Novel inhibitor of enterovirus D68, preparation method and use thereof

Abstract

The present invention relates to quinoline derivatives represented by Formula 1 and Formula 2 and pharmaceutically acceptable salts thereof, or solvates thereof or hydrates thereof, and also relates to pharmaceutical compositions containing the compounds, methods for preparing the compounds, and use of the compounds in preparing drugs for preventing and / or treating diseases caused by enteroviruses.

Description

Technical Field

[0001] The present invention relates to quinoline derivative compounds represented by Formula 1 and Formula 2 and pharmaceutically acceptable salts thereof, solvates thereof or hydrates thereof, and also relates to pharmaceutical compositions containing the compounds, methods for preparing the compounds, and use of the compounds in drugs for preventing and / or treating diseases caused by enteroviruses.

[0002] Background Art

[0003] Enterovirus D68 (EV-D68) is a non-polio enterovirus belonging to the genus Enterovirus of the family Picornaviridae. EV-D68 infection mainly causes respiratory diseases, with symptoms including cough, runny nose, fever, asthma, dyspnea and tissue hypoxia, but may also cause severe bronchiolitis or pneumonia, occasionally leading to death, and mainly infects infants and immunocompromised individuals. In addition to causing severe respiratory diseases, EV-D68 can also cause central nervous system diseases and acute flaccid paralysis, and in severe cases, quadriplegia. Unlike other enteroviruses, EV-D68 is mainly transmitted through the respiratory tract and binds to sialic acid receptors in the upper respiratory tract. This transmission route poses a potential threat to large-scale transmission. In 2014, an outbreak of severe respiratory diseases caused by EV-D68 occurred in the United States, with a total of 1,153 cases of infection and millions of undetected milder cases. During the same period, epidemics of EV-D68 were reported in Europe and many countries in Asia.

[0004] Although EV-D68 infection can cause severe disease and has been recognized as a public health threat, there are currently no antiviral drugs for the treatment of EV-D68 infection or vaccines for the prevention of EV-D68 infection. Therefore, there is an urgent need to develop new structural and specific antiviral drugs to better treat EV-D68 infection.

[0005] EV-D68 is a non-enveloped virus surrounded by capsid protein, which is a structural protein composed of 60 protomers, including VP1, VP2 and VP3 on the surface and VP4 subunits inside. The bottom of the VP1 protein contains a small hydrophobic pocket, which is usually filled with lipid parts or pocket factors. The pocket factor stabilizes the capsid structure of the virus by filling the hydrophobic pocket of the capsid protein VP1. When the virus binds to the receptor, the "pocket factor" is expelled, the protein structure on the surface of the virus changes, and then the RNA genome of the virus is released and enters the host cell for subsequent replication and translation. Capsid protein inhibitors can be used as inhibitors of competitive binding of pocket factors, which can enter the concave canyon on the surface of the VP1 protein, stabilize the capsid structure of the virus, and prevent the release of viral RNA to achieve the effect of anti-viral proliferation. Summary of the invention

[0006] According to the structural characteristics of VP1 protein, the inventors screened quinoline derivatives with novel skeleton structures and evaluated the inhibitory activity of these derivatives against enteroviruses such as EV-D68.

[0007] In particular, the present invention relates to a novel quinoline derivative compound, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, and also relates to a method for synthesizing the compound and its use in treating enterovirus.

[0008] The technical solution of the present invention is as follows:

[0009] The first aspect of the present invention provides a compound as shown in Formula 1, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof,

[0010]

[0011] in:

[0012] R1 is selected from C 1-8 alkyl;

[0013] R2 is selected from 5-14 membered substituted or unsubstituted aryl, 5-14 membered substituted or unsubstituted heteroaryl.

[0014] In certain embodiments, in the compound of formula 1 of the present invention, R1 is selected from C 1-8 alkyl.

[0015] In certain embodiments, in the compound of formula 1 of the present invention, R1 is selected from C 1-6 alkyl.

[0016] In certain embodiments, in the compound of formula 1 of the present invention, R1 is selected from C 1-3 alkyl.

[0017] In certain embodiments, in the compound of formula 1 described herein, R1 is ethyl.

[0018] In certain embodiments, in the compound of formula 1 of the present invention, R2 is selected from 5-14 membered aryl, 5-14 membered heteroaryl, and the 5-14 membered aryl or 5-14 membered heteroaryl may be optionally replaced by one or more R a Replace, each R a are independently hydrogen, amino, C 1-4 In some embodiments, the 5-14 membered aryl is a 5-10 membered aryl, such as a phenyl. In some embodiments, the 5-14 membered heteroaryl is a 5-6 membered monoheteroaryl, and the 5-6 membered monoheteroaryl contains 1-2 heteroatoms selected from nitrogen atoms, oxygen atoms, and sulfur atoms.

[0019] In certain embodiments, R2 is phenyl or a 5-6 membered heteroaryl group containing 1-2 nitrogen atoms (eg, 4H-pyrazolyl), wherein the phenyl group may be optionally substituted by one or more R a Replace, each R a are each independently selected from hydrogen, amino, C 1-4 Alkyl, aminoacyl.

[0020] In certain embodiments, in the compound of formula 1 of the present invention, R1 is ethyl, R2 is phenyl, and the phenyl group may be optionally replaced by one or more R a Replace, each R a are each independently selected from hydrogen, amino, C 1-4 Alkyl (eg, methyl, ethyl, n-propyl, isopropyl or n-butyl), aminoacyl.

[0021] In certain embodiments, in the compound of formula 1 described in the present invention, R1 is ethyl, and R2 is a 5-6 membered heteroaryl group containing 1-2 nitrogen atoms, such as 4H-pyrazolyl.

[0022] In certain embodiments, in the compound of formula 1 described in the present invention, R1 is ethyl, and R2 is selected from:

[0023]

[0024] In certain embodiments, the compound of formula 1 of the present invention is selected from:

[0025]

[0026] The compound of formula 1 described in the present invention can be prepared by conventional synthetic routes as required.

[0027] The second aspect of the present invention provides a compound as shown in Formula 2, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, comprising:

[0028]

[0029] in:

[0030] R3 is C 1-12 a substituted or unsubstituted alkyl group;

[0031] R4 is selected from 5-14 membered substituted or unsubstituted aryl, 5-14 membered substituted or unsubstituted heteroaryl.

[0032] In certain embodiments, in the compound of formula 2 of the present invention, R3 is selected from C 1-12 Alkyl, the C 1-12 The alkyl group may be optionally replaced by one or more R b Replace, each R b are each independently hydrogen or halogen.

[0033] In certain embodiments, in the compound of formula 2 of the present invention, R3 is selected from C 1-6 Alkyl, the C 1-6 The alkyl group may be optionally replaced by one or more R b Replace, each R b are each independently hydrogen or halogen.

[0034] In certain embodiments, in the compound of formula 2 of the present invention, R3 is selected from C 1-4 Alkyl, the C 1-4 The alkyl group may be optionally replaced by one or more R b Replace, each R b Each is independently hydrogen or halogen (eg fluorine).

[0035] In certain embodiments, in the compound of formula 2 described in the present invention, R3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, and trifluoromethyl.

[0036] In certain embodiments, in the compound of formula 2 of the present invention, R4 is selected from 5-8 membered aryl, 5-8 membered heteroaryl, and the 5-8 membered aryl or 5-8 membered heteroaryl may be optionally replaced by one or more R c Replace, each R c are each independently selected from hydrogen, halogen, amino, hydroxyl, cyano, (C 1-4 Alkyl)2-N-, C 1-8 Alkyl, C 1-3 Amide, C 1-6 Alkoxy, 5-8 membered aryl, 5-6 membered monoheterocyclic group.

[0037] In certain embodiments, in the compound of formula 2 of the present invention, R4 is selected from 5-6 membered aryl, 5-6 membered heteroaryl, and the 5-6 membered aryl or 5-6 membered heteroaryl may be optionally replaced by one or more R c Replace, each R c are each independently selected from hydrogen, halogen, amino, hydroxyl, cyano, (C 1-4 Alkyl)2-N-, C 1-8 Alkyl, C 1-3 Amide, C 1-6 Alkoxy, 5-8 membered aryl, 5-6 membered N and / or O containing monoheterocyclic group.

[0038] In certain embodiments, in the compound of formula 2 of the present invention, R4 is selected from phenyl and pyridyl, and the phenyl or pyridyl may be optionally replaced by one or more R c Replace, each R c Each independently selected from hydrogen, fluorine, chlorine, amino, dimethylamino, C 1-4 Alkyl, acetylamino, C 1-2 Alkoxy, hydroxy, phenyl, cyano, morpholino.

[0039] In certain embodiments, in the compound of formula 2 described in the present invention, R4 is selected from:

[0040]

[0041] In certain embodiments, the compound of formula 2 of the present invention is selected from:

[0042]

[0043]

[0044] In the compounds of the present invention, when referring to a group "substituted or unsubstituted", it means that the group is not substituted or is substituted by one or more (e.g., 2, 3 or 4) identical or different substituents, and the substituents can be selected from, for example, phenyl, halogen, hydroxyl, cyano, amino, aminoacyl, C 1-6 Alkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy.

[0045] When "one or more" is mentioned herein, the "plurality" is preferably 2, 3 or 4.

[0046] The third aspect of the present invention provides a pharmaceutical composition, comprising at least one compound of formula 1 described in the first aspect of the present invention and / or formula 2 described in the second aspect, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, and optionally, one or more pharmaceutically acceptable carriers or excipients. The compound of formula 1 described in the first aspect of the present invention and / or formula 2 described in the second aspect, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof is present in a therapeutically effective amount (e.g., an effective amount for treating a disease caused by enterovirus infection).

[0047] The fourth aspect of the present invention provides the use of the compound of formula 1 described in the first aspect and / or formula 2 described in the second aspect, its pharmaceutically acceptable salt, its hydrate or solvate, or the pharmaceutical composition of the third aspect of the present invention in the preparation of a drug, wherein the drug is used for one or more of the following:

[0048] 1) Prevent or treat enterovirus infection or diseases caused by enterovirus infection;

[0049] 2) Inhibit the replication or reproduction of enterovirus in cells (such as mammalian cells).

[0050] In certain embodiments, the enterovirus is selected from poliovirus (PV), Coxsackie A Virus (CV-A), Coxsackie B Virus (CV-B), Echovirus, Enterovirus 71 (EV71), Enterovirus D68 (EV-D68), or any combination thereof.

[0051] In certain embodiments, the enterovirus is selected from EV-D68.

[0052] In certain embodiments, the disease caused by the enterovirus infection is selected from hand, foot and mouth disease, respiratory system infection, central nervous system disease, acute flaccid paralysis, nonspecific febrile illness, pneumonia, bronchiolitis, encephalitis and myocarditis, acute flaccid myelitis or any combination thereof.

[0053] In certain embodiments, the disease caused by the enterovirus infection is selected from hand, foot and mouth disease, respiratory system infection, central nervous system disease, acute flaccid paralysis or any combination thereof.

[0054] The fifth aspect of the present invention provides a method for preventing and treating enterovirus infection or a disease caused by enterovirus infection, comprising: administering to a subject in need thereof an effective amount of a compound of formula 1 described in the first aspect of the present invention and / or formula 2 described in the second aspect, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, or a pharmaceutical composition of the third aspect of the present invention.

[0055] In certain embodiments, the enterovirus is selected from poliovirus (PV), Coxsackie A Virus (CV-A), Coxsackie B Virus (CV-B), Echovirus, Enterovirus 71 (EV71), Enterovirus D68 (EV-D68), or any combination thereof.

