Cepharanthine derivative and application thereof

Abstract

The invention relates to a cepharanthine derivative and application thereof. An anti-SARS-CoV-2 activity test is carried out on the cepharanthine derivative by utilizing a new coronavirus drug screening substitution model GXP2V, and a result shows that the cepharanthine derivative disclosed by the invention can be used for effectively inhibiting infection of a pangolin coronavirus strain GXP2V, so that the cepharanthine derivative disclosed by the invention can be applied to prevention, alleviation and / or treatment of COVID-19 infection. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of medicines, and in particular relates to cepharanthin derivatives and applications thereof. Background Art

[0002] Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible and pathogenic coronavirus that has overwhelmingly surpassed SARS-CoV and MERS-CoV in terms of the number of infected people and the spatial scope of the epidemic area. Unlike SARS-CoV and MERS-CoV, SARS-CoV-2 has spread globally and may continue to spread among humans. With the emergence of various mutant strains, the new coronavirus has a faster transmission speed and stronger immune escape ability, which may reduce the effectiveness of vaccines. Therefore, there is an urgent need to find safe, effective and readily available COVID-19 treatments, and new effective drugs for the treatment of new coronavirus infection remain the focus of COVID-19 prevention and control.

[0003] Cephalaenopsis is a benzylisoquinoline alkaloid that was first used clinically in Japan in 1951. It has shown anti-inflammatory, antioxidant, immunomodulatory, antiparasitic and antiviral properties. It is mainly used in the treatment of radiation-induced leukopenia, alopecia areata, exudative otitis media mucositis, snake bites, etc. Cephalaenopsis has not shown obvious toxic side effects in its more than 70 years of clinical use history, and it has a long history of clinical experimental treatment of pneumoconiosis in China, and has good clinical use value. In recent years, the applicant's team discovered for the first time that Cephalaenopsis can significantly inhibit the entry and replication of SARS-CoV-2 and the new coronavirus-like GX_P2V. Subsequently, many teams at home and abroad have successively reported the inhibitory activity of cephalothin on the new coronavirus. The team of Professor Wakita Takaji of Japan found that the combination of cephalothin and nelfinavir can further reduce viral infection; a research result published in Cell Reports by a research team of the University of Pennsylvania screened nearly 3,000 compounds and found that cephalothin can significantly inhibit SARS-CoV-2 infection; Drayman et al. found that cephalothin is one of the best anti-new coronavirus drugs among 1,900 drugs approved by the Food and Drug Administration, and its inhibitory activity is better than remdesivir; when screening drugs targeting virus-host factor interactions, the research team of Zhang Qiangfeng of Tsinghua University and Wang Jianwei of Peking Union Medical College found that cephalothin has good inhibitory activity against wild strains and mutant strains of the new coronavirus, and can reverse the damage of the new coronavirus to hACE2 transgenic mice. At the same time, clinical trials for cephalothin for new coronavirus infection have been actively carried out both at home and abroad. Canadian pharmaceutical company PharmaDrug has carried out clinical trials of cephalothin for the treatment of mild to moderate new coronavirus infection with the approval of the US FDA. A seminar on the efficacy of celastrol tablets was held in China on February 24, 2023. The results of the clinical trial of celastrol tablets for the treatment of new coronavirus patients (clinical trial number: NCT05398705) showed that celastrol tablets (60 mg / day) can inhibit new coronavirus infection in patients, effectively shorten the course of the disease in asymptomatic first-time infected patients, and have good safety.

[0004] In order to cope with the emergence of mutant strains of the new coronavirus, it is necessary to develop compounds with stronger antiviral infection activity and lower cytotoxicity. Therefore, it is necessary to optimize the structure of cephalothin. Summary of the invention

[0005] The object of the present invention is to provide an effective inhibitor of SARS-CoV-2, which can prevent, alleviate and / or treat diseases caused by novel coronavirus infection.

[0006] The present invention synthesized a series of cephalothin derivatives and tested their activity in inhibiting the new coronavirus.

[0007] The present invention provides a cephalaenopsis derivative or a pharmaceutically acceptable salt thereof as shown in the following formula I:

[0008]

[0009] Wherein, R is selected from halogen,

[0010] R1 is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 1-8 Alkyl, C 3-6 Cycloalkyl, -C 1-8 Alkyl OC 1-8 Alkyl, halogenated C 1-8 Alkyl, halogenated C 1-8 Alkoxy, C 2-6 Alkenyl, cyano C 1-8 Alkyl-, C 3-6 Cycloalkyl C 1-8 Alkyl-, 3-6 membered heterocyclic group C 1-8 Alkyl-, C 6-14 Aryl and 5-14 membered heteroaryl; said R b The same or different, independently selected from the following groups: C 1-8 Alkoxy, halogen, hydroxyl, halogenated C 1-8 alkyl;

[0011] R2 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: C 1-8 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-8 Alkyl, C 1-8 Alkoxy, -C 1-8 Alkyl OC 1-8 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, N(C 1-8 Alkyl)2, C 6-14 Aryl and 5-14 membered heteroaryl; said R c The same or different, independently selected from the following groups: C 1-8 Alkyl, halogen, halogenated C 1-8 Alkyl, amino, cyano, aldehyde, carboxyl, NHC 1-8 Alkyl, N(C 1-8 Alkyl)2, nitro, C 1-8 Alkoxy, hydroxyl, -SO3H, -SO3C 1-8 Alkyl, -COC 1-8 alkyl;

[0012] R3 and R4 are the same or different and are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, N(C 1-8 Alkyl)2, C 6-14 Aryl and 5-14 membered heteroaryl;

[0013] R5 is selected from C 1-8 alkyl;

[0014] R6 is selected from unsubstituted or optionally substituted with one, two or more R d Substituted with the following groups: C 1-8 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-8 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, N(C 1-8 Alkyl)2, C 6-14 Aryl or 5-14 membered heteroaryl; said R d The same or different, independently selected from the following groups: C 1-8 Alkyl, halogen, halogenated C 1-8 Alkyl, amino, cyano, aldehyde, carboxyl, NHC 1-8 Alkyl, N(C 1-8 Alkyl)2, nitro, C 1-8 Alkoxy, hydroxyl, -SO3H, -SO3C 1-8 Alkyl, -COC 1-8 alkyl;

[0015] R7 and R8 are the same or different and are independently selected from C 1-8 alkyl;

[0016] R9 is selected from halogen, OH, unsubstituted or optionally substituted by one, two or more R e Substituted with the following groups: C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 1-8 Alkoxy, -COO-C 1-8 Alkyl, -COO-C 3-6 Cycloalkyl, -COO-3-6 membered heterocyclic group, -COO-C 6-14 Aryl or -COO-5-14 membered heteroaryl,

[0017] R 10 , R 11 The same or different, each independently selected from C 1-8 Alkyl, -C 1-8 Alkyl-OH or C 6-14 Aryl;

[0018] R12 Selected from C 1-8 Alkyl, C 6-14 Aryl;

[0019] R 13 Selected from C 1-8 Alkyl, C 6-14 Aryl, -C 1-8 Alkyl-C 6-14 Aryl;

[0020] R 14 , R 15 The same or different, each independently selected from C 1-8 alkyl.

[0021] According to an embodiment of the present invention, R is selected from halogen,

[0022] R1 is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkyl OC 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, cyano C 1-6 Alkyl-, C 3-6 Cycloalkyl C 1-6 Alkyl-, 3-6 membered heterocyclic group C 1-6 Alkyl-, C 6-14 Aryl and 5-14 membered heteroaryl; said R b The same or different, independently selected from the following groups: C 1-6 Alkoxy, halogen, hydroxyl, halogenated C 1-6 alkyl;

[0023] R2 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: C 1-6 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl OC 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, N(C 1-6 Alkyl)2, C 6-14 Aryl and 5-14 membered heteroaryl; said R c The same or different, independently selected from the following groups: C 1-6Alkyl, halogen, halogenated C 1-6 Alkyl, amino, cyano, aldehyde, carboxyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, nitro, C 1-6 Alkoxy, hydroxyl, -SO3H, -SO3C 1-6 Alkyl, -COC 1-6 alkyl;

[0024] R3 and R4 are the same or different and are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, N(C 1-6 Alkyl)2, C 6-14 Aryl and 5-14 membered heteroaryl;

[0025] R5 is selected from C 1-6 alkyl;

[0026] R6 is selected from unsubstituted or optionally substituted with one, two or more R d Substituted with the following groups: C 1-6 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, N(C 1-6 Alkyl)2, C 6-14 Aryl or 5-14 membered heteroaryl; said R d The same or different, independently selected from the following groups: C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, amino, cyano, aldehyde, carboxyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, nitro, C 1-6 Alkoxy, hydroxyl, -SO3H, -SO3C 1-6 Alkyl, -COC 1-6 alkyl;

[0027] R7 and R8 are the same or different and are independently selected from C 1-6 alkyl;

[0028] R9 is selected from halogen, OH, unsubstituted or optionally substituted by one, two or more R e Substituted with the following groups: C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 1-6 Alkoxy, -COO-C 1-6 Alkyl, -COO-C 3-6 Cycloalkyl, -COO-3-6 membered heterocyclic group, -COO-C 6-14Aryl or -COO-5-14 membered heteroaryl,

[0029] R 10 , R 11 The same or different, each independently selected from C 1-6 Alkyl, -C 1-6 Alkyl-OH or C 6-14 Aryl;

[0030] R 12 Selected from C 1-6 Alkyl, C 6-14 Aryl;

[0031] R 13 Selected from C 1-6 Alkyl, C 6-14 Aryl, -C 1-6 Alkyl-C 6-14 Aryl;

[0032] R 14 , R 15 The same or different, each independently selected from C 1-6 alkyl.

