yield 32%). 1 H-NMR (400MHz, 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=8.8,2.4Hz,1H),7.56(t,J=9.2Hz,1H),7.38(d,J=8.8Hz,1H),7.07(d,J=8.8Hz,1H); MS( ESI) m/z [M+H] + = 521.0, 523.0 (3:1).

第三步:将6-(4-氯-2-三氟甲基)苯氧基-N-(3-氰基-4-氟苯基)-2-氟-3-三氟甲基苯甲酰胺(300.0mg,0.58mmol)，三乙胺(0.24mL,1.7mmol)和盐酸羟胺(400.0mg,12.0mmol)加入到无水乙醇中,回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷：甲醇(v/v)＝100～20：1过硅胶柱(300～400目)得到6-(4-氯-2-三氟甲基)苯氧基-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-三氟甲基苯甲酰胺(I-78)(130.0mg,收率40.8％)。1H-NMR(400MHz,DMSO-d6)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)。The third step: 6-(4-chloro-2-trifluoromethyl)phenoxy-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-trifluoromethylbenzene Amide (300.0mg, 0.58mmol), triethylamine (0.24mL, 1.7mmol) and hydroxylamine hydrochloride (400.0mg, 12.0mmol) were added to absolute ethanol, and reacted 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 (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) (130.0mg, 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 = 8.8 Hz, 1H), 5.84 (brs, 2H); MS (ESI) m/z [M+H] + = 554.1, 556.1 (3:1).

实施例79 6-(4-氟-2-三氟甲基)苯氧基-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-三氟甲基苯甲酰胺(I-79)的制备Example 79 6-(4-fluoro-2-trifluoromethyl)phenoxy-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-trifluoro Preparation of methyl benzamide (I-79)

第一步:先将6-溴-2-氟-3-三氟甲基苯甲酸(1.2g,4.2mmol)，4-氟-2-三氟甲基苯酚(790.0mg,4.4mmol)，碳酸铯(2.7g,7.0mmol)和碘化亚铜(160.0mg,0.2mmol)，加入到甲苯(50mL)中，氮气置换，随后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中， 随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝10～2：1(v/v)过硅胶柱(200～300目)得到6-(4-氯-2-三氟甲基)苯氧基-2-氟-3-三氟甲基苯甲酸(1.27g,收率78.6％)。1H-NMR(400MHz,DMSO-d6)δ:7.81～7.85(m,2H),7.64(t,J＝8.4Hz,1H),7.42(s,1H),6.88(d,J＝8.8Hz,1H)；MS(ESI)m/z[M+H]+＝386.8。The first step: first 6-bromo-2-fluoro-3-trifluoromethylbenzoic acid (1.2g, 4.2mmol), 4-fluoro-2-trifluoromethylphenol (790.0mg, 4.4mmol), carbonic acid Cesium (2.7g, 7.0mmol) and cuprous iodide (160.0mg, 0.2mmol) were added into toluene (50mL), replaced with nitrogen, and then heated to 100°C to react until the reaction of the raw materials was complete. Pour the reaction system into ice water, Subsequent extraction with ethyl acetate, the organic phase was dried and concentrated to give the crude product. Use petroleum ether for the crude product: ethyl acetate = 10～2:1 (v/v) to pass through a silica gel column (200～300 mesh) to obtain 6-(4-chloro-2-trifluoromethyl)phenoxy-2-fluoro -3-Trifluoromethylbenzoic acid (1.27g, yield 78.6%). 1 H-NMR (400MHz, DMSO-d 6 )δ: 7.81～7.85(m, 2H), 7.64(t, J＝8.4Hz, 1H), 7.42(s, 1H), 6.88(d, J＝8.8Hz , 1H); MS (ESI) m/z [M+H]+ = 386.8.

第二步:装有干燥管的反应瓶中，将6-(4-氟-2-三氟甲基)苯氧基-2-氟-3-三氟甲基苯甲酸(1.16g,3.0mmol)溶于二氯甲烷(20mL)中，加入催化量的DMF后将反应体系冷却到0℃左右，随后缓慢滴加草酰氯(2.54mL,30.0mmol)，滴加完毕后于室温下反应直到酸全部转化为酰氯。将反应体系浓缩除去多余的草酰氯和二氯甲烷，再将残留物溶于二氯甲烷中并冷却到0℃左右缓慢加入三乙胺(1.25mL,9.0mmol)，随后加入5-氨基-2-氟苯腈(430.0mg,3.15mmol)于室温下反应直到反应完全，加入水，用稀盐酸中和，静止分液得到二氯甲烷相，浓缩得粗品。粗品用石油醚：二氯甲烷＝20～4：1(v/v)过硅胶柱(200～300目)得到6-(4-氟-2-三氟甲基)苯氧基-N-(3-氰基-4-氟苯基)-2-氟-3-三氟甲基苯甲酰胺(1.0g,收率66.7％)。1H-NMR(400MHz,DMSO-d6):11.30(s,1H),8.14(s,1H),7.88～7.93(q,2H),7.80(dd,J＝2.0,8.4Hz),7.68(td,J＝8.8,2.8Hz,1H),7.56(t,J＝9.2Hz,1H),7.46(q,1H),6.95(d,J＝8.8Hz,1H)；MS(ESI)m/z[M+H]+＝504.7；The second step: in the reaction flask equipped with a drying tube, 6-(4-fluoro-2-trifluoromethyl)phenoxy-2-fluoro-3-trifluoromethylbenzoic acid (1.16g, 3.0mmol ) was dissolved in dichloromethane (20mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then slowly added dropwise oxalyl chloride (2.54mL, 30.0mmol), and reacted at room temperature until the acid All were converted to acid chlorides. Concentrate the reaction system to remove excess oxalyl chloride and dichloromethane, then dissolve the residue in dichloromethane and cool to about 0°C and slowly add triethylamine (1.25mL, 9.0mmol), followed by 5-amino-2 -Fluorobenzonitrile (430.0mg, 3.15mmol) was reacted at room temperature until the reaction was complete, water was added, neutralized with dilute hydrochloric acid, static liquid separation was obtained to obtain a dichloromethane phase, and the crude product was concentrated. Use petroleum ether for the crude product: dichloromethane=20～4:1 (v/v) to pass through a silica gel column (200～300 mesh) to obtain 6-(4-fluoro-2-trifluoromethyl)phenoxy-N-( 3-cyano-4-fluorophenyl)-2-fluoro-3-trifluoromethylbenzamide (1.0 g, yield 66.7%). 1 H-NMR (400MHz, DMSO-d 6 ): 11.30(s, 1H), 8.14(s, 1H), 7.88～7.93(q, 2H), 7.80(dd, J=2.0, 8.4Hz), 7.68( td,J=8.8,2.8Hz,1H),7.56(t,J=9.2Hz,1H),7.46(q,1H),6.95(d,J=8.8Hz,1H); MS(ESI)m/z [M+H]+=504.7;

第三步:将6-(4-氟-2-三氟甲基)苯氧基-N-(3-氰基-4-氟苯基)-2-氟-3-三氟甲基苯甲酰胺(850.0mg,1.7mmol)，三乙胺(0.7mL,5.0mmol)和盐酸羟胺(234.0mg,3.4mmol)加入到无水乙醇中,回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷：甲醇(v/v)＝100～20：1(v/v)过硅胶柱(300～400目)得到6-(4-氟-2-三氟甲基)苯氧基-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-三氟甲基苯甲酰胺(I-79)(590.0mg,收率65％)。1H-NMR(400MHz,DMSO-d6)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。The third step: 6-(4-fluoro-2-trifluoromethyl)phenoxy-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-trifluoromethylbenzene Amide (850.0mg, 1.7mmol), triethylamine (0.7mL, 5.0mmol) and hydroxylamine hydrochloride (234.0mg, 3.4mmol) were added to absolute ethanol, and reacted 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 a 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-trifluoromethylbenzamide (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 = 8.8 Hz, 1H), 5.84 (brs, 2H); MS (ESI) m/z [M+H] + = 538.1.