[0056] In certain embodiments, the enterovirus is selected from EV-D68.

[0057] In certain embodiments, the disease caused by the enterovirus infection is selected from hand, foot and mouth disease, respiratory system infection, central nervous system disease, acute flaccid paralysis, nonspecific febrile illness, pneumonia, bronchiolitis, encephalitis and myocarditis, acute flaccid myelitis or any combination thereof.

[0058] In certain embodiments, the disease caused by the enterovirus infection is selected from hand, foot and mouth disease, respiratory system infection, central nervous system disease, acute flaccid paralysis or any combination thereof.

[0059] The sixth aspect of the present invention provides a method for inhibiting the replication or propagation of enterovirus in cells (e.g., mammalian cells), comprising administering to cells (e.g., mammalian cells) an effective amount of the compound of formula 1 described in the first aspect of the present invention and / or the compound of formula 2 described in the second aspect, a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, or a pharmaceutical composition of the third aspect of the present invention. The method can be performed in vivo or in vitro, for example, in an in vitro cell line. The method can be used for therapeutic purposes or for non-therapeutic purposes (e.g., drug research).

[0060] In certain embodiments, the enterovirus is selected from poliovirus (PV), Coxsackie A Virus (CV-A), Coxsackie B Virus (CV-B), Echovirus, Enterovirus 71 (EV71), Enterovirus D68 (EV-D68), or any combination thereof.

[0061] In certain embodiments, the enterovirus is selected from EV-D68.

[0062] The seventh aspect of the present invention provides a method for preparing the compound of formula 2 or its pharmaceutically acceptable salt, hydrate or solvate thereof according to the second aspect of the present invention. The method comprises: using the intermediate shown in the following structural formula 6 as a raw material, reacting with a boronic acid derivative shown by R4-B(OH)2, to obtain the compound of the second aspect of the present invention, its pharmaceutically acceptable salt, hydrate or solvate thereof, and the general reaction formula is as follows:

[0063]

[0064] Wherein, R3 and R4 are as described above.

[0065] In certain embodiments, the intermediate represented by structural formula 6 is prepared by reacting the intermediate represented by structural formula 5 as a raw material with an acid anhydride represented by (R3-CO)2O.

[0066]

[0067] Wherein, R3 is as described above.

[0068] In certain embodiments, the intermediate represented by structural formula 5 is obtained by reacting 6-bromoquinoline-3-carbonitrile with hydroxylamine.

[0069] In certain embodiments of the present invention, the reaction flow of the preparation method of the compound represented by Formula 2 or its pharmaceutically acceptable salt, hydrate or solvate thereof is as follows:

[0070]

[0071] wherein R3 and R4 are as described above.

[0072] definition

[0073] In the present invention, unless otherwise specified, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Meanwhile, in order to better understand the present invention, the definitions and explanations of the relevant terms are provided below.

[0074] In the present invention, in certain embodiments, the subjects described in the present invention include mammalian subjects, particularly human subjects, including male and female subjects and including newborns, infants, adolescents, teenagers, adults and elderly subjects, and including various races and ethnicities, including but not limited to, white, black, Asian, American Indian and Hispanic.

[0075] In the present invention, in certain embodiments, the mammals of the present invention include bovines, equines, porcines, canines, felines, rodents, primates, such as humans, cats, dogs, monkeys or pigs.

[0076] The compounds of the present invention can be used either as such or in the form of pharmaceutically acceptable salts thereof. Pharmaceutically acceptable salts of the compounds shown in Formula 1 and Formula 2 include salts formed with pharmaceutically acceptable inorganic or organic acids, or with pharmaceutically acceptable inorganic or organic bases. Examples of suitable acid addition salts include salts formed with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid, citric acid, pamoic acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid or tannic acid. Examples of suitable base addition salts include salts formed with sodium, lithium, potassium, magnesium, aluminum, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N-methylglucamine or procaine. Methods for preparing pharmaceutically acceptable salts of the compounds of the present invention are known to those skilled in the art. When referring to the compounds of the present invention herein, it includes compounds shown in Formula 1 or Formula 2 and pharmaceutically acceptable salts thereof.

[0077] In the present invention, solvate refers to a substance formed by the association of the compound represented by Formula 1 or Formula 2 or its pharmaceutically acceptable salt with organic solvent molecules, and the organic solvent includes but is not limited to methanol, ethanol, propanol, acetonitrile, etc. The compound represented by Formula 1 or Formula 2 or its pharmaceutically acceptable salt can form a hydrate with water.

[0078] The pharmaceutical composition of the present invention comprises the compound represented by Formula 1 and Formula 2 of the present invention or a pharmaceutically acceptable salt thereof, a hydrate thereof or a solvate thereof, and may further comprise a pharmaceutically acceptable carrier and / or excipient. The pharmaceutical composition of the present invention may be prepared into various dosage forms according to conventional methods in the art, including but not limited to tablets, capsules, solutions, suspensions, granules or injections, and may be administered, for example, orally or parenterally.

[0079] It should also be noted that the dosage and method of use of the compounds of Formula 1 and Formula 2 or their pharmaceutically acceptable salts, hydrates or solvates thereof of the present invention depend on many factors, including the patient's age, weight, gender, natural health, nutritional status, activity strength of the compound, time of administration, metabolic rate, severity of the disease, and subjective judgment of the treating physician. The preferred dosage is between 0.001-1000 mg / kg body weight / day.

[0080] The term "pharmaceutically acceptable" used in the present invention means that the substance described is not only physiologically acceptable to the subject, but also refers to a substance with pharmaceutical use value. For example, when describing a "pharmaceutically acceptable salt", it means that the salt is not only physiologically acceptable to the subject, but also refers to a synthetic substance with pharmaceutical use value.

[0081] The term "pharmaceutically acceptable carrier and / or excipient" used in the present invention refers to a carrier and / or excipient that is pharmacologically and / or physiologically compatible with a subject and an active ingredient, which is well known in the art (see, for example, Remington's Pharmaceutical Sciences. Edited by Gennaro AR, 19th ed. Pennsylvania: Mack Publishing Company, 1995), including but not limited to binders, diluents, fillers, disintegrants, wetting agents, lubricants, colorants, flavoring agents, solubilizers, osmotic pressure regulators or other conventional additives. Typical pharmaceutically acceptable carriers and / or excipients include, for example, microcrystalline cellulose, starch, cross-linked polyvinylpyrrolidone, polyvinylpyrrolidone, maltitol, citric acid, sodium lauryl sulfate or magnesium stearate, etc.

[0082] The term "effective amount" as used herein refers to an amount that is effective in achieving the intended purpose. For example, an effective amount for treating a disease (e.g., a viral infection or a disease caused by a viral infection) refers to an amount that is able to alleviate or eliminate a disease state or symptom. Determining such an effective amount is within the capabilities of those skilled in the art.

[0083] The term "optionally" as used herein means that the event or situation it describes occurs or does not occur.

[0084] The term "C 1-12 "Alkyl" refers to a saturated straight-chain or branched monovalent hydrocarbon group having 1 to 12 carbon atoms, which may include subgroups such as C 1-8 Alkyl, C 1-6 Alkyl, C 1-4 Alkyl, C 1-3 Alkyl, etc. "C 1-12Typical examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, tert-pentyl, neopentyl, n-hexyl, and the like.

[0085] The term "alkoxy" as used herein refers to an alkyl group, as defined above, attached to the parent molecular moiety through an oxygen atom. 1-6 "Alkoxy" refers to an alkoxy group having a specified number of carbon atoms, which may include its subgroups such as C 1-6 Alkoxy, C 1-4 Alkoxy, C 1-2 Alkoxy, etc. Typical examples of "alkoxy" include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, and the like.

[0086] The term "amide" as used herein refers to an acyl group attached to the parent molecular moiety through an amino group. 1-3 "Acyl" refers to an acyl group having the specified number of carbon atoms, which may include subgroups such as C 1-3 Alkoxy, C 1-2 Alkoxy, etc. Typical examples of "amide" include, but are not limited to, acetamide, propionamide, and the like.

[0087] The term “C 1-6 "Haloalkyl" refers to a C group as defined above which is mono- or poly-substituted by halogen, such as fluorine, chlorine, bromine or iodine. 1-6 Alkyl. Halogenated C 1-6 Representative examples of alkyl include, but are not limited to, chloromethyl, chloroethyl, dichloroethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, and the like.

[0088] The term "5-14 substituted or unsubstituted aryl" as used herein refers to an unsaturated aromatic carbocyclic group containing 5-14 carbon atoms having a single ring or two or more condensed rings, and the group is unsubstituted or substituted. The aryl group, for example, has 5-10 carbon atoms. Typical examples of the aryl group include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like.

[0089] The term "5-14 yuan substituted or unsubstituted heteroaryl" as used herein means a heteroaromatic ring group having 5-14 ring members, including monocyclic heteroaromatic rings and polycyclic aromatic rings, and the group is unsubstituted or substituted. "5-14 yuan heteroaryl" has one or two or more heteroatoms selected from oxygen, sulfur or nitrogen, and the carbon atom, nitrogen atom or sulfur atom on the heteroaryl may optionally be oxo (oxo). The example of "5-14 yuan heteroaryl" includes but is not limited to 5-8 yuan heteroaryl, 8-10 yuan heteroaryl, 10-14 yuan heteroaryl, such as 5-6 yuan single heteroaryl, 8-10 yuan or 10-14 yuan polyheteroaryl, such as 5-6 yuan single heteroaryl containing 1-2 heteroatoms, and the heteroatoms are selected from nitrogen atom, oxygen atom or sulfur atom. Also included within the scope of the term "heteroaryl" as used herein are groups in which an aromatic ring is fused to one or more non-aromatic rings (carbocyclic or heterocyclic), wherein the radical or point of attachment is located on the aromatic or non-aromatic rings. Typical examples of "5-14 membered heteroaryl" include, but are not limited to, furanyl, imidazolyl, triazolyl, indolyl, tetrazolyl, pyridyl, oxadiazolyl, pteridinyl, pyrimidinyl, triazolyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, etc.

[0090] The term "monoheterocyclic group" as used herein refers to a non-aromatic monocyclic group in which at least one (e.g., 1, 2, or 3) ring atom is a heteroatom (e.g., a nitrogen atom, an oxygen atom, or a sulfur atom). Optionally, the ring atom (e.g., a carbon atom, a nitrogen atom, or a sulfur atom) in the cyclic structure may be oxo-substituted. When containing multiple heteroatoms, the heteroatoms may be the same or different.

[0091] Beneficial technical effects of the present invention

[0092] 1. The compounds of Formula 1 and Formula 2 of the present invention have strong inhibitory activity against enteroviruses such as EV-D68.

[0093] 2. The compounds of Formula 1 and Formula 2 described in the present invention have low in vivo toxicity. DETAILED DESCRIPTION

[0094] The following specific examples are preferred embodiments of the present invention and should not be construed as limiting the present invention in any way.