[0033] In some embodiments of the present invention, R1 is selected from trifluoroethyl, methyl, isopropyl, CH3OC2H4-, 2-fluoroethyl, 3-propenyl, fluoromethyl, ethyl, CNCH2-, cyclopropylmethyl;

[0034] R2 is selected from methyl, n-heptyl, vinyl, cyclopropyl, 2-thienyl, N,N-dimethyl, N-morpholinyl, 4-methylpiperazinyl, 3-pyridyl, 2-furyl, 3-chloro-2-thienyl, 3-thienyl, 2-benzothiophene, N,N-diethyl, 4-N,N-dimethylphenyl, 3-pyridyl, 4-pyridyl, 4-tetrahydro-2H-pyranyl, 2-bromoisopropyl, cyclobutyl, piperidinyl, phenyl, 2-trifluoromethoxyphenyl, 2,5-ditrifluoromethoxyphenyl, CH3OCH2-, N-pyrrolidinyl, 4-methyl-2-thienyl, 4-bromo-2-thienyl, 3-chloro-2-thienyl, 2-chloro-3-thienyl, or the following radicals:

[0035]

[0036] R5 is selected from n-pentyl;

[0037] R6 is selected from methyl, 4-methylphenyl, 2-thienyl;

[0038] R7 and R8 are selected from methyl;

[0039] R9 is selected from halogen, hydroxyl, methoxy, or the following groups:

[0040]

[0041] As an example, the cephalaenopsis derivative or a pharmaceutically acceptable salt thereof represented by Formula I is selected from the following structures:

[0042]

[0043]

[0044] According to an embodiment of the present invention, the pharmaceutically acceptable salt is selected from the acid addition salt of the nitrogen atom with sufficient basicity in the structure of the cephalanthrin derivative, and the acid addition salt includes the cephalanthrin derivative and an inorganic acid such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid; an organic acid such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2 - salts formed from naphthoic acid, nicotinic acid, pamoic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.

[0045] According to an embodiment of the present invention, the cephaladin derivatives shown in Formula I also include isomers, racemates, deuterated compounds and hydrates thereof.

[0046] The derivatives of the present invention, their pharmaceutically acceptable salts, isomers, racemates, deuterated compounds and hydrates thereof can be prepared by conventional methods in the art.

[0047] The present invention also provides the use of at least one of the cephalaenopsis derivatives or pharmaceutically acceptable salts thereof as shown in the above formula I in the preparation of a drug for preventing, alleviating and / or treating diseases caused by coronavirus infection.

[0048] The present invention also provides a composition, which comprises at least one of the cephalaenopsis derivatives or pharmaceutically acceptable salts thereof.

[0049] According to the embodiments of the present invention, the composition can be configured into various suitable pharmaceutical preparation forms. It can be used alone, or mixed with pharmaceutical excipients (such as excipients, diluents, etc.) to be configured into tablets, capsules, granules, syrups, etc. for oral administration or powder injections, solutions for injection, and developed into functional foods, functional drinks, medicinal wines, nasal drops and mouthwashes, etc.

[0050] According to an embodiment of the present invention, the composition is a medicine, a food, a skin care product, a cosmetic, a daily necessities and a health care product, preferably a medicine.

[0051] According to an embodiment of the present invention, the disease caused by coronavirus infection is novel coronavirus infection.

[0052] According to the embodiments of the present invention, the cepharanthin derivatives and their pharmaceutically acceptable salts or compositions as described above can be configured into various suitable pharmaceutical preparation forms. They can be used alone, or mixed with pharmaceutical excipients (such as excipients, diluents, etc.), configured into tablets, capsules, granules, syrups, etc. for oral administration or powder injections, solutions for injection, and developed into functional foods, functional drinks, medicinal wines, nasal drops and mouthwashes, etc.

[0053] The present invention also provides a method for preventing, alleviating and / or treating diseases caused by coronavirus infection, comprising administering at least one of the cephalaenopsis derivatives and pharmaceutically acceptable salts thereof or the composition as described above to an individual in need thereof.

[0054] Beneficial Effects

[0055] The present invention prepares cephalothin derivatives, and the anti-SARS-CoV-2 activity of the cephalothin derivatives is tested by using the novel coronavirus drug screening alternative model GX_P2V. The results show that the cephalothin derivatives of the present invention can effectively inhibit the infection of the pangolin coronavirus strain GX_P2V. Therefore, the cephalothin derivatives of the present invention can be used for the prevention, relief and / or treatment of COVID-19 infection.

[0056] Terms and Definitions

[0057] Unless otherwise defined, all technical and scientific terms herein have the same meaning as commonly understood by one of ordinary skill in the art to which the claimed subject matter belongs.

[0058] In some groups, "-", "*" or The ligation site is indicated.

[0059] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0060] The term "C 1-8The term "alkyl" refers to straight-chain and branched alkyl groups having 1, 2, 3, 4, 5, 6, 7 or 8 carbon atoms. The alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 2-ethylpentyl, In some embodiments, the alkyl group is a butyl group, ...

[0061] The above-mentioned term "alkyl" such as "C 1-8 The definition of "alkyl" also applies to compounds containing "C 1-8 Other terms for "alkyl", such as "C3-C6 cycloalkyl C 1-8 Alkyl" etc.

[0062] The term "C 1-8 "Alkoxy" means "-OC 1-8 Alkyl", where "C 1-8 "Alkyl" has the same meaning as above.

[0063] The term "halogenated C 1-8 "Alkyl" should be understood as the above C 1-8 1, 2, 3, 4, 5 or 6 hydrogen atoms on the alkyl group are replaced by halogen atoms (fluorine, chlorine, bromine or iodine), for example CF3CH2-.

[0064] The term "C 2-8 The term "alkenyl" is understood to mean a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2, 3, 4, 5, 6, 7 or 8 carbon atoms, for example, having 2, 3, 4, 5 or 6 carbon atoms (i.e., C 2-6 alkenyl), having 2 or 3 carbon atoms (i.e., C 2-3It is understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from one another or conjugated. The alkenyl group is, for example, vinyl, allyl, (E)-2-methylvinyl, (Z)-2-methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z)-pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)- Pent-1-enyl, (Z)-pent-1-enyl, hex-5-enyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3-enyl, (E)-hex-2-enyl, (Z)-hex-2-enyl, (E)-hex-1-enyl, (Z)-hex-1-enyl, isopropenyl, 2-methylprop-2-enyl, 1-methylprop-2-enyl , 2-methylprop-1-enyl, (E)-1-methylprop-1-enyl, (Z)-1-methylprop-1-enyl, 3-methylbut-3-enyl, 2-methylbut-3-enyl, 1-methylbut-3-enyl, 3-methylbut-2-enyl, (E)-2-methylbut-2-enyl, (Z)-2-methylbut-2-enyl, (E)-1-methylbut-2-enyl, (Z)-1-methyl but-2-enyl, (E)-3-methylbut-1-enyl, (Z)-3-methylbut-1-enyl, (E)-2-methylbut-1-enyl, (Z)-2-methylbut-1-enyl, (E)-1-methylbut-1-enyl, (Z)-1-methylbut-1-enyl, 1,1-dimethylprop-2-enyl, 1-ethylprop-1-enyl, 1-propylvinyl, 1-isopropylvinyl.

[0065] The term "C 3-6 "Cycloalkyl" refers to a saturated or partially unsaturated monocyclic cyclic hydrocarbon radical which may contain 3 to 6 carbon atoms, for example 3, 4, 5, 6 carbon atoms. The carbocycle may be a saturated cycloalkyl or may optionally contain one, two or more double bonds and / or triple bonds on its ring, thereby forming a so-called cycloalkenyl or cycloalkynyl group. For example, non-limiting examples of monocyclic carbocycles include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl.

[0066] The term "3-6 membered heterocyclyl" means a saturated or unsaturated non-aromatic ring or ring system, and contains at least one heteroatom selected from O, S and N. The heterocyclyl may be connected to the rest of the molecule through any one of the carbon atoms or the nitrogen atom (if present). The heterocyclyl may include fused or bridged rings and spirocyclic rings. In particular, the heterocyclyl may include, but is not limited to, a 4-membered ring such as azetidinyl, oxetanyl, a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, or a 6-membered ring such as tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.

[0067] The term "C 6-14 The term "aryl" is understood to mean a monovalent aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring ("C 6-14 or a ring having 9 carbon atoms ("C9 aryl"), for example indanyl or indenyl, or a ring having 10 carbon atoms ("C 10 aryl), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, or a ring having 13 carbon atoms ("C 13 aryl), such as fluorenyl, or a ring having 14 carbon atoms ("C 14 aryl”), such as anthracenyl. When the C 6-20 When the aryl group is substituted, it may be monosubstituted or polysubstituted. Also, there is no limitation on the substitution position, for example, it may be substituted at the ortho position, para position or meta position.