实施例80 6-(2-环丙基-4-(三氟甲氧基)苯氧基)-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-三氟甲基苯甲酰胺(I-80)的制备Example 80 6-(2-Cyclopropyl-4-(trifluoromethoxy)phenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl) - Preparation of 3-trifluoromethylbenzamide (I-80)

第一步:先将6-溴-2-氟-3-(三氟甲基)苯甲酸(600mg,2.1mmol),2-环丙基-4-)三氟甲氧基)苯酚(501.6mg,2.3mmol)，碳酸铯(1.36g,4.2mmol)和碘化亚铜(39.6mg,0.21mmol)，加入到甲苯(25mL)中，氮气置换后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后调节pH至2-3，用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝8～6：1(v/v)过硅胶柱(200～300目)得到6-(2-环丙基-4-(三氟甲氧基)苯氧基)-2-氟-3-(三氟甲基)苯甲酸(570mg,收率64.2％)。1H NMR(400MHz,Chloroform-d)δ:7.56(t,J＝8.3Hz,1H),7.06(s,2H),6.80(s,1H),6.51(d,J＝8.9Hz,1H),1.96(tt,J＝8.4,5.2Hz,1H),0.96～0.89 (m,2H),0.67～0.61(m,2H)；MS(ESI)m/z[M+H]+＝424.8。The first step: first 6-bromo-2-fluoro-3-(trifluoromethyl)benzoic acid (600mg, 2.1mmol), 2-cyclopropyl-4-)trifluoromethoxy)phenol (501.6mg , 2.3mmol), cesium carbonate (1.36g, 4.2mmol) and cuprous iodide (39.6mg, 0.21mmol), were added to toluene (25mL), replaced with nitrogen, and heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, then the pH was adjusted to 2-3, extracted with ethyl acetate, the organic phase was dried and concentrated to obtain a crude product. Petroleum ether: ethyl acetate = 8-6:1 (v/v) for the crude product through a silica gel column (200-300 mesh) to obtain 6-(2-cyclopropyl-4-(trifluoromethoxy)phenoxy )-2-fluoro-3-(trifluoromethyl)benzoic acid (570 mg, yield 64.2%). 1 H NMR (400MHz, Chloroform-d) δ: 7.56(t, J=8.3Hz, 1H), 7.06(s, 2H), 6.80(s, 1H), 6.51(d, J=8.9Hz, 1H), 1.96(tt,J＝8.4,5.2Hz,1H),0.96～0.89 (m,2H), 0.67~0.61 (m,2H); MS (ESI) m/z [M+H]+=424.8.

第二步:将6-(2-环丙基-4-(三氟甲氧基)苯氧基)-2-氟-3-)三氟甲基)苯甲酸(550.0mg,1.3mmol)溶于二氯亚砜(20mL)中，于80℃回流反应2h直到酸全部转化为酰氯。将反应体系浓缩除去多余的二氯亚砜，再将残留物溶于二氯甲烷(20mL)中,加入三乙胺(0.360mL,2.60mmol)，随后加入5-氨基-2-氟苯腈(176.0mg,1.30mmol)于室温下反应直到反应完全，加入水，乙酸乙酯萃取，有机相干燥，浓缩得粗品。粗品用石油醚：乙酸乙酯＝20～6：1(v/v)过硅胶柱(200～300目)得到6-(2-环丙基-4-(三氟甲氧基)苯氧基)-N-(3-氰基-4-氟苯基)-2-氟-3-三氟甲基苯甲酰胺(606.0mg,收率86.2％)。1H NMR(400MHz,DMSO-d6)δ:11.32(s,1H),8.21～8.15(m,1H),7.97～7.89(m,1H),7.86(t,J＝8.7Hz,1H),7.57(t,J＝9.1Hz,1H),7.29～7.25(m,2H),7.01(s,1H),6.73(d,J＝8.9Hz,1H),1.96(tt,J＝8.6,4.8Hz,1H),0.92～0.81(m,2H),0.74～0.68(m,2H)；MS(ESI)m/z[M+H]+＝542.7；The second step: 6-(2-cyclopropyl-4-(trifluoromethoxy)phenoxy)-2-fluoro-3-)trifluoromethyl)benzoic acid (550.0mg, 1.3mmol) was dissolved In thionyl chloride (20 mL), reflux at 80° C. for 2 h until the acid is completely converted to acid chloride. The reaction system was concentrated to remove excess thionyl chloride, then the residue was dissolved in dichloromethane (20mL), triethylamine (0.360mL, 2.60mmol) was added, followed by 5-amino-2-fluorobenzonitrile ( 176.0mg, 1.30mmol) was reacted at room temperature until the reaction was complete, water was added, extracted with ethyl acetate, the organic phase was dried and concentrated to obtain a crude product. Petroleum ether: ethyl acetate = 20-6:1 (v/v) for the crude product to pass through a silica gel column (200-300 mesh) to obtain 6-(2-cyclopropyl-4-(trifluoromethoxy)phenoxy )-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-trifluoromethylbenzamide (606.0 mg, yield 86.2%). 1 H NMR (400MHz,DMSO-d 6 )δ:11.32(s,1H),8.21～8.15(m,1H),7.97～7.89(m,1H),7.86(t,J＝8.7Hz,1H), 7.57(t, J=9.1Hz, 1H), 7.29～7.25(m, 2H), 7.01(s, 1H), 6.73(d, J=8.9Hz, 1H), 1.96(tt, J=8.6, 4.8Hz ,1H),0.92～0.81(m,2H),0.74～0.68(m,2H); MS(ESI)m/z[M+H]+＝542.7;

第三步:将6-(2-环丙基-4-(三氟甲氧基)苯氧基)-N-(3-氰基-4-氟苯基)-2-氟-3-三氟甲基苯甲酰胺(100.0mg,0.18mmol)，三乙胺(0.08mL,0.55mmol)和盐酸羟胺(25.6mg,0.37mmol)加入到无水乙醇中，回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷：甲醇＝30：1(v/v)爬层析硅胶板得到6-(2-环丙基-4-(三氟甲氧基)苯氧基)-2-氟-N-(4-氟-3-(N-羟基氨基甲酰)苯基)-3-三氟甲基苯甲酰胺(I-80)(63.0mg,收率60.0％)。1H NMR(600MHz,DMSO-d6)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。The third step: 6-(2-cyclopropyl-4-(trifluoromethoxy)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-tri Fluoromethylbenzamide (100.0mg, 0.18mmol), triethylamine (0.08mL, 0.55mmol) and hydroxylamine hydrochloride (25.6mg, 0.37mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain the crude product, which was then used to climb a silica gel plate with dichloromethane:methanol=30:1 (v/v) to obtain 6-(2-cyclopropyl-4-(trifluoromethoxy)phenoxy Base)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-trifluoromethylbenzamide (I-80) (63.0mg, 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.