[0095] Embodiment 1:

[0096] Preparation of compounds 1-1 to 1-9 in Formula 1

[0097] Compound 1-1

[0098]

[0099] Ethyl 6-bromoquinoline-3-carboxylate (1.0 equiv), 4,4,5,5-tetramethyl-2-(4-propylphenyl)-1,3,2-dioxaborane (1.3 equiv), PdCl2(dppf) (0.05 equiv) and K2CO3 (2 equiv) were dissolved in a solvent of DME / water = 5:1, and the mixture was subjected to microwave reaction at 120°C for 40 min under nitrogen protection. The reaction solution was concentrated under reduced pressure, and the residue was purified by n-hexane / ethyl acetate column chromatography to obtain a white solid with a yield of 70%. 1 H NMR (600MHz, DMSO-d6) δ9.28(d,J=2.2Hz,1H),9.02(dd,J=2.2,0.8Hz,1H),8.48(d,J=2.1Hz,1H),8.23(dd,J=8.8,2.1Hz,1H),8.15(dd,J=8.8,0.9Hz,1H) ,7.78–7.73(m,2H),7.37–7.32(m,2H),4.42(q,J=7.1Hz,2H),2.61(dd,J=8.3 ,6.9Hz,2H),1.68–1.59(m,2H),1.39(t,J=7.1Hz,3H),0.92(t,J=7.3Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ164.83,149.23,148.53,142.37,139.03,138.69,136.24,131.22,129.3 7,129.22,127.05,126.92,126.46,123.16,61.34,36.94,24.08,14.24,13.74.HRMS(ESI)calcd for C 21 H 21 NO2[M+H] + 320.1651, found 320.1645.

[0100] Compound 1-2

[0101]

[0102] The preparation method of compound 1-1 in Example 1 was adopted, and the 4,4,5,5-tetramethyl-2-(4-propylphenyl)-1,3,2-dioxaborolane was replaced with 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to obtain a yellow solid with a yield of 41.3%. 1H NMR (600MHz, DMSO-d6) δ9.29(d,J=2.2Hz,1H),9.05(d,J=2.1Hz,1H),8.40(d,J=2.0Hz,1H),8.18–8.10(m,2H),7.24(t,J=7. 8Hz,1H),7.10(t,J=2.0Hz,2H),7.07(dt,J=7.7,1.2Hz,1H),6.77–6.72(m,1H),4.42(q,J=7.1Hz,2H),1.39(t,J=7.1Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ164.85,149.24,148.59,147.46,139.83,139.76,138.77,131.33,129 .86,129.32,126.88,126.55,123.20,116.31,114.95,113.63,61.35,14.25.HRMS(ESI)calcd for C 18 H 16 N2O2[M+H] + 293.1290, found 293.1287

[0103] Compound 1-3

[0104]

[0105] The preparation method of compound 1-1 in Example 1 was adopted, and 4,4,5,5-tetramethyl-2-(4-propylphenyl)-1,3,2-dioxaborane was replaced with 2-(4-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane to obtain a white solid with a yield of 83%. 1 H NMR (600MHz, DMSO-d6) δ9.27(d,J=2.2Hz,1H),8.99(d,J=2.4Hz,1H),8.45(d,J=2.2Hz,1H),8.19(dd,J=8.7,2.2Hz,1H),8.13(d,J=8.7Hz,1 H),7.74(d,J=7.9Hz,2H),7.38(d,J=7.9Hz,2H),4.41(q,J=7.1Hz,2H),2.94(m,J=6.9Hz,1H),1.38(t,J=7.1Hz,3H),1.24(d,J=7.0Hz,6H). 13C NMR(151MHz,DMSO-d6)δ164.83,149.24,148.58,139.07,138.69,136.41,131.27,12 9.38,127.18,126.92,126.49,123.16,61.35,33.23,23.88,14.25.HRMS(ESI)calcd for C 21 H 21 NO2[M+H] + 320.1651, found 320.1646

[0106] Compound 1-4

[0107]

[0108] The preparation method of compound 1-1 in Example 1 was adopted, and 4,4,5,5-tetramethyl-2-(4-propylphenyl)-1,3,2-dioxaborane was replaced with 2-(4-butylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane to obtain a white solid with a yield of 30%. 1 H NMR(600MHz,DMSO-d6)δ9.29(d,J=2.1Hz,1H),9.03(d,J=2.1Hz,1H),8.49(d, J=2.1Hz,1H),8.23(dd,J=8.7,2.2Hz,1H),8.15(d,J=8.8Hz,1H),7.78–7.73(m ,2H),7.37–7.32(m,2H),4.42(q,J=7.1Hz,2H),2.64(t,J=7.7Hz,2H),1.64–1. 55(m,2H),1.39(t,J=7.1Hz,3H),1.33(h,J=7.4Hz,2H),0.91(t,J=7.4Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ164.83,149.23,148.53,142.58,139.03,138.69,136.20,131.22,129.37,1 29.17,127.07,126.93,126.45,123.17,61.34,34.52,33.11,21.85,14.25,13.86.HRMS(ESI)calcd for C 22 H 23 NO2[M+H] + 334.1807, found 334.1803.

[0109] Compound 1-5

[0110]

[0111] The preparation method of compound 1-1 in Example 1 was adopted, and 4,4,5,5-tetramethyl-2-(4-propylphenyl)-1,3,2-dioxaborane was replaced with 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborane to obtain a white solid with a yield of 20%. 1 H NMR (600MHz, DMSO-d6) δ9.30(d,J=2.1Hz,1H),9.04(d,J=2.1Hz,1H),8.52(d,J=2.1Hz,1H),8.25(dd,J=8.7,2.2Hz,1H),8.1 7(d,J=8.8Hz,1H),7.88–7.83(m,2H),7.55(t,J=7.7Hz,2H),7.48–7.42(m,1H),4.42(q,J=7.1Hz,2H),1.39(t,J=7.1Hz,3H). 13 CNMR(151MHz,DMSO-d6)δ164.81,149.40,148.63,139.08,138.88,138.78,131.32,12 9.44,129.24,128.25,127.23,126.93,126.89,123.21,61.36,14.25.HRMS(ESI)calcd forC 18 H 15 NO2[M+H] + 278.1181, found 278.1176.

[0112] Compound 1-6

[0113]

[0114] The preparation method of compound 1-1 in Example 1 was adopted, and the 4,4,5,5-tetramethyl-2-(4-propylphenyl)-1,3,2-dioxaborolane was replaced with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to obtain a yellow solid with a yield of 76%. 1H NMR (600MHz, DMSO-d6) δ9.21(d,J=2.1Hz,1H),8.94(d,J=2.1Hz,1H),8.31(d,J=2.2Hz,1H),8.15(dd,J=8.8,2.2Hz,1H) ,8.06(d,J=8.7Hz,1H),7.60–7.54(m,2H),6.73–6.69(m,2H),5.40(s,2H),4.40(q,J=7.1Hz,2H),1.38(t,J=7.1Hz,3H). 13 C NMR (151MHz, DMSO-d6) δ164.93,149.26,148.37,148.00,139.64,138.26,130.69,129. 09,127.83,127.13,125.67,124.08,123.00,114.37,61.26,14.24.HRMS(ESI)calcdfor C 18 H 16 N2O2[M+H] + 293.1290, found 293.1288.

[0115] Compound 1-7

[0116]

[0117] The preparation method of compound 1-1 in Example 1 was adopted, and the 4,4,5,5-tetramethyl-2-(4-propylphenyl)-1,3,2-dioxaborolane was replaced with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to obtain a yellow solid with a yield of 67%. 1 H NMR (600MHz, DMSO-d6) δ9.30(d,J=2.2Hz,1H),9.00(d,J=2.0Hz,1H),8.23(d,J=2.0Hz,1H),8.14(d,J=8.7Hz,1H),7.97(dd,J=8.7,2.0Hz, 1H),7.15–7.08(m,2H),6.83(dd,J=7.9,1.0Hz,1H),6.70(td,J=7.4,1.2Hz,1H),5.05(s,2H),4.42(q,J=7.1Hz,2H),1.39(t,J=7.1Hz,3H). 13C NMR(151MHz,DMSO-d6)δ164.90,149.14,148.31,145.43,139.09,138.60,133.68,130.49,129 .10,128.89,128.84,126.89,124.48,122.93,116.97,115.67,61.33,14.26.HRMS(ESI)calcd for C 18 H 16 N2O2[M+H] + 293.1290, found 293.1287.

[0118] Compound 1-8

[0119]

[0120] The preparation method of compound 1-1 in Example 1 was adopted, and the 4,4,5,5-tetramethyl-2-(4-propylphenyl)-1,3,2-dioxaborolane was replaced with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole to obtain a black solid with a yield of 10%. 1 H NMR (600MHz, DMSO-d6) δ13.12(s,1H),9.22(t,J=1.6Hz,1H),8.88(d,J=1.9Hz,1H),8.45–8.37(m,2H),8.2 1(dt,J=8.7,1.6Hz,1H),8.12(s,1H),8.07(d,J=8.7Hz,1H),4.41(q,J=7.1Hz,2H),1.39(t,J=7.1Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ164.84,148.39,148.06,137.86,136.84,132.32,130.67 ,129.26,127.13,126.53,123.71,123.11,120.26,61.29,14.22.HRMS(ESI)calcd for C 15 H 13 N3O2[M+H] + 268.1086, found 268.1081.

[0121] Compound 1-9

[0122]

[0123] The preparation method of compound 1-1 in Example 1 was adopted, and the 4,4,5,5-tetramethyl-2-(4-propylphenyl)-1,3,2-dioxaborolane was replaced with 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide to obtain a white solid with a yield of 51%. 1 H NMR (600MHz, DMSO-d6) δ9.32(d,J=2.1Hz,1H),9.07(d,J=2.1Hz,1H),8.67–8.57(m,1H),8.36–8.29(m,1H),8.19(d,J=8.8H z,1H),8.09(s,1H),8.05(d,J=8.0Hz,2H),7.96(d,J=7.9Hz,2H),7.45(s,1H),4.43(q,J=7.1Hz,2H),1.40(t,J=7.1Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ167.48,164.78,149.69,148.83,141.40,138.91,138.12,133.79 ,131.25,129.54,128.42,127.47,127.02,126.88,123.31,61.40,14.25.HRMS(ESI)calcd for C 18 H 16 N2O2[M+H] + 321.1239, found 321.1234.

[0124] Example 2

[0125] Intermediate 4

[0126]

[0127] Add stannous chloride dihydrate (26.49 g, 117.39 mmol) to a solution of 5-bromo-2-nitrobenzaldehyde (9.0 g, 39.13 mmol) and ethanol (250 mL) and stir for 10 min. Add ethyl 3,3-diethoxypropionate (14.0 g, 97.83 mmol) and heat under reflux for 5 h. After the reaction is completed, filter the reaction solution, rinse the solid with ethanol, and dry to obtain 7.72 g of a yellow solid with a yield of 85%. 1 H NMR (600MHz, DMSO-d6) δ9.20(d,J=2.3Hz,1H),9.02(q,J=2.0Hz,1H),8.38(q,J=2.2Hz,1H),8.11–8.03(m,2H). 13C NMR(151MHz,DMSO-d6)δ150.67,146.73,141.74,135.96,131.29,130.75,127.19,121.42,117.17,106.83.HRMS(ESI)calcd forC 10 H5BrN2[M+H] + 232.9714, found 232.9704.

[0128] Example 3

[0129] Intermediate 5

[0130]

[0131] Intermediate 4 (3.08 g, 13.3 mmol) and 50% aqueous hydroxylamine solution (1.05 g, 16.0 mmol) were heated to reflux in ethanol (30 mL) for 4 h. After the reaction was completed, the reaction mixture was filtered, the filter cake was rinsed with ethyl acetate, and dried to obtain 3.2 g of a white solid with a yield of 91%. 1 H NMR(600MHz,DMSO-d6)δ10.08(s,1H),9.23(d,J=2.1Hz,1H),8.55(d,J=2.2Hz,1H),8 .25(d,J=2.2Hz,1H),7.96(d,J=8.9Hz,1H),7.88(dd,J=8.9,2.2Hz,1H),6.12(s,2H). 13 C NMR(151MHz,DMSO-d6)δ148.96,148.80,146.08,132.91,131.16,131.00,130.31,128.52,127.22,120.09.HRMS(ESI)calcd for C 10 H8BrN3O[M+H] + 265.9929, found 265.9920.