[0068] "5-14 membered heteroaryl" refers to a 5-14 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-14 membered heteroaryl"). In some embodiments, the heteroaryl is a 5-8 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-8 membered heteroaryl"). In some embodiments, the heteroaryl is a 5-6 membered aromatic ring system having ring carbon atoms and 1-4 ring heteroatoms provided in the aromatic ring system, wherein each heteroatom is independently selected from nitrogen, oxygen and sulfur ("5-6 membered heteroaryl"). In some embodiments, the 5-6 membered heteroaryl has 1-3 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1-2 ring heteroatoms selected from nitrogen, oxygen and sulfur. In some embodiments, the 5-6 membered heteroaryl has 1 ring heteroatom selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, but are not limited to, pyrrolyl, furanyl, and thienyl; imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl; triazolyl, oxadiazolyl, and thiadiazolyl; tetrazolyl; pyridinyl; pyridazinyl, pyrimidinyl, and pyrazinyl; triazinyl and tetrazinyl; azacycloheptatrienyl, oxepinyl, and thiepigenyl; indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothienyl, isobenzothienyl, benzofuranyl, benzisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzothiazolyl, benzisothiazolyl, benzothiadiazolyl, indolizinyl, and purinyl; naphthyridinyl, pteridinyl, quinolyl, isoquinolyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl. BRIEF DESCRIPTION OF THE DRAWINGS

[0069] Figure 1 These are the test results of the inhibitory effects of cephalothin derivatives CP-01, CP-02, CP-04, and CP-05 on GX_P2V virus.

[0070] Figure 2 These are the test results of the inhibitory effects of cephalothin derivatives CP-43, CP-44, CP-45, CP-46, CP-47, CP-50, CP-51 and CP-52 on GX_P2V virus.

[0071] Figure 3 These are the test results of the inhibitory effects of cephalothin derivatives CP-21, CP-22, CP-23, CP-24, CP-25, CP-204, CP-207, CP-208, CP-209, CP-210, CP-211, CP-212, CP-213, CP-215 and CP-221 on the GX_P2V virus.

[0072] Figure 4 These are the test results of the inhibitory effects of cephalothin derivatives CP-201, CP-202, CP-203, CP-216, CP-217 and CP-218 on GX_P2V virus.

[0073] Figure 5 These are the test results of the inhibitory effects of cephalothin derivatives CP-222, CP-223, CP-224, CP-225, CP-229, CP-230, CP-234, CP-237, CP-239 and CP-240 on GX_P2V virus.

[0074] Figure 6 These are the test results of the inhibitory effects of cephalothin derivatives CP-26, CP-27, CP-28, CP-205, CP-206, CP-214 and CP-242 on GX_P2V virus.

[0075] Figure 7 These are the test results of the inhibitory effects of cephalothin derivatives CP-61, CP-62, CP-63 and CP-67 on GX_P2V virus.

[0076] Figure 8 These are the test results of the inhibitory effects of cephalothin derivatives CP-69, CP-70, CP-71 and CP-73 on GX_P2V virus.

[0077] Fig. 9 These are the test results of the inhibitory effects of cephalothin derivatives CP-65 and CP-72 on GX_P2V virus.

[0078] Fig.10 These are the test results of the inhibitory effect of the cephalothin derivative CP-68 on the GX_P2V virus.

[0079] Fig.11 These are the test results of the inhibitory effects of cephalothin derivatives CP-82 and CP-83 on GX_P2V virus.

[0080] Fig.12 These are the test results of the inhibitory effects of cephalothin derivatives CP-80 and CP-81 on GX_P2V virus.

[0081] Fig.13 These are the test results of the inhibitory effect of cephalaenopsis in GX_P2V virus. DETAILED DESCRIPTION

[0082] The technical scheme of the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the following embodiments are only exemplary descriptions and explanations of the present invention and should not be construed as limiting the scope of protection of the present invention. All technologies implemented based on the above content of the present invention are included in the scope that the present invention is intended to protect.

[0083] Unless otherwise specified, the raw materials and reagents used in the following examples are commercially available or can be prepared by known methods.

[0084] 1. Implementation

[0085] Example 1: Synthesis of CP-01

[0086] Under ice-salt bath (0-5°C), 250mL reaction flask was added with 100mL trifluoroacetic acid (10g, 1 equivalent) and 100mL trifluoroacetic acid as solvent, and then N-bromosuccinimide (1.05 equivalent) was added in batches. The reaction was complete by thin layer chromatography. After the reaction was completed, the solvent was removed by vacuum concentration, and the excess trifluoroacetic acid was neutralized with sodium carbonate solution. The product was dissolved and extracted with dichloromethane, washed with water twice, washed with saturated sodium chloride once, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The product was recrystallized from ethyl acetate and petroleum ether with a yield of 88%. After the mother liquor was concentrated, it was purified by column chromatography to obtain the product with a yield of 8%. CP-01: 1 H NMR(400MHz, CDCl3)δ7.36(d,J=7.9Hz,1H),6.99(s,1H),6.96(d,J=5.6Hz,2H) ,6.77(s,2H),6.64(s,1H),6.35(s,2H),5.69(s,1H),5.65(s,1H),5.45(s,1H), 4.19(s,1H),3.88(s,3H),3.69(s,3H),3.61(s,1H),3.31(d,J=13.9Hz,1H),3.2 4–3.04(m,2H),2.99–2.67(m,6H),2.62(s,3H),2.56(s,3H),2.51–2.27(m,3H). 13C NMR (101MHz, CDCl3) δ152.32,148.77,148.47,146.52,145.03,141.46,138.81,1 37.54,133.24,132.66,131.62,130.61,128.06,125.58,125.48,123.80,122.34 ,120.94,118.46,116.65,110.99,110.86,110.74,100.80,95.68,64.09,61.84, 55.91,54.95,51.17,44.87,43.92,42.02,40.18,37.72,28.96,25.70.HRMS(ESI + )m / e[M+H] + :685.18876,687.18748,C 37 H 37 BrN2O6.

[0087] Example 2: Synthesis of CP-02

[0088] Method 1. Add CP-01 (1.0 g, 1 equivalent), 20 ml of 1,4-dioxane, 2% molar ratio of tris(dibenzylideneacetone)dipalladium, 4% molar ratio of SPhos, KOH (3 equivalents, dissolved in 3 ml of water) into a reaction bottle, replace with nitrogen three times, heat in an oil bath under nitrogen protection, stir and react at 80 degrees Celsius for 2 hours, cool, filter, and concentrate under reduced pressure. The crude product is purified by column chromatography to obtain the product with a yield of 85%.

[0089] Method 2, CP-01 (1.0 g, 1 equivalent), 10 ml of N-methylpyrrolidone (NMP), 5% molar ratio of palladium acetate, 10% molar ratio of t-BuBrettPhos, boric acid (2 equivalents), cesium carbonate (2 equivalents) were added to the reaction bottle, and nitrogen was replaced 3 times. The oil bath was heated under nitrogen protection, and the reaction was stirred at 80 degrees Celsius for 20 hours. The temperature was lowered, filtered, 100 mL of water was added, filtered, the filter cake was collected, and the product was obtained by column chromatography with a yield of 72%.

[0090] 1H NMR(400MHz, CD3OD+CDCl3)δ7.38(d,J=8.4Hz,1H),7.01(s,1H),6.94–6.74(m, 3H),6.65(s,1H),6.42(s,2H),5.61(s,1H),5.59(d,J=1.3Hz,1H),5.47(s,1H) ,4.25(s,1H),3.90(s,3H),3.80–3.50(m,4H),3.33–3.02(m,3H),3.00–2.90(m ,2H),2.89–2.66(m,4H),2.58(s,3H),2.56(s,3H),2.54–2.21(m,3H).HRMS(ESI + )m / e[M+H] + :623.27393,C 37 H 38 N2O7.

[0091] Example 3: Synthesis of CP-03

[0092] In a 100 mL reaction bottle, add cephalaenopsis (2 g, 1 equivalent), add paraformaldehyde (3 equivalents), and then add 20 mL of concentrated hydrochloric acid to stir and dissolve, and stir and react at room temperature for 10 hours. After the reaction is completed, the reaction solution is concentrated to obtain the product. 1 H NMR(400MHz, CDCl3) δ7.39(d,J=7.7Hz,1H),7.01(s,1H),6.94(d,J=6.1Hz,1H),6.78(s,2H) ,6.64(s,1H),6.35(s,2H),5.63(s,1H),5.59(d,J=1.3Hz,1H),5.44(s,1H),4.67(s,2H),4.2 2(s,1H),3.89(s,3H),3.69(s,3H),3.63(s,1H),3.34(d,J=13.9Hz,1H),3.24–2.99(m,3H),2 .94(dd,J=12.0,7.0Hz,1H),2.87–2.72(m,4H),2.65(s,3H),2.57(s,3H),2.51–2.30(m,3H). 13C NMR (101MHz, CDCl3) δ152.36,148.85,148.73,146.58,146.01,141.59,138.95 ,137.78,132.37,131.68,130.51,127.99,125.46,123.78,122.31,120.94,11 8.52,116.59,113.03,111.00,110.89,110.75,100.61,64.00,61.91,56.43,5 5.91,55.01,51.03,44.89,43.85,42.05,40.09,37.69,28.69,22.20.HRMS(ESI + )m / e[M+H] + :655.25522,C 38 H 39 ClN2O6.