实施例81 6-(2,4-双(三氟甲基)苯氧基)-2-氟-N-(4-氟-3-(N-羟基氨基甲酰基)苯基)-3-(三氟甲基)苯甲酰胺(I-81)的制备Example 81 6-(2,4-bis(trifluoromethyl)phenoxy)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-( Preparation of trifluoromethyl)benzamide (I-81)

第一步:先将6-溴-2-氟-3-三氟甲基苯甲酸(500.0mg,1.74mmol)，2,4-二三氟甲基苯酚(421.0mg,1.83mmol)，碳酸铯(1.14g,3.48mmol)和碘化亚铜(66.0mg,0.35mmol)，加入到甲苯(20mL)中，氮气置换后升温到100℃反应直到原料反应完全。将反应体系倒入冰水中，随后用乙酸乙酯萃取，有机相干燥，浓缩得到粗品。粗品用石油醚：乙酸乙酯＝10～2：1(v/v)过硅胶柱(200～300目)得到6-(2,4-双(三氟甲基)苯氧基)-2-氟-3-(三氟甲基)苯甲酸(540.0mg,收率71.0％)。1H-NMR(400MHz,DMSO-d6)δ:8.15(s,1H),8.07(d,J＝8.4Hz,1H),7.95(t,J＝9.2Hz,1H),7.38(d,J＝8.8Hz,1H),7.23(d,J＝8.8Hz,1H)；MS(ESI)m/z[M+H]+＝437.1。The first step: first 6-bromo-2-fluoro-3-trifluoromethylbenzoic acid (500.0mg, 1.74mmol), 2,4-ditrifluoromethylphenol (421.0mg, 1.83mmol), cesium carbonate (1.14g, 3.48mmol) and cuprous iodide (66.0mg, 0.35mmol), were added to toluene (20mL), replaced with nitrogen, and heated to 100°C to react until the raw materials were completely reacted. The reaction system was poured into ice water, followed by extraction with ethyl acetate, and the organic phase was dried and concentrated to obtain a crude product. Petroleum ether: ethyl acetate = 10～2:1 (v/v) for the crude product to pass through a silica gel column (200～300 mesh) 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=8.4Hz, 1H), 7.95(t, J=9.2Hz, 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.

第二步:装有干燥管的反应瓶中，将6-(2,4-双(三氟甲基)苯氧基)-2-氟-3-(三氟甲基)苯甲酸(400.0mg,9.2mmol)溶于二氯甲烷(20mL)中，加入催化量的DMF后将反应体系冷却到0℃左右，随后缓慢滴加草酰氯(0.78mL,9.2mmol)，滴加完毕后于室温下反应直到酸全部转化 为酰氯。将反应体系浓缩除去多余的草酰氯和二氯甲烷，再将残留物溶于二氯甲烷中并冷去到0℃左右缓慢加入三乙胺(0.38mL,2.7mmol)，随后加入5-氨基-2-氟苯腈(131.0mg,0.96mmol)于室温下反应直到反应完全，加入水，用稀盐酸中和，静止分液得到二氯甲烷相，浓缩的粗品。粗品用石油醚：乙酸乙酯＝20～4：1(v/v)过硅胶柱(200～300目)得到6-(2,4-双(三氟甲基)苯氧基)-N-(3-氰基-4-氟苯基)-2-氟-3-(三氟甲基)苯甲酰胺(330.0mg,收率64.9％)。1H-NMR(400MHz,DMSO-d6):11.32(s,1H),8.12(brs,2H),8.06(s,1H),8.00(t,J＝8.4Hz,1H),7.84～.88(m,1H),7.55(t,J＝9.2Hz,1H),7.47(d,J＝9.2Hz,1H),7.29(d,J＝8.8Hz,1H)；MS(ESI)m/z[M+H]+＝554.6；The second step: in the reaction flask equipped with a drying tube, 6-(2,4-bis(trifluoromethyl)phenoxy)-2-fluoro-3-(trifluoromethyl)benzoic acid (400.0mg , 9.2mmol) was dissolved in dichloromethane (20mL), after adding a catalytic amount of DMF, the reaction system was cooled to about 0°C, then slowly added dropwise oxalyl chloride (0.78mL, 9.2mmol), and after the dropwise addition, the React until all acid is converted For acid chloride. The reaction system was concentrated to remove excess oxalyl chloride and dichloromethane, then the residue was dissolved in dichloromethane and cooled to about 0°C, slowly added triethylamine (0.38mL, 2.7mmol), followed by 5-amino- 2-Fluorobenzonitrile (131.0 mg, 0.96 mmol) was reacted at room temperature until the reaction was complete, water was added, neutralized with dilute hydrochloric acid, static liquid separation was obtained to dichloromethane phase, concentrated crude product. Petroleum ether: ethyl acetate = 20-4:1 (v/v) for the crude product to pass through a silica gel column (200-300 mesh) 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 H-NMR (400MHz, DMSO-d 6 ): 11.32(s, 1H), 8.12(brs, 2H), 8.06(s, 1H), 8.00(t, J=8.4Hz, 1H), 7.84～.88 (m,1H),7.55(t,J=9.2Hz,1H),7.47(d,J=9.2Hz,1H),7.29(d,J=8.8Hz,1H); MS(ESI)m/z[ M+H] + = 554.6;

第三步:将6-(2,4-双(三氟甲基)苯氧基)-N-(3-氰基-4-氟苯基)-2-氟-3-(三氟甲基)苯甲酰胺(140.0mg,0.25mmol)，三乙胺(0.1mL,0.75mmol)和盐酸羟胺(25.7mg,0.50mmol)加入到无水乙醇中,回流下反应直到原料反应完全。浓缩，加入水，用乙酸乙酯萃取。有机相干燥，浓缩得到粗品，随后用二氯甲烷：甲醇(v/v)＝100～20：1过柱(300～400目)得到6-(2,4-双(三氟甲基)苯氧基)-2-氟-N-(4-氟-3-(N-羟基氨基甲酰基)苯基)-3-(三氟甲基)苯甲酰胺(I-81)(103.0mg,收率70％)。1H-NMR(600MHz,DMSO-d6)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。The third step: 6-(2,4-bis(trifluoromethyl)phenoxy)-N-(3-cyano-4-fluorophenyl)-2-fluoro-3-(trifluoromethyl ) benzamide (140.0mg, 0.25mmol), triethylamine (0.1mL, 0.75mmol) and hydroxylamine hydrochloride (25.7mg, 0.50mmol) were added to absolute ethanol, and reacted under reflux until the reaction of the raw materials was complete. Concentrate, add water, and extract with ethyl acetate. The organic phase was dried and concentrated to obtain a crude product, which was then passed through a column (300-400 mesh) with dichloromethane:methanol (v/v)=100-20:1 to obtain 6-(2,4-bis(trifluoromethyl)benzene Oxygen)-2-fluoro-N-(4-fluoro-3-(N-hydroxycarbamoyl)phenyl)-3-(trifluoromethyl)benzamide (I-81) (103.0mg, yield rate of 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.

实验例生物部分测试：本发明化合物对钠离子通道1.8(Navl.8)的阻滞活性Experimental example Biological part test: the inhibitory activity of compound of the present invention to sodium ion channel 1.8 (Nav1.8)

1.检测方法：全细胞手动膜片钳技术检测化合物对电压门控Nav1.8通道电流的影响1. Detection method: Whole-cell manual patch clamp technique to detect the effect of compounds on voltage-gated Nav1.8 channel current

2.检测化合物的配制和分析2. Preparation and Analysis of Detection Compounds

阴性对照：含0.5％DMSO的电生理细胞外液Negative control: electrophysiological extracellular fluid containing 0.5% DMSO