[0132] Example 4

[0133] Preparation of Intermediates 6-1 to 6-9

[0134] Compound 6-1

[0135]

[0136] 6-Bromo-N-hydroxyquinoline-3-carboxylic acid oxime amide (1 equiv) and trifluoroacetic anhydride (1.2 equiv) were added to pyridine, and the reaction mixture was heated under reflux for 3 h and then cooled to room temperature. The reaction mixture was poured into water and 1.0 N HCl was added to adjust the pH to 4, then extracted with ethyl acetate, the ethyl acetate phases were combined and dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the residue was purified by column chromatography (n-hexane / ethyl acetate) to obtain a yellow solid with a yield of 71%. 1 H NMR(600MHz,chloroform-d)δ9.57(d,J=2.1Hz,1H),8.84–8.80(m,1H),8.12(d,J=2.2Hz,1H),8.06(d,J=8.9Hz,1H),7.91(dd,J=8.9,2.2Hz,1H). 13 C NMR(151MHz,chloroform-d)δ167.21,166.38(q,J=44.8Hz),148.22,148.10,13 5.21,134.99,131.38,130.64,128.20,122.01,119.20,115.88(q,J=273.7Hz). 19 F NMR(565MHz,Chloroform-d)δ-65.19.HRMS(ESI)calcd for C 12 H5BrF3N3O[M+H] + 343.9646, found 343.9642.

[0137] Compound 6-2

[0138]

[0139] The preparation method of compound 6-1 in Example 4 was adopted, and the trifluoroacetic anhydride was replaced by acetic anhydride to obtain a white solid with a yield of 57%. 1 H NMR(600MHz,chloroform-d)δ9.54(d,J=2.1Hz,1H),8.73(d,J=2.1Hz,1H),8.06( d,J=2.1Hz,2H),8.03(d,J=8.9Hz,1H),7.85(dd,J=9.1,2.2Hz,1H),2.71(s,3H). 13C NMR(151MHz,chloroform-d)δ177.19,166.29,148.69,147.56,134.44,134.07,131.19,130.46,128.46,121.52,121.05,12.44.HRMS(ESI)calcd for C 12 H8BrN3O[M+H] + 289.9929, found 289.9921.

[0140] Compound 6-3

[0141]

[0142] The preparation method of compound 6-1 in Example 4 was adopted, and the trifluoroacetic anhydride was replaced by propionic anhydride to obtain a yellow solid with a yield of 52%. 1 H NMR(600MHz,chloroform-d)δ9.55(d,J=2.1Hz,1H),8.75(d,J=2.0Hz,1H),8.07(d,J=2.2Hz,1H) ,8.03(d,J=8.9Hz,1H),7.85(dd,J=8.9,2.2Hz,1H),3.03(q,J=7.6Hz,2H),1.49(t,J=7.6Hz,3H). 13 C NMR(151MHz,chloroform-d)δ181.40,166.16,148.74,147.52,134.40,134.12,131.18,130.48,128.48,121.49,121.21,20.37,10.81.HRMS(ESI)calcd for C 13 H 10 BrN3O[M+H] + 304.0085, found 304.0079.

[0143] Compound 6-4

[0144]

[0145] The preparation method of compound 6-1 in Example 4 was adopted, and the trifluoroacetic anhydride was replaced with butyric anhydride to obtain a yellow solid with a yield of 50%. 1H NMR(600MHz,chloroform-d)δ9.57(d,J=2.1Hz,1H),8.77(d,J=2.5Hz,1H),8.11–8.03(m,2H),7 .86(dd,J=8.9,2.2Hz,1H),2.99(t,J=7.5Hz,2H),1.96(h,J=7.4Hz,2H),1.10(t,J=7.4Hz,3H). 13 C NMR(151MHz,chloroform-d)δ180.61,166.14,148.70,147.43,134.49,134.24,131.13,130.50,128.53,121.57,121.26,28.49,20.20,13.66.HRMS(ESI)calcd for C 14 H 12 BrN3O[M+H] + 318.0242, found 318.0233.

[0146] Compound 6-5

[0147]

[0148] The preparation method of compound 6-1 in Example 4 was adopted, and the trifluoroacetic anhydride was replaced with isobutyric anhydride to obtain a yellow solid with a yield of 60%. 1 H NMR(600MHz,chloroform-d)δ9.55(d,J=2.1Hz,1H),8.76(d,J=2.0Hz,1H),8.08(d,J=2.2Hz,1H) ,8.03(d,J=9.0Hz,1H),7.85(dd,J=9.0,2.2Hz,1H),3.34(m,J=7.0Hz,1H),1.50(d,J=7.0Hz,6H). 13 C NMR(151MHz,chloroform-d)δ184.61,166.05,148.79,147.51,134.35,134.13,131.19,130.47,128.49,121.46,121.30,27.61,20.20.HRMS(ESI)calcd for C 14 H 12 BrN3O[M+H] + 318.0242, found 318.0236.

[0149] Compound 6-6

[0150]

[0151] The preparation method of compound 6-1 in Example 4 was adopted, and the trifluoroacetic anhydride was replaced with valeric anhydride to obtain a yellow solid with a yield of 56%. 1 H NMR(600MHz,chloroform-d)δ9.56(d,J=2.2Hz,1H),8.75(d,J=2.1Hz,1H),8.07(d,J=2.2Hz,2H),8.03(d,J=8.9Hz,1H) ,7.85(dd,J=9.0,2.2Hz,1H),3.01(t,J=7.6Hz,2H),1.90(p,J=7.5Hz,2H),1.50(h,J=7.4Hz,2H),1.00(t,J=7.4Hz,3H). 13 C NMR(151MHz,chloroform-d)δ180.73,166.13,148.77,147.54,134.35,134.06,131 .19,130.45,128.46,121.45,121.19,28.62,26.34,22.18,13.56.HRMS(ESI)calcd forC 15 H 14 BrN3O[M+H] + 332.0398, found 332.0393.

[0152] Compound 6-7

[0153]

[0154] The preparation method of compound 6-1 in Example 4 was adopted, and the trifluoroacetic anhydride was replaced with pivalic anhydride to obtain a yellow solid with a yield of 40%. 1 H NMR(600MHz,chloroform-d)δ9.55(d,J=2.1Hz,1H),8.76(d,J=2.0Hz,1H),8.08( d,J=2.2Hz,1H),8.03(d,J=8.9Hz,1H),7.84(dd,J=9.0,2.2Hz,1H),1.53(s,9H). 13 C NMR(151MHz,chloroform-d)δ186.95,165.98,148.84,147.50,134.29,134.13,131.20,130.47,128.49,121.42,121.39,33.77,28.42.HRMS(ESI)calcd forC 15 H14 BrN3O[M+H] + 332.0398, found 332.0390.

[0155] Embodiment 5:

[0156] Preparation of compounds 2-1 to 2-42 of formula 2

[0157] Compound 2-1

[0158]

[0159] Compound 6-1 (1.0 equiv), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (1.3 equiv), PdCl2(dppf) (0.05 equiv) and K2CO3 (2 equiv) were dissolved in a solvent of DME / water = 5:1, and the mixture was reacted at 120°C for 40 min under a nitrogen atmosphere by microwave conditions. The reaction solution was concentrated under reduced pressure, and the residue was purified by n-hexane / ethyl acetate column chromatography to obtain a yellow solid with a yield of 58%. 1 H NMR (600MHz, DMSO-d6) δ9.35(d,J=2.2Hz,1H),9.07(d,J=2.1Hz,1H),8.37(d,J=2.1Hz,1H),8.17 (dd,J=8.8,2.2Hz,1H),8.09(d,J=8.8Hz,1H),7.60–7.55(m,2H),6.74–6.69(m,2H),5.42(s,2H). 13 C NMR(151MHz,DMSO-d6)δ167.13,165.28(q,J=44.5,44.1Hz),149.33,147.63,146.39,139.98,13 5.96,130.53,129.24,127.85,127.47,125.58,123.78,118.25,115.87(q,J=273.0Hz),114.36. 19 F NMR(565MHz,DMSO-d6)δ-64.65.HRMS(ESI)calcd for C 18 H 11 F3N4O[M+H] + 357.0963, found 357.0958.

[0160] Compound 2-2

[0161]

[0162] The preparation method of compound 2-1 in Example 5 was adopted, and compound 6-1 was replaced by 6-2 to obtain a yellow solid with a yield of 29%. 1 H NMR (600MHz, DMSO-d6) δ9.31(d,J=2.0Hz,1H),8.95(d,J=2.0Hz,1H),8.30(d,J=2.0Hz,1H),8.12(dd,J= 8.8, 2.1Hz, 1H), 8.07 (d, J = 8.8Hz, 1H), 7.60–7.55 (m, 2H), 6.74–6.69 (m, 2H), 5.41 (s, 2H), 2.72 (s, 3H). 13 C NMR(151MHz,DMSO-d6)δ177.91,166.19,149.24,147.32,146.74,139.72,134.91,129 .91,129.20,127.84,127.62,125.76,123.62,119.92,114.36,12.16.HRMS(ESI)calcd for C 18 H 14 N4O[M+H] + 303.1246,found303.1241

[0163] Compound 2-3

[0164]

[0165] The preparation method of compound 2-1 in Example 5 was adopted, and compound 6-1 therein was replaced by compound 6-3 to obtain a yellow solid with a yield of 48%. 1 H NMR (600MHz, DMSO-d6) δ9.32(d,J=2.0Hz,1H),8.96(d,J=2.0Hz,1H),8.33(d,J=2.0Hz,1H),8.13(dd,J=8.8,2.0Hz,1H),8. 07(d,J=8.7Hz,1H),7.58(d,J=8.1Hz,2H),6.71(d,J=8.2Hz,2H),5.40(s,2H),3.07(q,J=7.6Hz,2H),1.39(t,J=7.5Hz,3H). 13C NMR(151MHz,DMSO-d6)δ181.67,166.08,149.24,147.32,146.74,139.72,134.93,129.90 ,129.19,127.83,127.63,125.77,123.66,119.97,114.36,19.73,10.53.HRMS(ESI)calcd for C 19 H 16 N4O[M+H] + 317.1402, found 317.1396.

[0166] Compound 2-4

[0167]

[0168] The preparation method of compound 2-1 in Example 5 was adopted, and compound 6-1 therein was replaced by compound 6-4 to obtain a yellow solid with a yield of 48%. 1 H NMR (600MHz, DMSO-d6) δ9.31(d,J=2.2Hz,1H),8.96(d,J=2.3Hz,1H),8.32(d,J=2.2Hz,1H),8.13(dd,J=8.8,2.1Hz,1H),8.07(d,J=8.7 Hz,1H),7.58(d,J=8.2Hz,2H),6.71(d,J=8.2Hz,2H),5.40(s,2H),3.03(t,J=7.4Hz,2H),1.85(h,J=7.4Hz,2H),1.02(t,J=7.4Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ180.70,166.08,149.24,147.32,146.74,139.71,134.94,129.89,12 9.19,127.83,127.62,125.77,123.65,119.95,114.35,27.69,19.60,13.48.HRMS(ESI)calcd for C 20 H 18 N4O[M+H] + 331.1559, found 331.1553.