[0093] Example 4: Synthesis of CP-04

[0094] CP-03 (1.0 g, 1 equivalent) was dissolved in 10 mL of tetrahydrofuran, 5 mL of saturated potassium carbonate solution was added at room temperature, the pH was adjusted to 9-10, stirred at room temperature for 2 hours, filtered and dried under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain the product as a white powder with a yield of 65%. 1 H NMR (400MHz, CDCl3) δ7.37(d,J=8.1Hz,1H),7.02(d,J=6.0Hz,1H),6.94(d,J=6.9Hz,1H), 6.77(s,2H),6.64(s,1H),6.35(s,2H),5.61(s,1H),5.57(s,1H),5.45(s,1H),4.66(s,2H) ,4.20(s,1H),3.88(s,3H),3.68(s,3H),3.61(s,1H),3.32(d,J=14.1Hz,1H),3.20–2.99( m,3H),2.97–2.87(m,2H),2.86–2.70(m,4H),2.63(s,3H),2.56(s,3H),2.50–2.32(m,3H). 13C NMR (101MHz, CDCl3) δ152.29,148.85,148.69,146.52,145.93,141.64,139.15,1 37.76,132.49,132.31,131.69,130.71,127.95,125.60,123.95,123.75,122.26 ,120.95,118.52,116.64,113.05,111.01,110.69,100.56,64.07,61.88,56.37, 55.91,55.01,51.15,44.94,43.89,42.14,40.07,37.69,28.84,22.31.HRMS(ESI + )m / e[M+H] + :637.28921,C 38 H 40 N2O7.

[0095] Example 5: Synthesis of CP-05

[0096] CP-04 (1.0 g, 1 equivalent) was dissolved in 30 mL of dichloromethane, and Dessmartin reagent (1.2 times the amount) was added. The mixture was reacted at room temperature for 2 hours, filtered, and concentrated to obtain the product aldehyde with a yield of 92%. 1 H NMR (400MHz, CDCl3) δ10.29(s,1H),7.37(d,J=7.8Hz,1H),7.01(d,J=8.5Hz,1H),6.97(d,J=8.0Hz,1H),6.77(s ,2H),6.66(s,1H),6.37(s,2H),5.77(s,1H),5.73(d,J=1.2Hz,1H),5.43(s,1H),4.19(d,J=5.6Hz,1H),3.88(s ,3H),3.72(s,3H),3.63(s,1H),3.36(d,J=14.4Hz,1H),3.27(dd,J=10.8,7.6Hz,1H),3.22(d,J=4.2Hz,1H),3. 18–3.05(m,2H),2.94(dd,J=12.3,6.9Hz,1H),2.90–2.73(m,3H),2.66(s,3H),2.57(s,3H),2.50–2.33(m,3H). 13C NMR (101MHz, CDCl3) δ187.48,152.35,152.20,148.82,148.37,146.55,142.54,141 .03,138.94,133.41,133.02,131.64,130.46,128.94,128.21,127.88,124.87,123 .83,122.48,120.99,118.49,116.64,111.80,110.92,110.74,101.98,64.03,61.8 2,55.89,54.99,51.11,44.58,43.93,42.13,39.81,37.64,29.01,24.16.HRMS(ESI + )m / e[M+H] + :635.27319,C 38 H 38 N2O7.

[0097] Example 6: Synthesis of 5-ether derivatives

[0098]

[0099] CP-02 and the corresponding chloroform, bromoform, iodoform, sulfonate or trifluoromethanesulfonate are used as raw materials, DMF is used as solvent, sodium hydride is used as base, and the reaction is carried out at -10 to 60° C. for 5 minutes to 2 hours. After the reaction is completed, the crude product is obtained by extraction, washing with water, drying and concentration, and the product is purified by column chromatography.

[0100] CP-41: Using CP-02 and 2,2,2-trifluoroethyl trifluoromethanesulfonate (CAS: 6626-25-1) as raw materials, the product was synthesized as a light yellow powder with a yield of 82%. 1 H NMR(400MHz, CDCl3)δ7.28(d,J=7.4Hz,1H),7.01–6.80(m,2H),6.70(s,2H),6.5 6(s,1H),6.27(s,2H),5.55(s,1H),5.50(s,1H),5.39(s,1H),4.53–4.26(m,2H) ,4.10(s,1H),3.81(s,3H),3.59(s,3H),3.52(s,1H),3.22(d,J=13.9Hz,1H),3. 11–2.91(m,2H),2.90–2.59(m,6H),2.54(s,3H),2.48(s,3H),2.41–2.19(m,3H). 13C NMR (101MHz, CDCl3) δ150.19,146.56,146.32,144.42,139.65,136.62,133.22,132.19,131 .90,130.92,130.01,129.40,128.46,125.87,122.66(q,J=277.0Hz),121.58,112.04,119.8 9,118.71,116.37,116.19,114.44,108.90,108.70,108.53,98.79,66.57(q,J=35.0Hz),61 .92,59.31,53.70,52.76,48.91,42.22,41.66,39.91,37.62,35.47,26.60,17.73.HRMS(ESI + )m / e[M+H] + :705.27667, C 39 H 39 F3N2O7.

[0101] CP-42: The product was synthesized using CP-02 and iodomethane as raw materials. It is a light yellow powder with a yield of 86%. 1 H NMR(400MHz, CDCl3)δ7.45(d,J=7.8Hz,1H),7.05-6.89(m,2H),6.81(d,J=17 .4Hz,2H),6.63(s,1H),6.35(s,2H),5.62(s,1H),5.58(s,1H),5.44(s,1H), 4.26(s,1H),3.93(s,3H),3.89(s,3H),3.68(s,4H),3.42(d,J=13.9Hz,1H), 3.19(s,2H),3.01–2.75(m,6H),2.66(s,3H),2.59(s,3H),2.53–2.36(m,3H). 13C NMR (101MHz, CDCl3) δ152.49,148.71,146.84,144.68,141.80,138.35,136.17 ,135.50,134.44,133.49,131.58,131.51,130.28,128.31,123.88,122.33,12 0.78,118.38,116.53,111.13,111.07,110.83,100.76,64.04,61.71,59.66,5 5.92,55.03,50.57,44.44,43.58,41.73,40.09,37.88,28.15,19.75.HRMS(ESI + )m / e[M+H] + :637.28966, C 38 H 40 N2O7.

[0102] CP-43: The product was synthesized using CP-02 and isopropyl bromide as raw materials. It is a light yellow powder with a yield of 81%. 1 H NMR(400MHz, CDCl3)δ7.36(d,J=8.2Hz,1H),7.07–6.88(m,2H),6.77(s,2H),6.63(s,1H),6.3 4(s,2H),5.59(s,1H),5.54(d,J=1.2Hz,1H),5.48(s,1H),4.57(dt,J=12.2,6.1Hz,1H),4.19 (d,J=5.2Hz,1H),3.88(s,3H),3.64(s,3H),3.59(s,1H),3.28(d,J=13.9Hz,1H),3.16–2.97( m,2H),2.96–2.67(m,6H),2.61(s,3H),2.55(s,3H),2.48-2.35(m,3H),1.33(d,J=6.1Hz,6H). 13C NMR (101MHz, CDCl3) δ152.25,148.79,148.58,146.61,142.13,139.02,136.47,133. 98,133.35,131.61,130.80,128.15,128.02,123.73,122.21,121.97,120.91,119.6 1,118.29,116.94,116.67,111.18,110.94,110.76,100.49,73.53,64.18,61.57,55 .91,54.98,51.19,44.92,43.89,42.22,39.97,37.73,28.77,22.77,22.61.HRMS(ESI + )m / e[M+H] + :665.32017,C 40 H 44 N2O7.

[0103] CP-44: The product was synthesized from CP-02 and methyl glycol p-toluenesulfonate (CAS: 17178-10-8), a light yellow powder, with a yield of 76%. 1 H NMR(400MHz, CDCl3)δ7.36(d,J=7.5Hz,1H),7.07–6.88(m,2H),6.77(s,2H),6.62(s,1 H),6.34(s,2H),5.59(s,1H),5.54(s,1H),5.47(s,1H),4.25(tt,J=11.3,5.6Hz,2H),4 .17(d,J=4.6Hz,1H),3.88(s,3H),3.73–3.57(m,5H),3.44(s,3H),3.29(d,J=12.9Hz,1 H),3.19–3.01(m,2H),2.95–2.68(m,6H),2.61(s,3H),2.55(s,3H),2.48–2.29(m,3H). 13CNMR (101MHz, CDCl3) δ152.47,148.78,148.55,146.57,142.19,138.88,136.13,134. 30,134.07,133.81,131.62,128.13,127.98,123.74,123.42,122.18,120.87,119.01, 118.32,116.68,111.11,110.90,110.77,100.64,71.81,71.02,64.21,61.61,59.14,5 5.90,54.98,53.45,51.14,44.69,43.89,42.16,40.05,37.86,28.81,22.66.HRMS(ESI + )m / e[M+H] + :681.31532, C 40 H 44 N2O8.