测试化合物：称量一定质量的化合物用DMSO溶解，配制20mM的DMSO母液。测试当天，将20mM的化合物母液用细胞外液梯度稀释至需要检测的最终浓度，保证测试药物溶液中的DMSO含量不超过0.5％，此浓度的DMSO对检测的Nav1.8通道电流没有影响。例如配制100nM和1μM化合物溶液，其梯度稀释方法如下：先吸取5μL DMSO母液加入到10mL的细胞外液中，溶解均匀，得到10μM的化合物溶液；再吸取1mL的10μM的化合物，加入到9mL的细胞外液中，溶解均匀，得到1μM的化合物溶液；再吸取1mL的1μM的化合物，加入到9mL的细胞外液中，溶解均匀，得到100nM的化合物溶液。本实验的所有阳性对照使用VX-150为阳性对照药物，其半数抑制浓度为33.45±0.86nM，与原文献报道结果一致。本实验使用的阴性对照为含有0.5％DMSO的细胞外液，给药10分钟后通道的电流变化值≤5％。Test compound: Weigh a certain mass of compound and dissolve it in DMSO to prepare a 20 mM DMSO stock solution. On the day of the test, the 20mM compound mother solution was gradiently diluted with the extracellular fluid to the final concentration to be detected to ensure that the DMSO content in the test drug solution did not exceed 0.5%. This concentration of DMSO had no effect on the detected Nav1.8 channel current. For example, to prepare 100nM and 1μM compound solutions, the gradient dilution method is as follows: first absorb 5μL DMSO mother solution and add it to 10mL extracellular fluid, dissolve evenly, and obtain a 10μM compound solution; then absorb 1mL of 10μM compound and add it to 9mL of cells In the external fluid, dissolve evenly to obtain a 1 μM compound solution; then pipette 1 mL of the 1 μM compound, add it to 9 mL of extracellular fluid, and dissolve evenly to obtain a 100 nM compound solution. All positive controls in this experiment used VX-150 as the positive control drug, and its half inhibitory concentration was 33.45±0.86nM, which was consistent with the results reported in the original literature. The negative control used in this experiment was the extracellular fluid containing 0.5% DMSO, and the current change value of the channel was ≤5% after administration for 10 minutes.

3.细胞培养3. Cell culture

(1)Nav1.8细胞株：稳定表达人源Nav1.8钠通道的HEK293(Flp-In T-Rex-293)细胞， 编码基因信息如下：NM_001293306.2。(1) Nav1.8 cell line: HEK293 (Flp-In T-Rex-293) cells stably expressing human Nav1.8 sodium channel, The encoding gene information is as follows: NM_001293306.2.

(2)培养和传代条件与方法：细胞株培养在37℃、5％CO2的恒温培养箱中。Nav1.8稳转株用含10％无四环素的胎牛血清(HyClone公司)和100μg/mL Hygromycin B的DMEM(Gibco公司)高糖的完全培养基培养。实验前一天细胞生长到90％左右密度时消化传代，首先吸去培养基，用37℃预热的磷酸缓冲液(PBS)洗涤细胞，弃掉PBS缓冲液后，加入胰酶消化后转移至离心管中，800rpm离心3分钟，弃去上清，加入含1μg/mL Doxcycline的完全培养基重悬，传代至6孔板中，诱导培养20小时后，分离传代至用多聚赖氨酸包被的盖玻片中继续培养1-2小时后，用于电生理记录实验。(2) Conditions and methods for culture and passage: the cell lines were cultured in a constant temperature incubator at 37° C. and 5% CO 2 . Nav1.8 stably transfected strains were cultured with 10% tetracycline-free fetal bovine serum (HyClone Company) and 100 μg/mL Hygromycin B in DMEM (Gibco Company) high-glucose complete medium. The day before the experiment, when the cells grew to about 90% density, they were digested and passaged. First, the medium was sucked off, and the cells were washed with 37°C preheated phosphate buffer solution (PBS). In the tube, centrifuge at 800rpm for 3 minutes, discard the supernatant, add complete medium containing 1 μg/mL Doxcycline to resuspend, and pass to a 6-well plate. After 20 hours of induction culture, separate and pass to coat with poly-lysine After continuing to culture on the coverslip for 1-2 hours, it was used for electrophysiological recording experiments.

4.电生理实验4. Electrophysiological Experiments

(1)在室温(23～25℃)下用全细胞电压钳技术记录Nav1.8钠通道电流。(1) Nav1.8 sodium channel current was recorded by whole-cell voltage-clamp technique at room temperature (23-25°C).

(2)全细胞电压钳记录实验采用Axon patch 700B膜片钳放大器(Molecular Devices公司)，数模转换器为Digidata 1440A(Molecular Devices公司)，玻璃微电极由玻璃电极毛胚(World Precision Instrunents公司)经拉制仪(P97，Sutter公司)拉制而成，灌注电极内液后的尖端电阻为1.5-2.5MΩ左右，将玻璃微电极插入放大器探头即可连接至膜片钳放大器。钳制电压和数据记录由pClamp 10软件(Molecular Devices公司)通过电脑控制和记录，采样频率为20kHz，滤波频率为2kHz。(2) Axon patch 700B patch clamp amplifier (Molecular Devices Company) was used in the whole-cell voltage clamp recording experiment, the digital-to-analog converter was Digidata 1440A (Molecular Devices Company), and the glass microelectrodes were made of glass electrode blanks (World Precision Instruments Company) It is drawn by a drawing machine (P97, Sutter Company), and the resistance of the tip after filling the electrode inner liquid is about 1.5-2.5 MΩ. Insert the glass microelectrode into the amplifier probe to connect to the patch clamp amplifier. The clamping voltage and data recording are controlled and recorded by the pClamp 10 software (Molecular Devices) through a computer, the sampling frequency is 20kHz, and the filtering frequency is 2kHz.

(3)电生理实验用细胞外液和细胞内液：(3) Extracellular fluid and intracellular fluid for electrophysiological experiments:

细胞外液配方(mM)：140NaCL,3KCL,1CaCl2,1MgCl2,10HEPES and 20Glucose，用NaOH调节pH至7.3。Extracellular fluid formula (mM): 140NaCL, 3KCL, 1CaCl 2 , 1MgCl 2 , 10HEPES and 20Glucose, adjust the pH to 7.3 with NaOH.

细胞内液配方(mM)：140CsF,10NaCL,10HEPES，1.1EGTA and 20Glucose，用CsOH调节pH至7.3。Intracellular fluid formula (mM): 140CsF, 10NaCL, 10HEPES, 1.1EGTA and 20Glucose, adjust the pH to 7.3 with CsOH.

(4)电生理刺激方案：得到全细胞记录(达到高阻抗的GΩ封接条件)后，在-80mV下钳制电压下等待4-5分钟至电极内液与细胞内液平衡，然后开始电生理记录。电流刺激和化合物活性检测方案：细胞钳制在-80mV，给予时长20ms，+10mV的去极化电压刺激，再复极化到-80mV，刺激频率为0.5Hz。确定Nav1.8钠通道电流稳定后(约1分钟)开始给药过程，至细胞电流不再变化为止(化合物抑制达到稳态)。化合物每个浓度至少测试3个细胞(n≥3)。所有检测化合物后给予单浓度100nM VX-150作阳性对照。(4) Electrophysiological stimulation protocol: After obtaining whole-cell recordings (reaching high-impedance GΩ sealing conditions), wait for 4-5 minutes at a clamping voltage of -80mV until the electrode internal fluid and intracellular fluid are balanced, and then start electrophysiological stimulation Record. Current stimulation and compound activity detection scheme: cells were clamped at -80mV, given a depolarization voltage stimulation of +10mV for 20ms, then repolarized to -80mV, and the stimulation frequency was 0.5Hz. After confirming that the Nav1.8 sodium channel current is stable (about 1 minute), the administration process starts until the cell current no longer changes (compound inhibition reaches a steady state). At least 3 cells (n > 3) were tested for each concentration of compound. A single concentration of 100nM VX-150 was given as a positive control after all the tested compounds.