[0169] Compound 2-5

[0170]

[0171] The preparation method of compound 2-1 in Example 5 was adopted, and compound 6-1 therein was replaced by compound 6-5 to obtain a yellow solid with a yield of 37%. 1 H NMR (600MHz, DMSO-d6) δ9.32(d,J=2.1Hz,1H),8.97(d,J=2.0Hz,1H),8.34(d,J=2.4Hz,1H),8.13(dd,J=8.8,2.1Hz,1H) ,8.07(d,J=8.8Hz,1H),7.61–7.56(m,2H),6.74–6.68(m,2H),5.40(s,2H),3.41(m,J=7.0Hz,1H),1.43(d,J=7.0Hz,6H). 13 C NMR(151MHz,DMSO-d6)δ184.54,166.03,149.24,147.32,146.74,139.72,134.97,129.89 ,129.19,127.83,127.64,125.78,123.69,119.97,114.36,26.95,19.92.HRMS(ESI)calcd for C 20 H 18 N4O[M+H] + 331.1559, found 331.1553.

[0172] Compound 2-6

[0173]

[0174] The preparation method of compound 2-1 in Example 5 was adopted, and compound 6-1 therein was replaced by compound 6-6 to obtain a yellow solid with a yield of 20%. 1 H NMR (600MHz, DMSO-d6) δ9.32(d,J=2.1Hz,1H),8.96(d,J=2.0Hz,1H),8.33(d,J=2.0Hz,1H),8.13(dd,J=8.8,2.1Hz,1H),8.07(d,J=8.8Hz, 1H),7.61–7.55(m,2H),6.74–6.68(m,2H),5.40(s,2H),3.05(t,J=7.5Hz,2H),1.85–1.77(m,2H),1.47–1.38(m,2H),0.94(t,J=7.3Hz,3H). 13C NMR(151MHz,DMSO-d6)δ180.85,166.09,149.25,147.32,146.74,139.72,134.96,129.90,129.1 9,127.83,127.63,125.76,123.66,119.95,114.35,28.09,25.57,21.64,13.56.HRMS(ESI)calcd for C 21 H 20 N4O[M+H] + 345.1715, found 345.1711.

[0175] Compound 2-7

[0176]

[0177] The preparation method of compound 2-1 in Example 5 was adopted, and compound 6-1 therein was replaced by compound 6-7 to obtain a yellow solid with a yield of 48%. 1 H NMR (600MHz, DMSO-d6) δ9.32(d,J=2.2Hz,1H),8.96(d,J=2.1Hz,1H),8.35(d,J=2.3Hz,1H),8.13(dd,J= 8.7, 2.1Hz, 1H), 8.07 (d, J = 8.8Hz, 1H), 7.61–7.54 (m, 2H), 6.74–6.67 (m, 2H), 5.40 (s, 2H), 1.49 (s, 9H). 13 C NMR(151MHz,DMSO-d6)δ186.68,166.01,149.24,147.33,146.74,139.72,134.99,129.88 ,129.19,127.83,127.63,125.78,123.71,119.97,114.36,33.49,28.05.HRMS(ESI)calcd for C 21 H 20 N4O[M+H] + 345.1715, found 345.1710.

[0178] Compound 2-8

[0179]

[0180] The preparation method of compound 2-1 in Example 5 was adopted, and compound 6-1 therein was replaced by compound 6-8 to obtain a yellow solid with a yield of 12%. 1H NMR(600MHz, DMSO-d6)δ9.39(t,J=2.3Hz,1H),9.11(q,J=2.4Hz,1H),8.49–8.43(m,2H),8.20(dt,J=8.8, 2.2Hz, 1H), 8.13 (dd, J=8.8, 2.4Hz, 1H), 7.91 (dt, J=8.7, 2.0Hz, 1H), 6.60 (d, J=8.6Hz, 1H), 6.27 (s, 2H). 13 C NMR(151MHz,DMSO-d6)δ167.08,165.32(q,J=43.7Hz),159.77,147.80,146.75,146.59,137.53,1 36.06,135.68,130.25,129.48,127.43,124.10,122.33,118.39,115.87(q,J=273.4Hz),108.21. 19 F NMR(565MHz,DMSO-d6)δ-64.64.HRMS(ESI)calcd for C 17 H 10 F3N5O[M+H] + 358.0916, found 358.0910.

[0181] Compound 2-9

[0182]

[0183] The preparation method of compound 2-1 in Example 5 was adopted, and compound 6-1 therein was replaced by compound 6-9 to obtain a white solid with a yield of 35%. 1 H NMR(600MHz,chloroform-d)δ9.55(d,J=2.0Hz,1H),8.96(d,J=2.0Hz,1H),8.25(d,J=9.2Hz,1H),8.11(m,J=4.8,2.1Hz,2H ),7.67–7.62(m,2H),7.34(d,J=7.8Hz,2H),2.72–2.68(m,2H),1.71–1.64(m,2H),1.46–1.38(m,2H),0.97(t,J=7.4Hz,3H). 13C NMR(151MHz,chloroform-d)δ167.53,166.24(q,J=44.7Hz),148.61,147.48,143.27,140.78,136.84,136.36, 131.62,129.88,129.23,127.42,127.28,125.82,118.66,115.94(q,J=274.4Hz),35.33,33.60,22.41,13.97. 19 F NMR(565MHz,chloroform-d)δ-65.20.HRMS(ESI)calcd for C 22 H 18 F3N3O[M+H] + 398.1480, found 398.1475.

[0184] Compound 2-10

[0185]

[0186] The preparation method of compound 2-1 in Example 5 was adopted, and the 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced with 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane to obtain a white solid with a yield of 25%. 1 H NMR(600MHz,chloroform-d)δ9.55(d,J=2.1Hz,1H),8.95(d,J=2.0Hz,1H),8.24(d,J=9.2H z,1H),8.10(dt,J=5.2,2.6Hz,2H),7.65–7.60(m,2H),7.34(d,J=7.8Hz,2H),2.44(s,3H). 13 C NMR(151MHz,chloroform-d)δ167.54,166.23(q,J=44.7Hz),148.69,147.55,140.71,138.22,136.6 8,136.29,131.54,129.95,129.86,127.40,127.28,125.80,118.66,115.94(q,J=273.7Hz),21.17. 19 F NMR(565MHz,chloroform-d)δ-65.20.HRMS(ESI)calcd for C 19 H 12 F3N3O[M+H] +356.1011, found 356.1005.

[0187] Compound 2-11

[0188]

[0189] The preparation method of compound 2-1 in Example 5 was adopted, and the 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced with 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolan to obtain a white solid with a yield of 54%. 1 H NMR(600MHz,chloroform-d)δ9.57(d,J=2.2Hz,1H),8.97(d,J=2.0Hz,1H),8.27(d,J=8.6H z,1H),8.15–8.09(m,2H),7.75–7.71(m,2H),7.53(t,J=7.6Hz,2H),7.45(t,J=7.4Hz,1H). 13 C NMR(151MHz,chloroform-d)δ167.49,166.26(q,J=44.7Hz),148.71,147.68,140.83,139.59,13 6.41,131.64,129.99,129.15,128.23,127.47,127.38,126.23,118.73,115.94(q,J=273.3Hz). 19 F NMR(565MHz,chloroform-d)δ-65.20.HRMS(ESI)calcd for C 18 H 10 F3N3O[M+H] + 342.0854, found 342.0849.

[0190] Compound 2-12

[0191]

[0192] The preparation method of compound 2-1 in Example 5 was adopted, and the 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced with 2-(4-isopropylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan to obtain a white solid with a yield of 45%. 1H NMR(600MHz,chloroform-d)δ9.55(d,J=2.1Hz,1H),8.95(d,J=2.0Hz,1H),8.24(d,J=9.2Hz,1H),8.11( m,J=4.6,2.1Hz,2H),7.69–7.64(m,2H),7.42–7.37(m,2H),3.01(h,J=6.9Hz,1H),1.33(d,J=6.9Hz,6H). 13 C NMR(151MHz,acetone-d6)δ168.41,166.58(q,J=43.7Hz),149.75,149.60,148.10,140.98,137.74,13 6.86,131.80,130.67,128.28,128.05,127.91,126.85,119.64,116.99(d,J=272.5Hz),34.45,24.12. 19 FNMR(565MHz,chloroform-d)δ-65.19.HRMS(ESI)calcd for C 21 H 16 F3N3O[M+H] + 384.1324, found 384.1319.

[0193] Compound 2-13

[0194]

[0195] The preparation method of compound 2-1 in Example 5 was adopted, and the 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced with 2-(4-(tert-butyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to obtain a white solid with a yield of 44%. 1 H NMR(600MHz,chloroform-d)δ9.56(d,J=2.1Hz,1H),8.97(d,J=2.1Hz,1H),8.26(d, J=9.3Hz,1H),8.15–8.10(m,2H),7.71–7.65(m,2H),7.59–7.53(m,2H),1.40(s,9H). 13C NMR(151MHz,chloroform-d)δ167.52,166.24(q,J=44.7Hz),151.47,148.63,147.49,14 0.65,136.61,136.38,131.61,129.89,127.42,127.11,126.13,125.85,118.66,115.94(q,J=273.7Hz),34.67,31.32. 19 F NMR(565MHz,chloroform-d)δ-65.20.HRMS(ESI)calcd for C 22 H 18 F3N3O[M+H] + 398.1480, found 398.1475.

[0196] Compound 2-14

[0197]

[0198] The preparation method of compound 2-1 in Example 5 was adopted, and the 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced with 2-([1,1'-biphenyl]-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to obtain a white solid with a yield of 29%. 1 H NMR(600MHz,chloroform-d)δ9.58(d,J=2.1Hz,1H),8.99(d,J=2.0Hz,1H),8.29(d,J=8.5Hz,1H),8.20–8.15( m,2H),7.83–7.80(m,2H),7.76(d,J=8.3Hz,2H),7.69–7.66(m,2H),7.49(t,J=7.7Hz,2H),7.43–7.37(m,1H). 13 C NMR(151MHz,chloroform-d)δ167.49,166.26(q,J=44.8Hz),148.76,147.70,141.12,140.31,140.29,138.38,13 6.39,131.47,130.07,128.91,127.84,127.81,127.65,127.43,127.08,126.06,118.78,115.94(q,J=273.3Hz). 19 F NMR(565MHz,chloroform-d)δ-65.18.HRMS(ESI)calcdfor C24 H 14 F3N3O[M+H] + 418.1167, found 418.1162.

[0199] Compound 2-15

[0200]

[0201] The preparation method of compound 2-1 in Example 5 was adopted, compound 6-1 was changed to compound 6-2, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was changed to 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine to obtain a yellow solid with a yield of 32%. 1 H NMR (600MHz, DMSO-d6) δ9.33(d,J=2.2Hz,1H),8.96(d,J=2.4Hz,1H),8.46(d,J=2.5Hz,1H),8.36(d,J=2.1Hz,1H),8.14(d d,J=8.8,2.1Hz,1H),8.09(d,J=8.7Hz,1H),7.90(dd,J=8.6,2.6Hz,1H),6.60(d,J=8.6Hz,1H),6.25(s,2H),2.73(s,3H). 13 C NMR(151MHz,DMSO-d6)δ177.94,166.14,159.70,147.47,147.07,146.52,137.24,135.70, 134.96,129.61,129.42,127.56,123.94,122.48,120.02,108.20,12.16.HRMS(ESI)calcd for C 17 H 13 N5O[M+H] + 304.1198, found 304.1191.