[0104] CP-45: The product was synthesized using CP-02 and 2-fluoroethanol p-toluenesulfonate as raw materials. It is a light yellow powder with a yield of 78%. 1 HNMR(400MHz, CDCl3)δ7.36(d,J=7.1Hz,1H),7.09–6.90(m,2H),6.77(s,2H),6.63(s,1H),6.3 4(s,2H),5.60(s,1H),5.55(s,1H),5.47(s,1H),4.74(t,J=3.8Hz,1H),4.62(t,J=3.8Hz,1H), 4.45-4.25(m,2H),4.18(d,J=4.8Hz,1H),3.88(s,3H),3.66(s,3H),3.59(s,1H),3.29(d,J=13 .7Hz,1H),3.18–3.02(m,2H),3.01–2.69(m,6H),2.62(s,3H),2.56(s,3H),2.48–2.28(m,3H). 13CNMR(101MHz,CDCl3)δ152.27,148.78,148.56,146.56,141.94,138.92,135.99,134.05,1 33.94,133.82,132.11,131.64,128.15,123.75,122.18,120.88,119.05,118.35,116.88, 116.65,111.09,110.92,110.74,100.70,83.43(d,J=169.0Hz),70.95(d,J=20.0Hz),64.2 0,61.52,55.91,54.99,51.18,44.64,43.89,42.19,39.82,37.76,28.81,20.27.HRMS(ESI + )m / e[M+H] + :669.29535,C 39 H 41 FN2O7.

[0105] CP-46: The product was synthesized using CP-02 and allyl bromide as raw materials. It is a white powder with a yield of 74%. 1 H NMR (400MHz, CDCl3) δ7.36(d,J=8.1Hz,1H),6.99(d,J=6.3Hz,1H),6.93(d,J=6.2Hz,1H),6.77(s,2H),6.63(s, 1H),6.34(s,2H),6.10-6.00(m,1H),5.60(s,1H),5.55(d,J=1.4Hz,1H),5.48(s,1H),5.37(dd,J=17.2,1.6Hz, 1H),5.22(dd,J=10.4,1.4Hz,1H),4.76–4.52(m,2H),4.18(d,J=5.4Hz,1H),3.88(s,3H),3.66(s,3H),3.59(s, 1H),3.29(d,J=13.8Hz,1H),3.16–2.99(m,2H),2.93–2.67(m,6H),2.62(s,3H),2.56(s,3H),2.50–2.33(m,3H). 13CNMR (101MHz, CDCl3) δ152.75,148.80,148.58,146.59,142.27,142.07,138.92,136.1 6,134.21,134.11,134.06,133.75,131.69,131.64,130.77,128.45,128.15,123.74,12 2.20,120.87,118.95,118.32,117.40,116.95,111.13,110.80,100.61,72.56,64.12, 61.49,55.91,55.00,51.14,44.71,43.89,42.20,39.90,37.73,28.87,20.53.HRMS(ESI + )m / e[M+H] + :663.30491,C 40 H 42 N2O7.

[0106] CP-47: The product was synthesized from CP-02 and 4-methylbenzenesulfonic acid fluoromethyl ester (CAS: 114435-86-8), a light yellow powder, with a yield of 76%. 1 H NMR(400MHz, CDCl3) δ7.36(d,J=8.1Hz,1H),7.00(s,1H),6.93(d,J=6.8Hz,1H),6.77 (s,2H),6.63(s,1H),6.34(s,2H),5.61(s,1H),5.56(s,1H),5.47(s,1H),4.18(d,J=2 .8Hz,1H),3.92(s,2H),3.88(s,3H),3.67(s,3H),3.60(s,1H),3.29(d,J=13.9Hz,1H ),3.18–3.00(m,2H),2.99–2.68(m,6H),2.63(s,3H),2.56(s,3H),2.50–2.27(m,3H). 13C NMR (101MHz, CDCl3) δ148.78,148.59,146.51,145.24,142.05,138.36,136.00, 135.47,134.17,134.07,133.61,131.66,128.10,123.74,122.33,122.07,120.8 9,118.57,118.35,116.62,111.13,111.08,10.81,100.61,64.20,61.54,59.66, 55.91,55.03,51.15,44.70,43.90,42.20,39.84,37.83,28.81,20.29.HRMS(ESI + )m / e[M+H] + :655.28035,C 38 H 39 FN2O7.

[0107] CP-50: The product was synthesized using CP-02 and ethyl bromide as raw materials. It is a light yellow powder with a yield of 73%. 1 H NMR (400MHz, CDCl3) δ7.36(d,J=7.8Hz,1H),7.00(s,1H),6.93(d,J=6.6Hz,1H),6.77( s,2H),6.63(s,1H),6.34(s,2H),5.60(s,1H),5.54(s,1H),5.47(s,1H),4.22-4.11(m, 3H),3.88(s,3H),3.66(s,3H),3.59(s,1H),3.29(d,J=13.8Hz,1H),3.20–3.03(m,2H), 2.97–2.69(m,6H),2.62(s,3H),2.56(s,3H),2.51–2.31(m,3H),1.35(t,J=7.1Hz,3H). 13C NMR (101MHz, CDCl3) δ152.46,148.80,148.58,146.64,143.48,142.09,138.66,136. 25,134.42,134.05,133.63,131.64,130.73,128.17,123.73,123.48,122.18,120.9 2,119.02,118.33,116.74,111.10,110.85,110.74,100.56,67.61,64.16,61.43,55 .91,55.00,51.15,44.78,43.90,42.21,39.89,37.73,28.78,20.49,15.71.HRMS(ESI + )m / e[M+H] + :651.30421,C 39 H 42 N2O7.

[0108] CP-51: The product was synthesized using CP-02 and cyanomethyl p-toluenesulfonate (CAS: 14562-04-0) as raw materials. It is a light yellow powder with a yield of 76%. 1 H NMR(400MHz, CDCl3)δ7.36(d,J=8.1Hz,1H),7.12–6.87(m,2H),6.78(s,2H),6.63(s,1H),6.34( s,2H),5.62(s,1H),5.57(d,J=1.0Hz,1H),5.46(s,1H),4.78(d,J=2.3Hz,2H),4.18(d,J=4.5Hz, 1H),3.89(s,3H),3.66(s,3H),3.59(s,1H),3.29(d,J=13.5Hz,1H),3.21–3.03(m,2H),2.99-2.8 8(m,2H),2.88–2.70(m,4H),2.61(s,3H),2.56(s,3H),2.47(t,J=2.3Hz,1H),2.45-2.35(m,2H). 13C NMR (101MHz, CDCl3) δ152.29,148.78,148.55,147.02,142.07,138.94,136.41,13 4.34,133.19,131.61,129.47,128.25,128.12,123.75,122.14,120.92,119.56,11 8.45,118.37,116.75,116.26,111.23,111.07,110.87,100.86,64.15,61.65,59.1 4,55.92,55.01,51.24,44.63,43.88,42.15,40.12,37.70,28.77,20.34.HRMS(ESI + )m / e[M+H] + :662.28403,C 39 H 39 N3O7.

[0109] CP-52: The product was synthesized using CP-02 and chloromethyl oxirane as raw materials. It is a light yellow powder with a yield of 76%. 1 HNMR(400MHz, CDCl3) δ7.36(d,J=7.3Hz,1H),6.99(s,1H),6.93(d,J=6.9Hz,1H),6.77(s,2H),6.6 3(s,1H),6.34(s,2H),5.61(s,1H),5.55(d,J=1.0Hz,1H),5.47(s,1H),4.34(dd,J=11.4,3.2Hz,1H ),4.18(d,J=5.7Hz,1H),4.07(dd,J=11.4,6.0Hz,1H),3.89(s,3H),3.66(s,3H),3.59(s,1H),3.3 7–3.23(m,2H),3.18–3.02(m,2H),2.97–2.68(m,8H),2.62(s,3H),2.56(s,3H),2.50–2.33(m,3H). 13C NMR (101MHz, CDCl3) δ152.21,148.78,148.55,146.61,141.94,139.32,135.97,13 4.08,133.92,132.22,131.64,130.78,129.03,128.00,123.74,122.19,120.90,1 18.91,118.35,111.12,110.73,110.23,100.70,72.62,64.17,61.52,55.91,54.9 8,51.12,50.56,44.64,44.59,43.90,42.21,39.78,37.63,28.85,20.41.HRMS(ESI + )m / e[M+H] + :679.29954, C 40 H 42 N2O8.

[0110] Example 7: Synthesis of 5-ester derivatives

[0111]

[0112] Method 1: CP-02 and the corresponding acyl chloride or carboxylic acid are used as raw materials, triethylamine is used as an acid-binding agent, and the reaction is carried out in dichloromethane at a temperature of -10 to 10°C for a reaction time of 1 minute to 2 hours. After the reaction is completed, the crude product is washed with water and dried, and concentrated to obtain a crude product, which is then purified by recrystallization or column chromatography to obtain the product carboxylate, carbonate and sulfonate.