5.数据分析5. Data Analysis

数据采集分析处理采用pClamp10(Molecular Devices公司)GraphPad Prism 5(GraphPad Software公司)和Excel(Microsoft公司)软件，所有数据均以平均值±标准误差(Mean±SEM)表示。化合物对电流的影响用以下公式计算：
抑制率(％)＝[1-加药后电流的大小(IDrug)/加药前电流的大小(IControl)]×100。Data acquisition, analysis and processing were performed using pClamp10 (Molecular Devices), GraphPad Prism 5 (GraphPad Software) and Excel (Microsoft), and all data were expressed as mean ± standard error (Mean ± SEM). The effect of the compound on the current is calculated using the following formula:
Inhibition rate (%)=[1-the magnitude of the current after drug administration (I Drug )/the magnitude of the current before drug administration (I Control )]×100.

剂量效应曲线利用Hill方程拟合：Y＝Bottom+(Top-Bottom)/(1+10^(LogIC50-X)×k)， 其中，Bottom和Top分别表示抑制的最小数值和最大数值，X表示化合物浓度的对数值，Y表示IDrug/IControl数值，IC50表示产生半数抑制效应的药物剂量，k表示Hill系数。The dose-effect curve was fitted using the Hill equation: Y=Bottom+(Top-Bottom)/(1+10^(LogIC 50 -X)×k), Among them, Bottom and Top represent the minimum value and maximum value of inhibition respectively, X represents the logarithmic value of the compound concentration, Y represents the I Drug /I Control value, IC 50 represents the drug dose that produces half the inhibitory effect, and k represents the Hill coefficient.

结果如下表。The results are shown in the table below.

表1本发明化合物对Navl.8通道的活性IC50值(nM)
Table 1 The compounds of the present invention are to the active IC of Nav1.8 channel 50 value (nM)

表2本发明化合物在1nM的浓度下对Nav1.8通道的百分阻滞活性
Table 2 The compound of the present invention is to the percent blocking activity of Nav1.8 channel under the concentration of 1nM

表3本发明化合物在10nM的浓度下对Nav1.8通道的百分阻滞活性

Table 3 The compound of the present invention is to the percent blocking activity of Nav1.8 channel at the concentration of 10nM

表4本发明化合物在30nM浓度下对Nav1.8通道的百分阻滞活性
Table 4 The compound of the present invention is to the percent blocking activity of Nav1.8 channel under the concentration of 30nM

表5本发明部分化合物在100nM浓度下对Nav1.8通道的百分阻滞活性

Table 5 Some compounds of the present invention have a percentage blocking activity of Nav1.8 channel at a concentration of 100nM

药代部分测试：Pharmacokinetic part of the test:

本实验例对大鼠通过单次静脉注射或灌胃口服给药进行了体内药代动力学评价。In this experimental example, the in vivo pharmacokinetics of rats were evaluated by single intravenous injection or oral administration by gavage.

1.试验方法和条件：雄性SD大鼠，动物均禁食过夜，分别单次静脉给予待测化合物2mg/kg或者1mg/kg(静脉溶媒为5％DMSO/10％Solutol/10％EtOH/75％Saline，给药体积为5mL/kg)和灌胃给予10mg/kg或者5mg/kg(给药溶媒为0.5％CMC-Na，给药体积为10mL/kg)。1. Test method and condition: Male SD rats, all animals were fasted overnight, and the compound to be tested was administered intravenously at 2 mg/kg or 1 mg/kg (intravenous vehicle was 5% DMSO/10% Solutol/10% EtOH/75 %Saline, the administration volume is 5 mL/kg) and intragastric administration of 10 mg/kg or 5 mg/kg (the administration vehicle is 0.5% CMC-Na, the administration volume is 10 mL/kg).

2.采样信息：分别于给药前和给药后0.25、0.5、1.0、2.0、3.0、4.0、6.0、8.0、24(静脉给药组增加5min采样点)；在以上设定时间点经眼球后静脉丛取血0.2ml，置EDTA-K2试管中，11000rpm离心5min，分离血浆，于–20℃冰箱中冷冻。2. Sampling information: 0.25, 0.5, 1.0, 2.0, 3.0, 4.0, 6.0, 8.0, 24 before administration and after administration respectively (intravenous administration group increased 5min sampling point); Take 0.2ml of blood from the posterior venous plexus, put it in an EDTA-K2 test tube, centrifuge at 11,000rpm for 5min, separate the plasma, and freeze it in a -20°C refrigerator.

3.检测信息：采用LC/MS/MS法测定大鼠/小鼠静脉给予待测化合物和灌胃给予后大鼠/小鼠血浆中原形药物的浓度。计算两种给药方式下的大鼠/小鼠血浆药动学参数，计算各化合物在大鼠体内的生物利用度。结果如下表6和表7所示。3. Detection information: LC/MS/MS method was used to determine the concentration of the original drug in the plasma of rats/mouses after intravenous administration of the compound to be tested and intragastric administration. Calculate the rat/mouse plasma pharmacokinetic parameters under the two administration modes, and calculate the bioavailability of each compound in rats. The results are shown in Table 6 and Table 7 below.

表6代表性化合物静脉药动学信息
Table 6 Intravenous pharmacokinetic information of representative compounds

表7代表性化合物灌胃药动学信息
Table 7 Pharmacokinetic information of representative compounds by gavage

以上各实施例，以编号和对应的结构式为准，且仅用以举例说明本发明的技术方案，而非对其限制。尽管参照前述各实施例对本发明进行了详细的说明，本领域的普通技术人员应当理解：在没有脱离本发明权利要求所限定的精神和实质的范围内，可以对前述各实施例所记载的技术方案进行修改，或者对其中部分或者全部技术特征进行等同替换；而这些修改或者替换仍然在本发明权利要求所限定的范围内。 The above embodiments are subject to numbers and corresponding structural formulas, and are only used to illustrate the technical solution of the present invention, not to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled 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 technology described in the foregoing embodiments can be Modifications to the scheme, or equivalent replacement of some or all of the technical features; and these modifications or replacements are still within the scope of the claims of the present invention.

Claims (10)