[0202] Compound 2-16

[0203]

[0204] The preparation method of compound 2-1 in Example 5 was adopted, compound 6-1 was replaced by compound 6-2, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced by 2-(4-butylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to obtain a white solid with a yield of 17%. 1H NMR(600MHz,chloroform-d)δ9.53(d,J=2.1Hz,1H),8.88(d,J=1.9Hz,1H),8.22(d,J=8.6Hz,1H),8.09–8.03(m,2H),7.67–7.61( m,2H),7.35–7.31(m,2H),2.72(s,3H),2.71–2.67(m,2H),1.70–1.63(m,2H),1.41(dt,J=14.8,7.4Hz,2H),0.96(t,J=7.4Hz,3H). 13 C NMR(151MHz,chloroform-d)δ177.03,166.67,148.24,148.07,143.04,140.33,137.12,135.38,130.84 ,129.78,129.16,127.63,127.29,125.73,120.50,35.32,33.60,22.40,13.97,12.45.HRMS(ESI)calcd for C 22 H 21 N3O[M+H] + 344.1763, found 344.1757.

[0205] Compound 2-17

[0206]

[0207] The preparation method of compound 2-1 in Example 5 was adopted, and compound 6-1 was replaced by compound 6-2, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced by 4,4,5,5-tetramethyl-2-(4-propylphenyl)-1,3,2-dioxaborolan to obtain a white solid with a yield of 11%. 1 H NMR(600MHz,chloroform-d)δ9.53(d,J=2.1Hz,1H),8.88(d,J=2.2Hz,1H),8.23(d,J=8.6Hz,1H),8.10–8.04(m,2H),7.64 (d,J=8.0Hz,2H),7.33(d,J=7.9Hz,2H),2.72(s,3H),2.67(t,J=7.6Hz,2H),1.71(h,J=7.4Hz,2H),1.00(t,J=7.3Hz,3H). 13C NMR(151MHz,chloroform-d)δ177.04,166.64,148.13,148.00,142.83,140.37,137.14,135.45,130 .89,129.71,129.21,127.64,127.28,125.73,120.52,37.70,24.53,13.87,12.45.HRMS(ESI)calcd for C 22 H 21 N3O[M+H] + 330.1606, found 330.1601.

[0208] Compound 2-18

[0209]

[0210] The preparation method of compound 2-1 in Example 5 was adopted, compound 6-1 was replaced by compound 6-2, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced by 2-(4-ethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to obtain a white solid with a yield of 10%. 1 H NMR(600MHz,chloroform-d)δ9.54(d,J=2.0Hz,1H),8.88(d,J=2.0Hz,1H),8.22(d,J=8.6Hz,1H),8. 09–8.03(m,2H),7.68–7.63(m,2H),7.35(d,J=7.9Hz,2H),2.77–2.70(m,5H),1.31(t,J=7.6Hz,3H). 13 C NMR(151MHz,chloroform-d)δ177.04,166.67,148.26,148.09,144.36,140.32,137.20,135.38,1 30.84,129.79,128.62,127.63,127.38,125.76,120.51,28.56,15.56,12.45.HRMS(ESI)calcdfor C 20 H 17 N3O[M+H] + 316.1450, found 316.1442.

[0211] Compound 2-19

[0212]

[0213] The preparation method of compound 2-1 in Example 5 was adopted, compound 6-1 was changed to compound 6-2, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was changed to 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolane, and a white solid was obtained, 44%. 1 H NMR(600MHz,chloroform-d)δ9.53(d,J=2.0Hz,1H),8.87(d,J=2.0Hz,1H),8.21(d,J=8.5Hz ,1H),8.08–8.02(m,2H),7.64–7.59(m,2H),7.32(d,J=7.8Hz,2H),2.72(s,3H),2.43(s,3H). 13 C NMR(151MHz,acetone-d6)δ178.51,167.35,149.23,148.53,140.62,138.61,137.54,135.7 1,131.02,130.60,130.50,128.47,127.91,126.60,121.49,20.98,12.15.HRMS(ESI)calcd for C 19 H 15 N3O[M+H] + 302.1293, found 302.1290.

[0214] Compound 2-20

[0215]

[0216] The preparation method of compound 2-1 in Example 5 was adopted, compound 6-1 was replaced by compound 6-2, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced by 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolan, to obtain a white solid with a yield of 44%. 1 H NMR(600MHz,chloroform-d)δ9.54(d,J=2.1Hz,1H),8.88(d,J=2.4Hz,1H),8.24(d,J=8.7Hz,1H ),8.10–8.03(m,2H),7.74–7.69(m,2H),7.52(t,J=7.7Hz,2H),7.46–7.40(m,1H),2.72(s,3H). 13C NMR(151MHz,chloroform-d)δ177.05,166.61,148.27,148.21,140.36,139.83,135.44,1 30.86,129.84,129.06,128.04,127.58,127.45,126.11,120.57,12.44.HRMS(ESI)calcd for C 18 H 13 N3O[M+H] + 288.1137, found 288.1131.

[0217] Compound 2-21

[0218]

[0219] The preparation method of compound 2-1 in Example 5 was adopted, compound 6-1 was replaced by compound 6-2, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced by 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol to obtain a white solid with a yield of 24%. 1 H NMR (600MHz, DMSO-d6) δ9.72(s,1H),9.35(t,J=1.5Hz,1H),8.99(d,J=2.1Hz,1H),8.37(d ,J=2.0Hz,1H),8.17–8.08(m,2H),7.69(d,J=8.4Hz,2H),6.96–6.90(m,2H),2.73(s,3H). 13 C NMR(151MHz,DMSO-d6)δ177.95,166.15,157.88,147.55,147.22,139.23,135.13,130 .24,129.59,129.36,128.41,127.49,124.92,120.03,116.05,12.16.HRMS(ESI)calcd for C 18 H 13 N3O2[M+H] + 304.1086, found 304.1081.

[0220] Compound 2-22

[0221]

[0222] The preparation method of compound 2-1 in Example 5 was adopted, compound 6-1 was replaced by compound 6-2, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced by 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to obtain a white solid with a yield of 17%. 1 H NMR (600MHz, DMSO-d6) δ9.38(d,J=2.1Hz,1H),9.04(d,J=2.0Hz,1H),8.45(d,J=2.0Hz,1H),8.20(dd,J= 8.7, 2.2Hz, 1H), 8.15 (d, J = 8.7Hz, 1H), 7.85–7.79 (m, 2H), 7.14–7.08 (m, 2H), 3.84 (s, 3H), 2.74 (s, 3H). 13 C NMR(151MHz,DMSO-d6)δ178.00,166.14,159.56,147.68,147.42,138.86,135.25,131.21,1 30.33,129.44,128.41,127.48,125.40,120.09,114.70,55.36,12.17.HRMS(ESI)calcdfor C 19 H 15 N3O2[M+H] + 318.1243, found 318.1237.

[0223] Compound 2-23

[0224]

[0225] The preparation method of compound 2-1 in Example 5 was adopted, compound 6-1 was changed to compound 6-3, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was changed to 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine-2-amine to obtain a yellow solid, 42%. 1H NMR (600MHz, DMSO-d6) δ9.33(d,J=2.2Hz,1H),8.96(d,J=2.0Hz,1H),8.47(d,J=2.5Hz,1H),8.38(d,J=2.0Hz,1H),8.14(dd,J=8.8,2.1Hz ,1H),8.09(d,J=8.8Hz,1H),7.90(dd,J=8.7,2.6Hz,1H),6.60(d,J=8.6Hz,1H),6.24(s,2H),3.07(q,J=7.5Hz,2H),1.38(t,J=7.5Hz,3H). 13 C NMR (151MHz, DMSO-d6) δ181.68,166.01,159.70,147.46,147.05,146.55,137.23,135.66,134. 97,129.56,129.41,127.56,123.95,122.49,120.05,108.17,19.72,10.51.HRMS(ESI)calcdfor C 18 H 15 N5O[M+H] + 318.1355, found 318.1348

[0226] Compound 2-24

[0227]

[0228] The preparation method of compound 2-1 in Example 5 was adopted, and compound 6-1 was changed to compound 6-3, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was changed to 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to obtain a yellow solid with a yield of 34%. 1 H NMR (600MHz, DMSO-d6) δ9.39(d,J=2.2Hz,1H),9.05(d,J=2.1Hz,1H),8.38(d,J=2.1Hz,1H),8.15(d,J=8.7Hz,1H),8.09(dd,J=8.7,2.1Hz,1H),7.1 8(t,J=7.7Hz,1H),7.01(t,J=2.0Hz,1H),6.96(dt,J=7.7,1.2Hz,1H),6.6 7–6.62(m,1H),5.25(s,2H),3.08(q,J=7.6Hz,2H),1.39(t,J=7.6Hz,3H). 13C NMR(151MHz,DMSO-d6)δ181.73,166.02,149.39,147.88,147.56,140.21,139.78,135.36,130.57 ,129.72,129.35,127.37,125.99,120.11,114.88,113.86,112.54,19.73,10.53.HRMS(ESI)calcd for C 19 H 16 N4O[M+H] + 317.1402, found 317.1396

[0229] Compound 2-25

[0230]

[0231] The preparation method of compound 2-1 in Example 5 was adopted, and compound 6-1 was changed to compound 6-3, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was changed to 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to obtain a yellow solid with a yield of 35%. 1 H NMR (600MHz, DMSO-d6) δ9.41(d,J=2.2Hz,1H),9.02(d,J=2.1Hz,1H),8.23(d,J=2.0Hz,1H),8.14(d,J=8.6Hz,1H),7.94(dd,J=8.6,2. 0Hz,1H),7.15–7.08(m,2H),6.82(dd,J=8.1,1.2Hz,1H),6.73–6.67(m,1H),5.01(s,2H),3.08(q,J=7.6Hz,2H),1.39(t,J=7.6Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ181.75,166.05,147.63,147.51,145.53,139.20,135.27,132.87,130.47 ,129.19,128.86,128.40,127.40,124.53,119.91,116.86,115.58,19.73,10.54.HRMS(ESI)calcd for C 19 H 16 N4O[M+H] + 317.1402, found 317.1397

[0232] Compound 2-26

[0233]

[0234] The preparation method of compound 2-1 in Example 5 was adopted, compound 6-1 was replaced by compound 6-3, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced by 2-(4-butylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan, and a white solid was obtained with a yield of 38%. 1 H NMR(600MHz,chloroform-d)δ9.55(d,J=2.0Hz,1H),8.90(d,J=2.0Hz,1H),8.23(d,J=8.7Hz,1H),8.11–8.04(m,2H),7.66–7.62(m,2H),7.33(d ,J=8.1Hz,2H),3.04(q,J=7.6Hz,2H),2.72–2.66(m,2H),1.70–1.63(m, 2H), 1.51 (t, J = 7.6Hz, 2H), 1.41 (h, J = 7.4Hz, 2H), 0.96 (t, J = 7.4Hz, 3H). 13 C NMR(151MHz,acetone-d6)δ182.41,167.18,149.16,148.50,143.62,140.63,137.75,135.74,131.03,130 .55,129.89,128.48,127.93,126.64,121.55,35.70,34.30,22.87,20.56,14.07,10.80.HRMS(ESI)calcd for C 23 H 23 N3O[M+H] + 358.1919, found 358.1914

[0235] Compound 2-27

[0236]