[0113] CP-21: The product was synthesized using CP-02 and acetyl chloride as raw materials. The product was a light yellow powder. The product was purified by recrystallization with a yield of 83%. 1 H NMR(400MHz, CDCl3) δ7.37(d,J=9.8Hz,1H),7.01(s,1H),6.95(d,J=6.5Hz,1H),6.79 (s,2H),6.64(s,1H),6.36(s,2H),5.65(s,1H),5.62(d,J=1.2Hz,1H),5.47(s,1H),4. 19(s,1H),3.89(s,3H),3.69(s,3H),3.61(s,1H),3.31(d,J=13.9Hz,1H),3.23–3.07 (m,2H),3.01–2.69(m,6H),2.62(s,3H),2.57(s,3H),2.52–2.40(m,3H),2.33(s,3H). 13C NMR (101MHz, CDCl3) δ167.26,147.58,137.92,137.11,135.20,132.96,130.63,12 9.74,128.87,127.11,127.02,124.90,123.35,122.75,122.46,121.20,119.87,11 8.49,118.01,117.45,115.70,113.02,110.14,109.76,100.42,63.14,60.60,54.8 8,54.02,50.08,43.15,42.85,40.97,39.60,36.69,28.30,21.67,19.36.HRMS(ESI + )m / e[M+H] + :665.28444, C 39 H 40 N2O8.

[0114] CP-22: The product was synthesized using CP-02 and n-octanoyl chloride as raw materials. The product was a light yellow powder and was purified by column chromatography with a yield of 89%. 1 H NMR (400MHz, CDCl3) δ7.37(d,J=7.9Hz,1H),7.01(d,J=5.2Hz,1H),6.95(d,J=5.2Hz,1H),6.77(s,2H),6.63 (s,1H),6.34(s,2H),5.62(s,1H),5.60(s,1H),5.47(s,1H),4.18(s,1H),3.88(s,3H),3.68(s,3H),3.60(s, 1H),3.29(d,J=13.5Hz,1H),3.09(d,J=17.8Hz,2H),2.96–2.69(m,5H),2.60(s,3H),2.58(s,1H),2.56(s,3 H),2.44(dd,J=19.7,15.1Hz,3H),1.88–1.63(m,2H),1.36(dt,J=46.1,14.1Hz,10H),0.89(t,J=6.4Hz,3H). 13CNMR (101MHz, CDCl3) δ171.16,152.33,148.78,148.58,146.62,141.76,138.90,138.14,136. 15,133.99,132.39,131.66,130.70,128.09,128.00,125.96,123.77,123.41,122.23,120.89 ,119.51,118.45,116.77,111.16,110.74,101.41,64.19,61.67,55.91,55.07,51.16,44.20, 43.91,42.03,40.64,37.68,33.86,31.67,29.07,28.92,25.08,22.60,19.62,14.09.HRMS(ESI + )m / e[M+H] + :749.37600,C 45 H 52 N2O8.

[0115] CP-23: The product was synthesized using CP-02 and acryloyl chloride as raw materials. The product was a white powder and purified by recrystallization with a yield of 78%. 1 H NMR (400MHz, CDCl3) δ7.51–7.31 (dd, J=8.2, 1.2Hz, 1H), 7.05-6.92 (m, 2H), 6.77 (s, 2H), 6. 70–6.55(m,2H),6.49–6.20(m,3H),6.03(dd,J=10.4,1.2Hz,1H),5.63(s,1H),5.61(d,J=1. 3Hz,1H),5.47(s,1H),4.19(s,1H),3.88(s,3H),3.69(s,3H),3.60(s,1H),3.30(d,J=13.8 Hz,1H),3.22–2.99(m,2H),2.97–2.67(m,5H),2.61(s,3H),2.56(s,3H),2.53–2.28(m,4H). 13C NMR (101MHz, CDCl3) δ163.36,152.35,148.77,148.58,146.55,141.72,138.83,138. 17,134.05,133.03,132.37,131.67,130.64,128.04,127.15,125.68,123.79,123.48 ,122.23,120.90,119.59,118.46,116.72,111.15,110.79,110.74,101.50,64.12,6 1.72,55.91,55.09,51.15,44.18,43.9,42.03,40.67,37.80,28.88,19.57.HRMS(ESI + )m / e[M+H] + :677.28414, C 40 H 40 N2O8.

[0116] CP-24: The product was synthesized using CP-02 and cyclopropylcarbonyl chloride as raw materials. The product was a light yellow powder and was purified by column chromatography with a yield of 68%. 1 H NMR(400MHz, CDCl3)δ7.37(d,J=9.2Hz,1H),7.03–6.92(m,2H),6.78(s,2H),6.63(s,1H),6 .34(s,2H),5.63(s,1H),5.61(s,1H),5.46(s,1H),4.18(s,1H),3.88(s,3H),3.67(s,3H), 3.61(s,1H),3.30(d,J=13.5Hz,1H),3.13(s,2H),2.94–2.77(m,6H),2.60(s,3H),2.56(s, 3H),2.52-2.45(m,3H),1.93-1.84(m,1H),1.21–1.17(m,2H),1.07-1.01(m,2H).HRMS(ESI + )m / e[M+H] + :691.29915,C 41 H 42 N2O8.

[0117] CP-25: The product was synthesized using CP-02 and 2-thiophenecarbonyl chloride as raw materials. The product was a light yellow powder and was purified by column chromatography with a yield of 88%. 1H NMR (400MHz, CDCl3) δ8.00(d,J=2.9Hz,1H),7.67(d,J=4.9Hz,1H),7.38(d,J=8.1Hz,1H),7.21–7.15 (m,1H),7.06–7.00(m,1H),6.98-6.94(m,1H),6.78(s,2H),6.65(s,1H),6.36(s,2H),5.64(s,1H),5 .62(s,1H),5.47(s,1H),4.21(d,J=4.0Hz,1H),3.88(s,3H),3.70(s,3H),3.61(s,1H),3.31(d,J=13 .8Hz,1H),3.20-3.05(m,2H),3.01–2.72(m,6H),2.61(s,3H),2.60–2.51(m,4H),2.46–2.36(m,2H). 13 C NMR (101MHz, CDCl3) δ159.45,152.38,148.78,148.58,146.57,141.73,138.85,138.40,1 36.42,134.95,134.12,133.76,132.42,132.01,131.67,130.65,128.16,128.00,125.66 ,123.81,123.41,122.28,120.88,119.81,118.47,116.70,111.18,110.77,101.58,64.1 3,61.68,55.92,55.10,51.21,44.14,43.90,42.02,40.79,37.70,28.86,19.57.HRMS(ESI + )m / e[M+H] + :733.25534, C 42 H 40 N2O8S.

[0118] CP-204: The product was synthesized using CP-02 and benzothiophene-2-carbonyl chloride as raw materials. The product was a light yellow powder and was purified by column chromatography with a yield of 84%. 1H NMR(400MHz, CDCl3) δ8.20(d,J=0.8Hz,1H),7.91–7.79(m,2H),7.43(td,J=7.6,1.4Hz,1H),7.37(td,J=7 .6,1.3Hz,1H),7.31(d,J=8.6Hz,1H),6.96(s,1H),6.88(s,1H),6.71(s,2H),6.59(s,1H),6.29(s,2H),5. 59(s,1H),5.57(d,J=1.4Hz,1H),5.40(s,1H),4.24–4.06(m,1H),3.81(s,3H),3.64(s,3H),3.55(s,1H),3 .25(d,J=14.0Hz,1H),3.15–2.98(m,2H),2.94–2.59(m,6H),2.55(s,3H),2.49(s,3H),2.46–2.26(m,3H). 13 CNMR(101MHz, CDCl3)δ160.10,152.90,148.83,148.55,146.65,142.76,138.67,138.39,13 6.54,135.78,134.19,132.18,131.80,131.67,130.61,128.64,127.47,125.83,125.69,12 5.17,123.81,122.84,122.29,120.91,119.71,118.49,116.60,111.13,110.76,64.04,61. 63,101.64,55.92,55.11,51.04,44.12,43.82,42.00,40.68,37.72,29.38,22.71.HRMS(ESI + )m / e[M+H] + :783.27199,C 46 H 42 N2O8S.

[0119] CP-207: The product was synthesized using CP-02 and 4-dimethylaminobenzoyl chloride hydrochloride as raw materials. The product was a light yellow powder and was purified by column chromatography with a yield of 82%. 1H NMR (400MHz, CDCl3) δ8.08(d,J=9.0Hz,2H),7.39(dd,J=8.4,2.2Hz,1H),7.02(s,1H),6.94(d,J=8.1Hz, 1H),6.78(s,2H),6.70(d,J=9.1Hz,2H),6.65(s,1H),6.36(s,2H),5.64(s,1H),5.62(d,J=1.6Hz,1H),5. 48(s,1H),4.21(d,J=6.1Hz,1H),3.89(s,3H),3.70(s,3H),3.61(s,1H),3.44(q,J=7.2Hz,1H),3.31(d,J =14.0Hz,1H),3.16(s,1H),3.08(s,6H),2.94-2.75(m,5H),2.61(s,3H),2.56(s,3H),2.52–2.34(m,3H). 13 C NMR (101MHz, CDCl3) δ164.34,153.83,148.78,148.65,146.63,141.84,138.89,138.55,13 6.05,134.08,132.15,131.69,130.69,128.28,128.11,128.03,126.38,123.77,122.18,12 0.88,119.97,118.45,116.71,115.21,111.34,111.19,110.84,101.43,64.13,61.71,55. 92,55.13,51.14,44.22,43.89,42.00,40.90,40.29,40.09,37.73,28.81,19.54.HRMS(ESI + )m / e[M+H] + :770.34209,C 46 H 47 N3O8.