一种式I所述的化合物，其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，其氘代物或其药学上可接受的盐，
A compound described in formula I, its tautomers, mesomers, racemates, enantiomers, diastereomers, deuterated products or pharmaceutically acceptable salts thereof ,
其中：in: A环为取代或未取代的C6～C12芳基、取代或未取代的含有选自N、O、S的1至4个杂原子的5～10元杂芳基；所述取代的取代基选自卤素、C1～C6烷基、氘代C1～C6烷基、卤代C1～C6烷基、C1～C6烷氧基、氘代C1～C6烷氧基、卤代C1～C6烷氧基、C3～C8环烷基、氘代C3～C8环烷基、卤代C3～C8环烷基、C3～C8环烷氧基、氘代C3～C8环烷氧基、卤代C3～C8环烷氧基；优选选自F、Cl、C1～C3烷基、氘代C1～C3烷基、卤代C1～C3烷基、C1～C3烷氧基、氘代C1～C3烷氧基、卤代C1～C3烷氧基、C3～C6环烷基、氘代C3～C6环烷基、卤代C3～C6环烷基、C3～C6环烷氧基、氘代C3～C6环烷氧基、卤代C3～C6环烷氧基；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, and S; the substituted substituent is selected from 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 cycloalkane Oxygen; preferably 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; R1和R2各自独立地选自氢、C1～C6烷基、C3～C6环烷基、C(＝O)R1a、C(＝O)OR2a，其中，R1a选自氢、C1～C6烷基、C3～C6环烷基、苯基，R2a选自C1～C6烷基、C3～C6环烷基、苯基；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, phenyl, R 2a is selected from C1～C6 alkyl, C3～C6 cycloalkyl, phenyl; R3选自氢、-CN、-OH或C1～C6烷氧基；R 3 is selected from hydrogen, -CN, -OH or C1～C6 alkoxy; X1和X2之一为C，另一个选自N和CRg；One of X 1 and X 2 is C, and the other is selected from N and CR g ; R4、R5、R6各自独立地选自氢、卤素、C1～C3烷基、C1～C3烷氧基、C3～C6环烷基；R 4 , R 5 , and R 6 are each independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, and C3-C6 cycloalkyl; X3、X4和X5各自独立地选自N和CRa，且X3、X4和X5中至多存在一个N；X 3 , X 4 and X 5 are each independently selected from N and CR a , and there is at most one N in X 3 , X 4 and X 5 ; R7选自氢、卤素、C1～C6烷基、卤代C1～C6烷基、C1～C6烷氧基、卤代C1～C6烷氧基； R7 is selected from hydrogen, halogen, C1～C6 alkyl, halogenated C1～C6 alkyl, C1～C6 alkoxy, halogenated C1～C6 alkoxy; Ra、Rg在每次出现时独立地选自氢、卤素、C1～C6烷基、卤代C1～C6烷基、C1～C6烷氧基、卤代C1～C6烷氧基、C2～C6烯基、卤代C2～C6烯基、C2～C6烯氧基、卤代C2～C6 烯氧基、C2～C6炔基、卤代C1～C6炔基、C2～C6炔氧基、卤代C1～C6炔氧基、C3～C6环烷基、C3～C6环烷氧基；R a and R g are independently selected from hydrogen, halogen, C1~C6 alkyl, halogenated C1~C6 alkyl, C1~C6 alkoxy, halogenated C1~C6 alkoxy, C2~ C6 alkenyl, halogenated C2～C6 alkenyl, C2～C6 alkenyloxy, halogenated C2～C6 Alkenyloxy, C2-C6 alkynyl, halogenated C1-C6 alkynyl, C2-C6 alkynyloxy, halogenated C1-C6 alkynyloxy, C3-C6 cycloalkyl, C3-C6 cycloalkoxy; 或者，R7和Ra中相邻的两个取代基连同与其相连的碳原子共同构成环或取代或未取代的苯环；所述取代的取代基选自卤素、C1～C6烷基、C1～C6烷氧基；优选选自F、Cl、C1～C3烷基、C1～C3烷氧基；Alternatively, the two adjacent substituents in R 7 and R a together with the carbon atoms attached to them form a ring Or a substituted or unsubstituted benzene ring; the substituted substituent is selected from halogen, C1～C6 alkyl, C1～C6 alkoxy; preferably selected from F, Cl, C1～C3 alkyl, C1～C3 alkoxy base; Y1和Y2各自独立地选自O、CH2；Y 1 and Y 2 are each independently selected from O, CH 2 ; R8选自氢、卤素或C1～C3烷基。R 8 is selected from hydrogen, halogen or C1-C3 alkyl. 根据权利要求1所述的化合物，其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，其氘代物或其药学上可接受的盐，其中，The compound according to claim 1, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, its deuterated product or a pharmaceutically acceptable salt thereof ,in, A环为取代或未取代的苯基；和/或Ring A is substituted or unsubstituted phenyl; and/or R1、R2和R3至少一个为H，特别地，R1、R2和R3都为氢；和/或At least one of R 1 , R 2 and R 3 is H, in particular, R 1 , R 2 and R 3 are all hydrogen; and/or 为 for 根据权利要求1或2所述的化合物，其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，其氘代物或其药学上可接受的盐，其中，The compound according to claim 1 or 2, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, its deuterated product or its pharmaceutically acceptable of salt, of which, 式I化合物选自：
Compounds of formula I are selected from:
其中，in, X1、X2各自独立地选自N和CRg，X 1 and X 2 are each independently selected from N and CR g , R1、R2、R3、R4、R5、R6、R7、A环、X3、X4、X5的定义与相应权利要求相同；The definitions of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , Ring A, X 3 , X 4 , and X 5 are the same as those in the corresponding claims; 或者or 式I化合物选自如下式I-A化合物和式I-A’化合物：
The compound of formula I is selected from the following compounds of formula IA and formula IA':
其中，in, X1、X2各自独立地选自N和CRg；X 1 and X 2 are each independently selected from N and CR g ; R1、R2、R3、R4、R5、R6、R7、Rg、X3、X4、X5的定义同权利要求1；The definitions of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R g , X 3 , X 4 , and X 5 are the same as in claim 1; X6、X7、X8各自独立地选自N和CRb，且X6、X7和X8中至多存在一个N；X 6 , X 7 , X 8 are each independently selected from N and CR b , and there is at most one N in X 6 , X 7 and X 8 ; Rb、R9和R10在每次出现时各自独立地选自氢、卤素、C1～C6烷基、氘代C1～C6烷基、卤代C1～C6烷基、C1～C6烷氧基、氘代C1～C6烷氧基、卤代C1～C6烷氧基、C3～C8环烷基、氘代C3～C8环烷基、卤代C3～C8环烷基、C3～C8环烷氧基、氘代C3～C8环烷氧基、卤代C3～C8环烷氧基；优选选自氢、F、Cl、C1～C3烷基、氘代C1～C3烷基、卤代C1～C3烷基、C1～C3烷氧基、氘代C1～C3烷氧基、卤代C1～C3烷氧基、C3～C6环烷基、氘代C3～C6环烷基、卤代C3～C6环烷基、C3～C6环烷氧基、氘代C3～C6环烷氧基、卤代C3～C6环烷氧基；R b , R 9 and R 10 are 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 Group, deuterated C3～C8 cycloalkoxy, halogenated C3～C8 cycloalkoxy; 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 ring Alkyl, C3~C6 cycloalkoxy, deuterated C3~C6 cycloalkoxy, halogenated C3~C6 cycloalkoxy; 特别地，在I-A化合物中，In particular, in the I-A compound, X2选自N或CRg，优选为CRg，Rg选自氢、F、Cl、Br、C1～C6烷基或C1～C6烷氧基，优选为氢、F、Cl或Br，更优选为氢或F，特别是F；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; X3、X4各自独立地为CRa，X5选自N或CRa，Ra每次出现时相同或不同，选自氢、卤代C1～C6烷基、卤代C1～C6烷氧基，优选X3中的Ra选自三氟甲基或三氟甲氧基，X4和X5中的Ra为氢；X 3 and 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, halogenated C1-C6 alkyl, halogenated C1-C6 alkoxy group, preferably