[0237] The preparation method of compound 2-1 in Example 5 was adopted, and compound 6-1 was replaced by compound 6-3, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced by 4,4,5,5-tetramethyl-2-(4-propylphenyl)-1,3,2-dioxaborolan to obtain a white solid with a yield of 44%. 1H NMR(600MHz,chloroform-d)δ9.55(d,J=2.2Hz,1H),8.90(d,J=2.2Hz,1H),8.23(d,J=8.7Hz,1H),8.11–8.04(m,2H),7.67–7.62(m ,2H),7.35–7.31(m,2H),3.04(q,J=7.6Hz,2H),2.70–2.64(m,2H),1.76–1.66(m,2H),1.51(t,J=7.6Hz,3H),1.00(t,J=7.4Hz,3H). 13 C NMR(151MHz,acetone-d6)δ182.42,167.19,149.21,148.53,143.40,140.63,137.81,135.72,131.02, 130.59,129.94,128.48,127.92,126.65,121.56,38.09,25.16,20.55,13.94,10.80.HRMS(ESI)calcd for C 22 H 21 N3O[M+H] + 344.1763, found 344.1758

[0238] Compound 2-28

[0239]

[0240] The preparation method of compound 2-1 in Example 5 was adopted, compound 6-1 was replaced by compound 6-3, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced by 2-(4-ethylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan, to obtain a white solid with a yield of 48%. 1 H NMR(600MHz,chloroform-d)δ9.55(d,J=2.1Hz,1H),8.90(d,J=2.4Hz,1H),8.23(d,J=8.7Hz,1H),8.11–8.03(m,2H),7.65(d,J =8.0Hz,2H),7.35(d,J=7.9Hz,2H),3.04(q,J=7.6Hz,2H),2.74(q,J=7.6Hz,2H),1.51(t,J=7.6Hz,2H),1.31(t,J=7.6Hz,3H). 13C NMR(151MHz,acetone-d6)δ182.41,167.18,149.18,148.51,145.02,140.63,137.78,135.73,131. 03,130.56,129.33,128.47,128.01,126.64,121.54,28.95,20.55,15.88,10.80.HRMS(ESI)calcd for C 21 H 19 N3O[M+H] + 330.1606, found 330.1601

[0241] Compound 2-29

[0242]

[0243] The preparation method of compound 2-1 in Example 5 was adopted, compound 6-1 was replaced by compound 6-3, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced by 4,4,5,5-tetramethyl-2-(p-tolyl)-1,3,2-dioxaborolan, and a white solid was obtained with a yield of 39%. 1 H NMR(600MHz,chloroform-d)δ9.54(d,J=2.1Hz,1H),8.89(d,J=1.9Hz,1H),8.22(d,J=8.7Hz,1H),8.09–8.02 (m,2H),7.64–7.60(m,2H),7.32(d,J=7.8Hz,2H),3.04(q,J=7.6Hz,2H),2.43(s,3H),1.50(t,J=7.7Hz,3H). 13 C NMR(151MHz,methanol-d4)δ183.28,167.51,148.78,148.72,141.82,139.37,137.83,137.15, 132.07,130.84,129.80,129.23,128.30,126.88,122.21,21.22,21.06,11.02.HRMS(ESI)calcd for C 20 H 17 N3O[M+H] + 316.1450, found 316.1444

[0244] Compound 2-30

[0245]

[0246] The preparation method of compound 2-1 in Example 5 was adopted, compound 6-1 was replaced by compound 6-3, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced by 4,4,5,5-tetramethyl-2-phenyl-1,3,2-dioxaborolan, to obtain a white solid with a yield of 35%. 1 H NMR(600MHz,chloroform-d)δ9.56(d,J=2.1Hz,1H),8.91(d,J=2.0Hz,1H),8.24(d,J=8.7Hz,1H),8.12–8.04(m ,2H),7.75–7.70(m,2H),7.52(t,J=7.7Hz,2H),7.46–7.40(m,1H),3.04(q,J=7.6Hz,2H),1.51(t,J=7.6Hz,3H). 13 CNMR(151MHz,acetone-d6)δ182.40,167.15,149.29,148.70,140.62,140.44,135.76,131. 05,130.65,129.83,128.76,128.41,128.06,127.06,121.58,20.55,10.79.HRMS(ESI)calcd for C 19 H 15 N3O[M+H] + 302.1293, found 302.1289

[0247] Compound 2-31

[0248]

[0249] The preparation method of compound 2-1 in Example 5 was adopted, and compound 6-1 was replaced by compound 6-3, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced by 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol to obtain a white solid with a yield of 23%. 1 H NMR (600MHz, DMSO-d6) δ9.72(s,1H),9.36(d,J=2.1Hz,1H),9.00(d,J=2.2Hz,1H),8.40(d,J=2.2Hz,1H) ,8.17–8.09(m,2H),7.73–7.65(m,2H),6.96–6.90(m,2H),3.07(q,J=7.5Hz,2H),1.39(t,J=7.6Hz,3H). 13C NMR(151MHz,DMSO-d6)δ181.71,166.02,157.87,147.55,147.22,139.21,135.15,130.21,1 29.59,129.34,128.40,127.50,124.94,120.07,116.04,19.73,10.53.HRMS(ESI)calcdfor C 19 H 15 N3O2[M+H] + 318.1243, found 318.1237

[0250] Compound 2-32

[0251]

[0252] The preparation method of compound 2-1 in Example 5 was adopted, compound 6-1 was changed to compound 6-3, 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was changed to 2-(4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan, and a white solid was obtained with a yield of 62%. 1 H NMR (600MHz, DMSO-d6) δ9.37(d,J=2.0Hz,1H),9.02(d,J=2.0Hz,1H),8.45(d,J=2.1Hz,1H),8.18(dd,J=8.7,2.0Hz,1H),8 .13(d,J=8.8Hz,1H),7.81(d,J=8.6Hz,2H),7.13–7.08(m,2H),3.83(s,3H),3.07(q,J=7.5Hz,2H),1.39(t,J=7.6Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ181.71,166.00,159.54,147.66,147.39,138.80,135.23,131.19,13 0.25,129.41,128.37,127.47,125.38,120.10,114.67,55.34,19.72,10.51.HRMS(ESI)calcd for C 20 H 17 N3O2[M+H] + 332.1399, found 332.1394.

[0253] Compound 2-33

[0254]

[0255] The preparation method of compound 2-1 in Example 5 was adopted, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced with 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine to obtain a yellow solid with a yield of 16.7%. 1 H NMR (600MHz, DMSO-d6) δ9.41(d,J=2.2Hz,1H),9.15(d,J=2.1Hz,1H),8.50(d,J=2.1Hz,1H),8.25(dd,J=8.8,2.2H z,1H),8.15(d,J=8.7Hz,1H),7.78(d,J=8.9Hz,2H),7.11(d,J=8.9Hz,2H),3.84–3.69(m,4H),3.26–3.18(m,4H). 13 CNMR(151MHz,DMSO-d6)δ165.33,163.55(q,J=43.6Hz),149.31,146.13,145.07,137.47,134.46,128 .95,127.65,127.08,126.00,125.65,123.10,116.62,114.10(q,J=273.4Hz),113.56,64.34,46.23. 19 F NMR(565MHz,DMSO-d6)δ-64.64.HRMS(ESI)calcd forC 22 H 17 F3N4O2[M+H] + 427.1382, found 427.1376.

[0256] Compound 2-34

[0257]

[0258] The preparation method of compound 2-1 in Example 5 was adopted, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced with 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan to obtain a white solid with a yield of 17.5%. 1H NMR (600MHz, DMSO-d6) δ9.43(d,J=2.2Hz,1H),9.15(d,J=2.0Hz,1H),8.54(d,J=2.1Hz,1H) ,8.23(dd,J=8.7,2.2Hz,1H),8.18(d,J=8.7Hz,1H),7.92–7.88(m,2H),7.41–7.36(m,2H). 13 CNMR(151MHz,DMSO-d6)δ167.02,165.34(q,J=44.5,44.0Hz),162.42(d,J=245.4Hz),148.18,147.49,138.36,136.46,135.30(d,J =3.4Hz), 131.13–131.00 (m), 129.60, 129.30 (d, J = 8.1Hz), 127.18, 126.58, 118.52, 116.12 (d, J = 21.3Hz), 115.86 (q, J = 273.2Hz). 19 F NMR(565MHz,DMSO-d6)δ-64.66,-114.30.HRMS(ESI)calcd forC 18 H9F4N3O[M+H] + 360.0760, found 360.0755.

[0259] Compound 2-35

[0260]

[0261] The preparation method of compound 2-1 in Example 5 was adopted, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced with 2-(4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan to obtain a white solid with a yield of 9.52%. 1 H NMR(600MHz,DMSO-d6)δ9.45(d,J=2.2Hz,1H),9.18(d,J=2.1Hz,1H),8.59(d,J=2.2Hz,1H) ,8.25(dd,J=8.8,2.2Hz,1H),8.20(d,J=8.8Hz,1H),7.91–7.87(m,2H),7.64–7.60(m,2H). 13C NMR(151MHz,DMSO-d6)δ166.30,165.33–163.76(m),147.63,146.96,137.35,136.93,135.8 4,132.60,130.23,129.00,128.54,128.29,126.48,126.10,117.88,115.17(d,J=273.4Hz). 19 F NMR(565MHz,DMSO-d6)δ-64.65.HRMS(ESI)calcd forC 18 H9ClF3N3O[M+H] + 376.0464, found 376.0459.

[0262] Compound 2-36

[0263]

[0264] The preparation method of compound 2-1 in Example 5 was adopted, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was replaced with N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to obtain a yellow solid with a yield of 13.6%. 1 H NMR (600MHz, DMSO-d6) δ9.39(d,J=2.1Hz,1H),9.14(d,J=2.3Hz,1H),8.46(d,J=2.2Hz,1H),8.24 (dd,J=8.8,2.1Hz,1H),8.14(d,J=8.8Hz,1H),7.78–7.72(m,2H),6.91–6.85(m,2H),2.99(s,6H). 13 C NMR(151MHz,DMSO-d6)δ166.95,165.13(q,J=43.8Hz),150.26,147.56,146.37,139.40,135.91,130 .41,129.16,127.54,127.33,125.59,123.95,118.16,115.70(q,J=273.0,272.6Hz),112.56,29.82. 19 F NMR(565MHz,DMSO-d6)δ-64.63.HRMS(ESI)calcd for C 20 H 15 F3N4O[M+H] + 385.1276, found 385.1271.

[0265] Compound 2-37

[0266]

[0267] The preparation method of compound 2-1 in Example 5 was adopted, and the compound 6-1 therein was changed to compound 6-3, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was changed to 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to obtain a white solid with a yield of 23.8%. 1 H NMR(600MHz,DMSO-d6)δ9.39(d,J=2.1Hz,1H),9.04–9.00(m,1H),8.48(d,J=2.0Hz,1H),8.20–8 .12(m,2H),7.92–7.86(m,2H),7.41–7.34(m,2H),3.07(q,J=7.5Hz,2H),1.39(t,J=7.6Hz,3H). 13 C NMR (151MHz, DMSO-d6) δ181.73, 165.94, 163.18, 161.55, 147.82 (d, J = 10.3Hz), 138.07, 135.44 (d, J = 3.4Hz) ,135.37,130.39,129.54,129.27(d,J=8.5Hz),127.33,126.40,120.20,116.06(d,J=21.3Hz),19.72,10.51. 19 F NMR(565MHz,DMSO-d6)δ-114.44.HRMS(ESI)calcd forC 19 H 14 FN3O[M+H] + 320.1199, found 320.1194.