[0120] CP-208: The product was synthesized using CP-02 and nicotinoyl chloride hydrochloride as raw materials. The product was a light yellow powder and was purified by column chromatography with a yield of 81%. 1H NMR (400MHz, CDCl3) δ9.43(d,J=2.0Hz,1H),8.86(dd,J=4.9,1.8Hz,1H),8.47(dt,J=8.0,2.0Hz,1H),7.48(d d,J=7.8,4.9Hz,1H),7.38(d,J=8.2Hz,1H),7.03(s,1H),6.95(s,1H),6.78(s,2H),6.66(s,1H),6.37(s,2H), 5.66(s,1H),5.64(d,J=1.5Hz,1H),5.47(s,1H),4.20(d,J=17.7Hz,1H),3.89(s,3H),3.72(s,3H),3.62(s,1H ),3.33(d,J=14.0Hz,1H),3.25-3.05(m,2H),3.02-2.65(m,6H),2.63(s,3H),2.57(s,3H),2.50-2.32(m,3H). 13 C NMR (101MHz, CDCl3) δ162.68,154.14,153.44,152.39,151.45,148.77,148.60,146.56,141.72,138.23,138.74,137.70,137.07,136.53,134.18 131.67,130.63,128.07,125.55,125.03,123.81,123.57,122.25,120.93,119.55,118.48,116.69,111.13,110. 69,101.62,64.11,61.65,55.91,55.09,51.15,45.17,44.12,43.89,42.06,40.53,37.74,28.86,19.76.HRMS(ESI + )m / e[M+H] + :728.29586, C 43 H 41 N3O8.

[0121] CP-209: The product was synthesized using CP-02 and isonicotinoyl chloride as raw materials. The product was a light yellow powder and was purified by column chromatography with a yield of 80%. 1H NMR (400MHz, CDCl3) δ8.97–8.79(m,1H),8.13–7.91(m,1H),7.38(dd,J=8.3,2.4Hz,1H),7.04(s,1 H),6.95(s,1H),6.78(s,2H),6.66(s,1H),6.37(s,2H),5.66(s,1H),5.64(d,J=1.4Hz,1H),5.47( s,1H),4.20(d,J=18.9Hz,1H),3.89(s,3H),3.72(s,3H),3.61(s,1H),3.32(d,J=14.0Hz,1H),3.2 2-3.06(m,2H),2.92-2.71(m,1H),2.92–2.68(m,5H),2.63(s,3H),2.57(s,3H),2.51–2.30(m,3H). 13 C NMR (101MHz, CDCl3) δ162.57,152.34,150.91,150.63,148.78,148.66,148.54,147.04,1 46.59,141.66,136.59,136.19,134.20,131.67,130.63,128.06,125.53,123.81,123.77 ,123.27,122.27,120.94,119.44,118.49,116.68,111.13,110.69,101.65,64.13,61.66 ,55.91,55.09,51.18,45.19,44.11,43.91,42.08,40.41,37.70,28.89,19.80.HRMS(ESI + )m / e[M+H] + :728.29564, C 43 H 41 N3O8.

[0122] CP-210: The product was synthesized using CP-02 and tetrahydropyran-4-carbonyl chloride as raw materials. The product was a light yellow powder and was purified by column chromatography with a yield of 71%. 1H NMR(400MHz, CDCl3) δ7.36(dd,J=8.5,2.3Hz,1H),7.01(d,J=7.5Hz,1H),6.94(d,J=7.7Hz,1H),6.77(s,2H) ,6.63(s,1H),6.35(s,2H),5.63(s,1H),5.61(d,J=1.4Hz,1H),5.46(s,1H),4.18(d,J=6.5Hz,1H),4.03(dt, J=11.6,3.7Hz,2H),3.88(s,3H),3.68(s,3H),3.60(s,1H),3.52(td,J=11.0,3.0Hz,2H),3.29(d,J=14.0Hz ,1H),3.20-3.02(m,2H),2.97–2.73(m,6H),2.61(s,3H),2.56(s,3H),2.51–2.31(m,4H),2.05–1.93(m,4H). 13 C NMR (101MHz, CDCl3) δ171.85,152.32,148.77,148.56,141.71,138.07,136 .22,134.05,131.66,128.07,125.75,123.79,122.25,120.91,119.36,118. 44,116.68,111.14,101.48,66.97,64.13,61.62,55.91,55.07,51.18,44.1 5,43.91,42.05,40.51,39.89,37.71,28.88,28.74,28.71,19.65.HRMS(ESI + )m / e[M+H] + :735.32658,C 43 H 46 N2O9.

[0123] CP-211: The product was synthesized using CP-02 and 2-bromoisobutyryl chloride as raw materials. The product was a light yellow powder and was purified by column chromatography with a yield of 86%. 1H NMR(400MHz, CDCl3)δ7.38(d,J=8.1Hz,1H),7.05–6.88(m,2H),6.79(s,2H),6.64(s, 1H),6.35(s,2H),5.66(s,1H),5.64(d,J=1.4Hz,1H),5.45(s,1H),4.21(s,1H),3.89 (s,3H),3.68(s,3H),3.66–3.60(s,1H),3.33(d,J=13.9Hz,1H),3.25-3.08(m,2H),3 .04–2.71(m,6H),2.62(s,3H),2.58(s,3H),2.55-2.35(m,3H),2.10(s,6H).HRMS(ESI + )m / e[M+H] + :771.22720,773.22596,C 41 H 43 BrN2O8.

[0124] CP-212: The product was synthesized using CP-02 and cyclobutylcarbonyl chloride as raw materials. The product was a light yellow powder and was purified by column chromatography with a yield of 73%. 1 H NMR (400MHz, CDCl3) δ7.37 (d, J = 8.4Hz, 1H), 7.01 (s, 1H), 6.94 (s, 1H), 6.77 (s, 2H), 6.63 (s, 1H),6.35(s,2H),5.63(s,1H),5.61(d,J=1.5Hz,1H),5.47(s,1H),4.18(d,J=5.9Hz,1H),3.8 8(s,3H),3.68(s,3H),3.60(s,1H),3.43(p,J=7.8Hz,1H),3.29(d,J=15.1Hz,1H),3.20–3.0 4(m,2H),2.97–2.65(m,5H),2.60(s,3H),2.56(s,3H),2.50–2.31(m,6H),2.20–1.91(m,4H). 13CNMR(101MHz,CDCl3)δ172.83,152.35,148.78,148.58,146.56,141.80,138.81,138.1 6,136.13,134.02,132.36,131.65,130.65,128.06,125.92,123.78,123.25,122.31,1 20.90,119.52,118.44,116.76,111.16,110.72,101.44,61.62,55.91,55.07,51.16,4 4.16,43.89,42.00,40.73,37.76,28.82,25.43,22.71,19.41,18.56,14.14.HRMS(ESI + )m / e[M+H] + :705.31627, C 42 H 44 N2O8.

[0125] CP-213: The product was synthesized using CP-02 and 2-thiophenesulfonyl chloride as raw materials. The product was a light yellow powder and was purified by column chromatography with a yield of 82%. 1 H NMR (400MHz, CDCl3) δ7.78 (dd, J=3.9, 1.4Hz, 1H), 7.73 (dd, J=5.0, 1.4Hz, 1H), 7.36 (d, J=8.3 Hz,1H),7.14(t,J=5.0,4.0Hz,1H),7.07–6.89(m,2H),6.78(s,2H),6.63(s,1H),6.35(s,2H) ,5.47(s,1H),5.44(s,1H),4.18(s,1H),3.88(s,3H),3.68(s,3H),3.61(s,1H),3.29(d,J=14 .2Hz,1H),3.18-3.02(m,2H),2.98-2.65(m,6H),2.59(s,3H),2.56(s,3H),2.48-2.29(m,3H). 13C NMR (101MHz, CDCl3) δ152.28,148.78,148.44,146.56,141.47,139.30,138.72,137.1 5,135.94,135.30,134.51,134.11,132.54,131.55,130.47,128.02,127.53,125.00, 124.21,123.84,122.33,121.73,120.95,118.42,116.64,111.07,110.78,101.64,64 .04,61.67,55.92,55.01,51.07,44.34,43.86,42.04,40.46,37.66,20.01.HRMS(ESI + )m / e[M+H] + :769.22402, C 41 H 40 N2O9S2.

[0126] CP-215: The product was synthesized using CP-02 and benzoyl chloride as raw materials. It was a white powder. The product was purified by recrystallization with a yield of 83%. 1 H NMR (400MHz, CDCl3) δ8.23(dd,J=8.2,1.4Hz,2H),7.65(t,J=7.4Hz,1H),7.52(t,J=7.7Hz,2H),7.39(d,J =6.9Hz,1H),7.07(d,J=19.2Hz,1H),6.96(s,1H),6.78(s,2H),6.66(s,1H),6.36(s,2H),5.65(s,1H),5.6 3(d,J=1.5Hz,1H),5.48(s,1H),4.22(d,J=6.4Hz,1H),3.89(s,3H),3.71(s,3H),3.64–3.56(m,1H),3.32( d,J=14.0Hz,1H),3.24–3.04(m,2H),2.95-2.75(m,5H),2.62(s,3H),2.60–2.52(m,4H),250–2.30(m,3H). 13C NMR (101MHz, CDCl3) δ163.97,152.41,148.84,148.62,146.56,141.74,138.84,138.34,1 36.32,134.15,133.76,132.34,131.69,130.31,128.92,128.67,126.28,128.06,125.99 ,123.79,123.45,122.28,120.94,119.71,118.48,116.68,111.17,110.77,101.54,64.1 1,61.71,55.92,55.12,51.14,44.17,43.90,42.04,40.70,37.83,28.84,19.67.HRMS(ESI + )m / e[M+H] + :727.30013,C 44 H 42 N2O8.