R in X3 is selected from trifluoromethyl or trifluoromethoxy, and R in X4 and X5 is hydrogen; X6、X7、X8各自独立地选自CRb，Rb相同或不同，选自氢、卤素、C1～C6烷基、卤代C1～C6烷基、C1～C6烷氧基、卤代C1～C6烷氧基、C3～C8环烷基，优选选自氢、F、Cl、Br、三氟甲基、甲氧基或三氟甲氧基；X 6 , X 7 , and X 8 are each independently selected from CR b , R b is the same or different, selected from hydrogen, halogen, C1-C6 alkyl, halogenated C1-C6 alkyl, C1-C6 alkoxy, halogen Substitute C1～C6 alkoxy, C3～C8 cycloalkyl, preferably selected from hydrogen, F, Cl, Br, trifluoromethyl, methoxy or trifluoromethoxy; R9为氢；R10选自氢、三氟甲基、C3～C6环烷基、氘代C3～C6环烷基；R 9 is hydrogen; R 10 is selected from hydrogen, trifluoromethyl, C3～C6 cycloalkyl, deuterated C3～C6 cycloalkyl; R7选自卤素、C1～C6烷氧基，优选选自F、Cl、Br或甲氧基；R 7 is selected from halogen, C1～C6 alkoxy, preferably selected from F, Cl, Br or methoxy; R4、R5、R6各自独立地选自氢、卤素、C1～C3烷基、C1～C3烷氧基，优选为氢；R 4 , R 5 , and R 6 are each independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, preferably hydrogen; R1和R2各自独立地选自氢、C1～C6烷基，优选为氢； R 1 and R 2 are each independently selected from hydrogen, C1-C6 alkyl, preferably hydrogen; R3选自氢、-CN、-OH或C1～C6烷氧基，优选为-OH。R 3 is selected from hydrogen, -CN, -OH or C1-C6 alkoxy, preferably -OH. 根据权利要求3所述的化合物，其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，其氘代物或其药学上可接受的盐，其中，The compound according to claim 3, its tautomer, mesomer, racemate, enantiomer, diastereomer, its deuterated product or a pharmaceutically acceptable salt thereof ,in, 式I-A化合物选自如下式I-A-1化合物：
The compound of formula IA is selected from the following compounds of formula IA-1:
其中，R1、R2、R3、R4、R5、X5、R6、R7、R9、R10、Ra、Rb、Rg的定义同权利要求3；Wherein, the definitions of R 1 , R 2 , R 3 , R 4 , R 5 , X 5 , R 6 , R 7 , R 9 , R 10 , R a , R b , and R g are the same as in claim 3; 特别地，R1、R2和R3为氢；In particular, R 1 , R 2 and R 3 are hydrogen; 特别地，R4、R5、R6、Rg中至少两个为H，特别是至少三个为H，更特别是全部为H；In particular, at least two of R 4 , R 5 , R 6 , R g are H, especially at least three are H, more especially all are H; 特别地，R7、Ra中至少一个为H，特别是至少二个为H；In particular, at least one of R 7 and R a is H, especially at least two of them are H; 特别地，R9、R10、Rb中至少两个为H，特别是至少三个为H；In particular, at least two of R 9 , R 10 , R b are H, especially at least three are H; 特别地，式I-A-1化合物中，Particularly, in the compound of formula I-A-1, Rg选自氢、F、Cl、Br、C1～C6烷基或C1～C6烷氧基，优选为氢、F、Cl或Br，更优选为氢或F，特别是F；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; X5选自N或CRa，Ra每次出现时相同或不同，选自氢、卤代C1～C6烷基、卤代C1～C6烷氧基，优选X3中的Ra选自三氟甲基或三氟甲氧基，X4和X5中的Ra为氢；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 in X 3 is selected from three Fluoromethyl or trifluoromethoxy, R in X 4 and X 5 is hydrogen; Rb相同或不同，选自氢、卤素、C1～C6烷基、卤代C1～C6烷基、C1～C6烷氧基、卤代C1～C6烷氧基、C3～C8环烷基，优选选自氢、F、Cl、Br、三氟甲基、甲氧基或三氟甲氧基；R b is the same or different, 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; R9为氢；R10选自氢、三氟甲基、C3～C6环烷基、氘代C3～C6环烷基；R 9 is hydrogen; R 10 is selected from hydrogen, trifluoromethyl, C3～C6 cycloalkyl, deuterated C3～C6 cycloalkyl; R7选自卤素、C1～C6烷氧基，优选选自F、Cl、Br或甲氧基；R 7 is selected from halogen, C1～C6 alkoxy, preferably selected from F, Cl, Br or methoxy; R4、R5、R6各自独立地选自氢、卤素、C1～C3烷基、C1～C3烷氧基，优选为氢；R 4 , R 5 , and R 6 are each independently selected from hydrogen, halogen, C1-C3 alkyl, C1-C3 alkoxy, preferably hydrogen; R1和R2各自独立地选自氢、C1～C6烷基，优选为氢；R 1 and R 2 are each independently selected from hydrogen, C1-C6 alkyl, preferably hydrogen; R3选自氢、-CN、-OH或C1～C6烷氧基，优选为-OH。 R 3 is selected from hydrogen, -CN, -OH or C1-C6 alkoxy, preferably -OH. 根据权利要求4所述的化合物，其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，其氘代物或其药学上可接受的盐，其中，The compound according to claim 4, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, its deuterated product or a pharmaceutically acceptable salt thereof ,in, 式I-A-1化合物选自如下式I-A-1A化合物：
The compound of formula IA-1 is selected from the following compounds of formula IA-1A:
其中，X5、R7、R9、R10、Ra、Rb的定义同权利要求4；Wherein, the definitions of X 5 , R 7 , R 9 , R 10 , R a , R b are the same as those in claim 4; 特别地，式I-A-1A化合物中，Particularly, in the compound of formula I-A-1A, X5选自N或CRa，Ra每次出现时相同或不同，选自氢、卤素、卤代C1～C6烷基、卤代C1～C6烷氧基，特别是X3中的Ra选自三氟甲基或三氟甲氧基，X4和X5中的Ra为氢；X 5 is selected from N or CR a , R a is the same or different at each occurrence, selected from hydrogen, halogen, halogenated C1～C6 alkyl, halogenated C1～C6 alkoxy, especially R in X3 Be selected from trifluoromethyl or trifluoromethoxy, R in X 4 and X 5 is hydrogen; Rb相同或不同，选自氢、卤素、C1～C6烷基、卤代C1～C6烷基、C1～C6烷氧基、卤代C1～C6烷氧基、C3～C8环烷基，优选选自氢、F、Cl、Br、三氟甲基、甲氧基或三氟甲氧基；R b is the same or different, 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; R9为氢；R10选自氢、三氟甲基、C3～C6环烷基、氘代C3～C6环烷基；R 9 is hydrogen; R 10 is selected from hydrogen, trifluoromethyl, C3～C6 cycloalkyl, deuterated C3～C6 cycloalkyl; R7选自卤素、C1～C6烷氧基，优选选自F、Cl、Br或甲氧基。R 7 is selected from halogen, C1-C6 alkoxy, preferably from F, Cl, Br or methoxy. 根据权利要求5所述的化合物，其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，其氘代物或其药学上可接受的盐，其中，The compound according to claim 5, its tautomer, mesomer, racemate, enantiomer, diastereomer, its deuterated product or a pharmaceutically acceptable salt thereof ,in, 选自如下结构：
 Choose from the following structures:
根据权利要求1所述的化合物，其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，其氘代物或其药学上可接受的盐，其中，The compound according to claim 1, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, its deuterated product or a pharmaceutically acceptable salt thereof ,in, 式I化合物选自下列化合物：