[0268] Compound 2-38

[0269]

[0270] The preparation method of compound 2-1 in Example 5 was adopted, and the compound 6-1 therein was changed to compound 6-3, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was changed to N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetamide to obtain a white solid with a yield of 21.7%. 1H NMR (600MHz, DMSO-d6) δ10.12(s,1H),9.39(d,J=2.1Hz,1H),9.03(d,J=2.0Hz,1H),8.48(d,J=2.0Hz,1H),8.20(dd,J=8.8,2.1Hz, 1H), 8.15 (d, J = 8.7Hz, 1H), 7.82 (d, J = 8.7Hz, 2H), 7.76 (d, J = 8.6Hz, 2H), 3.09 (q, J = 7.5Hz, 2H), 2.10 (s, 3H), 1.40 (t, J = 7.6Hz, 3H). 13 C NMR(151MHz,DMSO-d6)δ181.56,168.38,165.82,147.59,147.33,139.38,138.55,135.10,133.11, 130.03,129.28,127.33,126.26,125.42,119.97,119.29,24.00,19.55,10.34.HRMS(ESI)calcdfor C 21 H 18 N4O2[M+H] + 359.1508, found 359.1503.

[0271] Compound 2-39

[0272]

[0273] The preparation method of compound 2-1 in Example 5 was adopted, and the compound 6-1 therein was changed to compound 6-3, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was changed to 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)morpholine to obtain a white solid with a yield of 24%. 1 H NMR (600MHz, DMSO-d6) δ9.37(d,J=2.1Hz,1H),9.04(d,J=2.2Hz,1H),8.46(d,J=2.1Hz,1H),8.20(dd,J=8.8,2.2Hz,1H),8.13(d,J=8 .7Hz,1H),7.81–7.75(m,2H),7.14–7.08(m,2H),3.80–3.75(m,4H),3.24–3.19(m,4H),3.09(q,J=7.6Hz,2H),1.40(t,J=7.6Hz,3H). 13C NMR(151MHz,DMSO-d6)δ181.56,165.87,150.84,147.40,146.98,138.80,134.99,129.89,129.1 8,128.86,127.57,127.40,124.55,119.90,115.15,65.93,47.85,19.55,10.35.HRMS(ESI)calcd forC 23 H 22 N4O2[M+H] + 387.1821, found 387.1816.

[0274] Compound 2-40

[0275]

[0276] The preparation method of compound 2-1 in Example 5 was adopted, and the compound 6-1 therein was changed to compound 6-3, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was changed to 2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to obtain a white solid with a yield of 26.1%. 1 H NMR (600MHz, DMSO-d6) δ9.33(d,J=2.2Hz,1H),8.97(d,J=2.0Hz,1H),8.39(d,J=2.1Hz,1H),8.14(dd,J=8.9,2.1Hz,1H),8.07(d,J=8.7Hz ,1H),7.75(d,J=2.2Hz,1H),7.58(dd,J=8.4,2.2Hz,1H),6.94(d,J=8.4Hz,1H),5.66(s,2H),3.07(q,J=7.5Hz,2H),1.39(t,J=7.6Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ181.68,166.01,147.50,147.11,144.98,138.18,135.07,129.76,129.31 ,127.53,127.49,127.24,126.52,124.40,120.06,117.81,115.83,19.72,10.51.HRMS(ESI)calcd for C 19 H 15 ClN4O[M+H] + 351.1013, found 351.1007.

[0277] Compound 2-41

[0278]

[0279] The preparation method of compound 2-1 in Example 5 was adopted, and the compound 6-1 therein was changed to compound 6-3, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was changed to 2-(4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to obtain a white solid with a yield of 27.3%. 1 H NMR(600MHz,DMSO-d6)δ9.42(s,1H),9.07(s,1H),8.56(s,1H),8.20(q,J=9.3,8.8Hz,2H), 7.89(d,J=8.0Hz,2H), 7.61(d,J=8.0Hz,2H), 3.08(d,J=8.9Hz,2H), 1.40(d,J=8.1Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ181.61,165.76,147.84,147.80,137.62,135.31,133.01,130 .11,129.47,129.03,128.81,127.18,126.48,120.10,19.55,10.34.HRMS(ESI)calcd for C 19 H 14 ClN3O[M+H] + 336.0904, found 336.0898.

[0280] Compound 2-42

[0281]

[0282] The preparation method of compound 2-1 in Example 5 was adopted, and the compound 6-1 therein was changed to compound 6-3, and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline was changed to 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile to obtain a white solid with a yield of 27.9%. 1H NMR (600MHz, DMSO-d6) δ9.45(d,J=2.1Hz,1H),9.10(d,J=2.0Hz,1H),8.67(d,J=2.0Hz,1H),8.28(dd,J=8.8,2.2H z,1H),8.22(d,J=8.7Hz,1H),8.11–8.06(m,2H),8.05–8.00(m,2H),3.09(q,J=7.5Hz,2H),1.40(t,J=7.6Hz,3H). 13 C NMR(151MHz,DMSO-d6)δ181.65,165.71,148.26,148.15,143.27,137.03,135.51,132.95,130 .10,129.63,127.92,127.53,127.12,120.23,118.67,110.59,19.55,10.34.HRMS(ESI)calcd for C 20 H 14 N4O[M+H] + 327.1246, found 327.1239.

[0283] Embodiment 5:

[0284] In vitro anti-enteroviral activity test

[0285] Experimental materials and reagents:

[0286] Virus strain: Enterovirus D68

[0287] Cell line: human rhabdoid tumor cells (RD)

[0288] Experimental reagents: DMEM high glucose medium, fetal bovine serum from Gibco, CellTiter- Chemiluminescent cell viability detection reagent, the cell growth medium is DMEM high-glucose medium containing 10% fetal bovine serum, and the cell maintenance medium and virus growth medium are both DMEM high-glucose medium containing 2% fetal bovine serum.

[0289] Experimental methods:

[0290] Determination of compound anti-EV-D68 activity: According to the mass and molecular weight of the test compound and the positive compound, the test compound and the positive compound were dissolved in DMSO to 100 mM. RD cells were cultured at 1.5×10 5 / mL concentration inoculated into a 96-well plate with white walls and transparent bottom, placed in a CO2 incubator, and cultured at 37°C for 24h. The compound to be tested was diluted with cell maintenance medium, with an initial concentration of 800μM, followed by 3-fold dilution, 10 gradients, and the diluted compound was added to the 96-well plate, 50μL per well, followed by addition of 100TCID 50 50 μL of EV-D68 virus dilution was added to each well and 3 days later, the cells were incubated with CellTiter- The cell viability value of each well was measured by chemiluminescent cell viability detection kit.

[0291] Cytotoxicity assay of compounds: RD cells were cultured at a rate of 1.5×10 5 / mL concentration inoculated white-walled transparent-bottom 96-well plates, the test compounds were diluted with cell maintenance medium, the initial concentration was 400μM, then 3-fold dilution, 10 gradients, the diluted compounds were added to the 96-well plate, 100μL per well, and after 72h, CellTiter- The cell viability value of each well was measured by chemiluminescent cell viability detection kit.

[0292] The anti-enterovirus D68 (EV-D68) activity and RD cell cytotoxicity test results of the compounds represented by Formula 1 and Formula 2 are shown in the following table, wherein EC 50 Stands for 50% effective concentration, CC 50 Represents 50% cytotoxic concentration, SI stands for selection index, SI = CC 50 / EC 50 .

[0293] Table 1 Anti-EV-D68 activity and toxicity to RD cells of the compounds shown in Formula 1

[0294]

[0295]

[0296] Table 2 Anti-EV-D68 activity and toxicity to RD cells of the compounds shown in formula 2

[0297]

[0298]

[0299]

[0300]

[0301] The results showed that the compounds represented by Formula 1 and Formula 2 of the present invention, such as Compounds 1-1 to 1-9 and Compounds 2-1 to 2-42 prepared in Examples, had inhibitory activity against enterovirus EV-D68.

[0302] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention rather than to limit it. Although the present invention has been described in detail with reference to the preferred embodiments, ordinary technicians in the field should understand that the specific implementation methods of the present invention can still be modified or some technical features can be replaced by equivalents without departing from the spirit of the technical solution of the present invention, which should be included in the scope of the technical solution for protection of the present invention.

Claims

1. A compound represented by Formula 1 or a pharmaceutically acceptable salt thereof, in: R1 is selected from C 1-8 alkyl; R2 is phenyl, which is optionally substituted by one or more R a Replace, each R a are independently selected from hydrogen, amino, C 1-4 Alkyl, aminoacyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from C 1-6 alkyl.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is selected from C 1-3 alkyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R1 is ethyl.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is selected from 6. The compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof, wherein: The compound represented by formula 1 is selected from the following:

7. The compound represented by formula 2 or a pharmaceutically acceptable salt thereof, in: R3 is selected from C 1-6 Alkyl, the C 1-6 The alkyl group is optionally substituted with one or more R b Replace, each R b are each independently hydrogen or halogen; R4 is selected from phenyl, pyridyl, and the phenyl or pyridyl is optionally substituted by one or two R c Replace, each R c Each independently selected from hydrogen, fluorine, chlorine, amino, dimethylamino, acetylamino, C 1-4 Alkyl, C 1-2 Alkoxy, hydroxy, morpholinyl.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R3 is selected from C 1-4 Alkyl, the C 1-4 The alkyl group is optionally substituted with one or more R b Replace, each R b are each independently hydrogen or halogen.

9. The compound or pharmaceutically acceptable salt thereof according to claim 7, wherein the halogen is fluorine.

10. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R3 is selected from trifluoromethyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, and tert-butyl.

11. The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R4 is selected from 12. The compound according to any one of claims 7 to 10 or a pharmaceutically acceptable salt thereof, wherein: The compound shown in formula 2 is selected from the following:

13. A pharmaceutical composition comprising the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition of claim 13, further comprising one or more pharmaceutically acceptable carriers or excipients.

15. The pharmaceutical composition according to claim 13 or 14, which is in the form of tablets, capsules, solutions, suspensions, granules or injections.

16. A method for preparing a compound according to any one of claims 7 to 12 or a pharmaceutically acceptable salt thereof, comprising: The intermediate shown in the following structural formula 6 is used as a raw material to react with a boronic acid derivative shown in R4-B(OH)2. The general reaction formula is as follows: wherein R3 and R4 are as defined in any one of claims 7-11.

17. The method of claim 16, wherein the intermediate represented by structural formula 6 is prepared by reacting the intermediate represented by structural formula 5 as a raw material with an acid anhydride represented by (R3-CO)2O, and the general reaction formula is as follows: in, R3 is as defined in any one of claims 7-10.

18. The method of claim 17, wherein the intermediate shown in structural formula 5 is obtained by reacting 6-bromoquinoline-3-carbonitrile with hydroxylamine.

19. The method of claim 18, wherein the compound according to any one of claims 7 to 12 is prepared by the following general reaction formula: in, R3 and R4 are as defined in any one of claims 7-11.

20. Use of the compound according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 13 to 15 in the preparation of a medicament for one or more of the following: 1) Prevent or treat enterovirus infection or diseases caused by enterovirus infection; 2) Inhibit the replication or reproduction of enterovirus in cells; The enterovirus is enterovirus D68.

21. The use of claim 20, wherein the disease caused by enterovirus infection is selected from hand, foot and mouth disease, respiratory system infection, central nervous system disease, acute flaccid paralysis, nonspecific febrile disease, pneumonia, bronchiolitis, encephalitis and myocarditis, acute flaccid myelitis or any combination thereof.

22. The use according to claim 20, wherein the disease caused by the enterovirus infection is selected from hand, foot and mouth disease, respiratory system infection, central nervous system disease, acute flaccid paralysis or any combination thereof.

23. The use of claim 20, wherein the cell is a mammalian cell.

24. The use of claim 23, wherein the mammal is selected from the group consisting of bovines, equines, porcines, canines, felines, rodents, and primates.

25. The use of claim 23, wherein the mammal is a human, a cat, a dog, a monkey or a pig.

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