The compound of formula I is selected from the following compounds:






一种权利要求1-7任一项所述的化合物的制备方法，其为下列方法之一：A preparation method of the compound described in any one of claims 1-7, which is one of the following methods: 方法一：
method one:
II-A化合物与醇在酸催化下，生成Pinner盐，随后加入NR1R2R3制备I-A化合物；II-A compound and alcohol generate Pinner salt under acid catalysis, then add NR 1 R 2 R 3 to prepare IA compound; 其中，各取代基定义与相应权利要求中的定义相同； Wherein, the definition of each substituent is the same as the definition in the corresponding claim; 方法二：
Method Two:
II-A’化合物与醇在酸催化下，生成Pinner盐，随后加入NR1R2R3制备I-A’化合物；Under acid catalysis, II-A' compound and alcohol generate Pinner salt, and then add NR 1 R 2 R 3 to prepare I-A'compound; 其中，各取代基定义与相应权利要求中的定义相同；Wherein, the definition of each substituent is the same as the definition in the corresponding claim; 方法三：
Method three:
II-A化合物在无水溶剂和碱存在下，与羟胺或羟胺的盐反应获得I-A化合物；Compound II-A is reacted with hydroxylamine or a salt of hydroxylamine in the presence of anhydrous solvent and base to obtain compound I-A; 其中，R1、R2为H，R3为OH，其它取代基定义与相应权利要求中的定义相同；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; 方法四：
Method four:
II-A’化合物在无水溶剂和碱存在下，与羟胺或羟胺的盐反应获得I-A’化合物；II-A' compound is reacted with hydroxylamine or a salt of hydroxylamine in the presence of anhydrous solvent and base to obtain I-A' compound; 其中，R1、R2为H，R3为OH，其它取代基定义与相应权利要求中的定义相同。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. 一种药物组合物，其包括选自权利要求1-7任一项所述的化合物，其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，其氘代物和其药学上可接受的盐中的一种或多种，以及任选的药学上可接受的辅料。A pharmaceutical composition comprising the compound selected from any one of claims 1-7, its tautomers, mesomers, racemates, enantiomers, diastereomers Construct, one or more of its deuterated substance and its pharmaceutically acceptable salt, and optional pharmaceutically acceptable auxiliary materials. 权利要求1-7任一项所述的化合物，其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，其氘代物或其药学上可接受的盐或权利要求9所述的药物组合物在制备Nav1.8抑制剂中的用途；或者The compound according to any one of claims 1-7, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, its deuterated product or its pharmaceutically Acceptable salt or the purposes of the pharmaceutical composition described in claim 9 in preparing Nav1.8 inhibitor; Or 权利要求1-7任一项所述的化合物，其互变异构体、内消旋体、外消旋体、对映异构体、非对映异构体，其氘代物或其药学上可接受的盐或权利要求9所述的药物组合物在制备用于治疗和/或减轻疼痛和疼痛相关疾病的药物中的用途；The compound according to any one of claims 1-7, its tautomer, mesomer, racemate, enantiomer, diastereoisomer, its deuterated product or its pharmaceutically Acceptable salt or the pharmaceutical composition described in claim 9 is used in the preparation of the medicine for treating and/or alleviating pain and pain-related diseases; 优选地，所述疼痛和疼痛相关疾病包括伤害性疼痛、炎性疼痛、神经病理性疼痛、功能性疼痛、肌肉或骨骼损伤相关疼痛、盆腔痛、腹腔痛、胸腔痛、腰骶神经痛、术前疼痛、术间疼痛、术后疼痛、急性或慢性疼痛、偏头痛、三叉神经痛、胰腺炎、肾绞痛、癌症痛、化学或药物疗法导致的疼痛、糖尿病神经痛、带状疱疹后神经痛、背部疼痛、幻肢痛、坐骨神经痛、小纤维神经痛、红斑性肢痛症、关节炎、瘙痒症、急性或慢性瘙痒、哮喘、多发性硬化症、心律失常、房颤、心衰、Brugada综合症、肾结石、癫痫、惊厥、夏-马-图三氏综合症、失禁。 Preferably, said pain and pain-related diseases include nociceptive pain, inflammatory pain, neuropathic pain, functional pain, pain associated with muscle or bone injury, pelvic pain, abdominal pain, chest pain, lumbosacral neuralgia, preoperative Pain, intraoperative pain, postoperative pain, acute or chronic pain, migraine, trigeminal neuralgia, pancreatitis, renal colic, cancer pain, pain from chemotherapy or drug therapy, diabetic neuralgia, postherpetic neuralgia , back pain, phantom limb pain, sciatica, small fiber neuralgia, erythromelalgia, arthritis, pruritus, acute or chronic pruritus, asthma, multiple sclerosis, arrhythmia, atrial fibrillation, heart failure, Brugada Syndrome, Kidney Stones, Epilepsy, Convulsions, Charming-Marine-Tuesman Syndrome, Incontinence.
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Families Citing this family (1)

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Publication number Priority date Publication date Assignee Title
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Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101883760A (en) * 2007-10-11 2010-11-10 沃泰克斯药物股份有限公司 Heteroarylamides as voltage-gated sodium channel inhibitors
WO2014120808A1 (en) * 2013-01-31 2014-08-07 Vertex Parmaceuticals Incorporated Pyridone amides as modulators of sodium channels
US20150166589A1 (en) * 2013-12-13 2015-06-18 Vertex Pharmaceuticals Incorporated Prodrugs of pyridone amides useful as modulators of sodium channels
WO2016029216A2 (en) * 2014-08-22 2016-02-25 Biocryst Pharmaceuticals, Inc. Method for producing amidine derivatives
WO2020146612A1 (en) * 2019-01-10 2020-07-16 Vertex Pharmaceuticals Incorporated Esters and carbamates as modulators of sodium channels
CN112390745A (en) * 2019-08-19 2021-02-23 江苏恒瑞医药股份有限公司 Pyridine nicotinamide derivatives, preparation method and medical application thereof
CN112689633A (en) * 2018-07-09 2021-04-20 利伯研究所公司 For inhibiting Nav1.8 pyridine carboxamide Compounds
US20210139456A1 (en) * 2018-07-09 2021-05-13 Lieber Institute, Inc. Pyridazine compounds for inhibiting nav1.8
CN114031518A (en) * 2020-12-08 2022-02-11 成都海博为药业有限公司 Benzylamine or benzyl alcohol derivative and application thereof
US20220048892A1 (en) * 2018-12-26 2022-02-17 Raqualia Pharma Inc. Heterocyclic derivatives as nav1.7 and nav1.8 blockers
CN114437062A (en) * 2020-04-30 2022-05-06 成都海博为药业有限公司 Compound capable of being used as sodium channel regulator and application thereof

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021018165A1 (en) * 2019-07-30 2021-02-04 江苏恒瑞医药股份有限公司 Pyridine benzamide derivative, preparation method for same, and medicinal applications thereof

Patent Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101883760A (en) * 2007-10-11 2010-11-10 沃泰克斯药物股份有限公司 Heteroarylamides as voltage-gated sodium channel inhibitors
WO2014120808A1 (en) * 2013-01-31 2014-08-07 Vertex Parmaceuticals Incorporated Pyridone amides as modulators of sodium channels
US20150166589A1 (en) * 2013-12-13 2015-06-18 Vertex Pharmaceuticals Incorporated Prodrugs of pyridone amides useful as modulators of sodium channels
WO2016029216A2 (en) * 2014-08-22 2016-02-25 Biocryst Pharmaceuticals, Inc. Method for producing amidine derivatives
CN112689633A (en) * 2018-07-09 2021-04-20 利伯研究所公司 For inhibiting Nav1.8 pyridine carboxamide Compounds
US20210139456A1 (en) * 2018-07-09 2021-05-13 Lieber Institute, Inc. Pyridazine compounds for inhibiting nav1.8
US20220048892A1 (en) * 2018-12-26 2022-02-17 Raqualia Pharma Inc. Heterocyclic derivatives as nav1.7 and nav1.8 blockers
WO2020146612A1 (en) * 2019-01-10 2020-07-16 Vertex Pharmaceuticals Incorporated Esters and carbamates as modulators of sodium channels
CN112390745A (en) * 2019-08-19 2021-02-23 江苏恒瑞医药股份有限公司 Pyridine nicotinamide derivatives, preparation method and medical application thereof
CN114437062A (en) * 2020-04-30 2022-05-06 成都海博为药业有限公司 Compound capable of being used as sodium channel regulator and application thereof
CN114031518A (en) * 2020-12-08 2022-02-11 成都海博为药业有限公司 Benzylamine or benzyl alcohol derivative and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE REGISTRY ANONYMOUS : "- Benzamide, N-[3-chloro-4-[(hydroxyamino)iminomethyl]phenyl]-2-phenoxy- (CA INDEX NAME)", XP093088577, retrieved from STN *

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