[0127] CP-221: The product was synthesized using CP-02 and n-pentyl chloroformate as raw materials. The product was a light yellow powder and was purified by column chromatography with a yield of 68%. 1 H NMR (400MHz, CDCl3) δ7.29(d,J=7.2Hz,1H),6.93(s,1H),6.87(s,1H),6.70(s,2H),6.56(s,1H),6.27(s ,2H),5.58(s,1H),5.56(d,J=1.4Hz,1H),5.39(s,1H),4.19(t,J=6.8Hz,2H),4.10(d,J=8.0Hz,1H),3.81 (s,3H),3.61(s,3H),3.53(s,1H),3.23(d,J=14.0Hz,1H),3.14–2.94(m,2H),2.88–2.67(m,5H),2.54(s ,3H),2.52–2.44(m,4H),2.42–2.26(m,3H),1.72–1.62(m,2H),1.36–1.27(m,4H),0.86(t,J=7.0Hz,3H). 13C NMR (101MHz, CDCl3) δ151.92,151.39,147.77,147.53,145.61,143.53,140.64,137.09, 135.30,133.09,131.29,130.63,129.59,127.05,125.50,122.75,121.21,119.86,118. 57,117.43,115.68,110.12,109.73,100.56,68.32,63.11,60.57,54.88,54.03,50.15, 43.10,42.85,41.00,39.47,36.71,27.87,27.26,26.73,21.26,18.41,12.93.HRMS(ESI + )m / e[M+H] + :737.34182, C 43 H 48 N2O9.

[0128] Method 2: Using CP-02 and the corresponding organic acid as raw materials, 4-dimethylaminopyridine as a catalyst, diisopropylcarbodiimide (DIC) as a condensation agent, and dichloromethane as a solvent, the condensation reaction is carried out at room temperature for 5 minutes to 10 hours. After the reaction is completed, the crude product is obtained by filtration and concentration, and the product is purified by column chromatography or recrystallization.

[0129] CP-201: The product was synthesized using CP-02 and furan-2-carboxylic acid as raw materials. The product was a light yellow powder and was purified by column chromatography with a yield of 88%. 1 H NMR (400MHz, CDCl3) δ7.75–7.63(m,1H),7.50–7.40(dd,J=4.0,0.8Hz,1H),7.38(dd,J=8.4,2.4Hz,1H),7. 06–6.98(m,1H),6.95(s,1H),6.78(s,2H),6.65(s,1H),6.60(dd,J=3.5,1.7Hz,1H),6.41-6.32(m,2H),5.6 5(s,1H),5.62(d,J=1.4Hz,1H),5.47(s,1H),4.21(d,J=6.7Hz,1H),3.89(s,3H),3.70(s,3H),3.61(s,1H), 3.31(d,J=14.0Hz,1H),3.21-3.05(m,2H),3.01-2.72(m,6H),2.61(s,3H),2.56(s,3H),2.48-2.35(m,3H). 13CNMR(101MHz,CDCl3)δ177.73,155.77,152.29,148.78,148.58,147.34,146.31,143.49,14 1.69,138.34,136.48,134.12,131.67,130.69,128.06,125.22,123.79,122.25,120.93,11 9.83,119.73,118.47,116.69,115.76,112.25,111.86,111.16,110.78,101.59,64.13,61. 71,55.92,55.09,51.14,46.12,44.14,43.90,42.02,40.80,37.70,28.89,19.54.HRMS(ESI + )m / e[M+H] + :717.27905,C 42 H 40 N2O9.

[0130] CP-202: The product was synthesized using CP-02 and 5-chlorothiophene-2-carboxylic acid as raw materials. The product was a light yellow powder and was purified by column chromatography with a yield of 82%. 1 H NMR(400MHz, CDCl3) δ7.71(d,J=4.0Hz,1H),7.30(dd,J=8.5,2.2Hz,1H),6.94(d,J=4.0Hz,2H),6 .89–6.80(m,1H),6.70(s,2H),6.57(s,1H),6.35-6.22(m,2H),5.60–5.55(m,1H),5.54(d,J=1.5H z,1H),5.39(s,1H),4.13(d,J=6.7Hz,1H),3.80(s,3H),3.62(s,3H),3.57–3.46(m,1H),3.23(d,J =13.6Hz,1H),3.15–2.97(m,2H),2.96–2.58(m,6H),2.54(s,3H),2.48(s,3H),2.44-2.25(m,3H). 13C NMR (101MHz, CDCl3) δ158.43,152.32,148.78,148.56,147.04,146.54,141.70,138.83,13 8.33,136.50,134.58,134.13,132.45,131.66,130.57,130.09,128.07,127.71,125.44,12 3.81,123.53,122.26,120.92,119.71,118.47,116.71,111.14,110.77,101.61,67.09,64. 11,61.69,55.91,55.08,51.16,44.11,43.90,42.03,40.65,37.72,28.86,19.64.HRMS(ESI + )m / e[M+H] + :767.21686, C 42 H 39 ClN2O8S.

[0131] CP-203: The product was synthesized using CP-02 and thiophene-3-carboxylic acid as raw materials. The product was a light yellow powder and was purified by column chromatography with a yield of 86%. 1 H NMR (400MHz, CDCl3) δ8.26(d,J=3.0Hz,1H),7.60(d,J=5.1Hz,1H),7.36–7.27(m,2H),6.97(d,J =8.2Hz,1H),6.87(d,J=8.0Hz,1H),6.71(s,2H),6.58(s,1H),6.29(s,2H),5.58(s,1H),5.55(d, J=1.4Hz,1H),5.39(s,1H),4.15(s,1H),3.81(s,3H),3.63(s,3H),3.58–3.48(m,1H),3.25(d,J= 13.9Hz,1H),3.18-2.98(m,2H),2.85-2.65(m,6H),2.55(s,3H),2.49(s,3H),2.44-2.26(m,3H). 13C NMR (101MHz, CDCl3) δ159.86,152.35,148.78,148.68,148.61,147.11,146.61,141.81,13 8.76,138.38,136.33,134.31,134.13,132.09,131.67,130.61,128.28,128.05,126.53,12 5.77,123.81,122.26,120.90,119.72,118.49,116.64,111.16,110.75,101.55,64.10,61. 70,55.92,55.10,53.45,51.06,44.14,43.84,42.00,40.73,37.78,28.66,19.60.HRMS(ESI + )m / e[M+H] + :733.25666, C 42 H 40 N2O8S.

[0132] CP-216: The product was synthesized using CP-02 and 3-trifluoromethoxybenzoic acid as raw materials. The product was white powder and purified by column chromatography with a yield of 89%. 1 H NMR (400MHz, CDCl3) δ8.08(d,J=7.7Hz,1H),7.99(s,1H),7.48(t,J=7.9Hz,1H),7.45–7.36(m,1H),7.30(dd, J=8.5,2.2Hz,1H),6.96(s,1H),6.88(s,1H),6.70(s,2H),6.58(s,1H),6.28(s,2H),5.56(s,1H),5.54(d,J= 1.4Hz,1H),5.40(s,1H),4.14(d,J=6.0Hz,1H),3.80(s,3H),3.63(s,3H),3.53(s,1H),3.24(d,J=14.0Hz,1H ),3.15–2.95(m,2H),2.89–2.63(m,5H),2.54(s,3H),2.48(s,3H),2.44(d,J=6.4Hz,1H),2.42–2.22(m,3H). 13C NMR (101MHz, CDCl3) δ162.61,152.34,149.38,148.78,148.57,146.58,141.70,138.82,138.22,13 6.49,134.18,132.52,131.67,130.97,130.68,130.29,128.59,128.09,126.18,125.73,123.81,12 3.70,122.66,122.29,121.71(q,J=257.0Hz),120.94,119.58,118.48,116.71,111.15,110.77,101 .60,64.14,61.68,55.91,55.09,51.21,44.13,43.91,42.05,40.64,37.71,28.91,19.68.HRMS(ESI + )m / e[M+H] + :811.28316,C 45 H 41 F3N2O9.

[0133] CP-217: The product was synthesized using CP-02 and 3,5-bis(trifluoromethoxybenzoic acid) as raw materials. The product was white powder and purified by column chromatography with a yield of 82%. 1 H NMR (400MHz, CDCl3) δ8.67(s,2H),8.16(s,1H),7.39(d,J=7.1Hz,1H),7.04(d,J=8.9Hz,1H),6.96( s,1H),6.79(s,2H),6.67(s,1H),6.37(s,2H),5.68(s,1H),5.65(d,J=1.4Hz,1H),5.47(s,1H),4.2 4(s,1H),3.89(s,3H),3.72(s,3H),3.65(s,1H),3.34(d,J=14.0Hz,1H),3.28–3.05(m,2H),2.97–2 .75(m,5H),2.64(s,3H),2.58(s,3H),2.54(d,J=5.4Hz,1H),2.56–2.31(d,J=27.0Hz,3H).HRMS(ESI + )m / e[M+H] + :863.27539,C 46 H 40 F6N2O8.

[0134] CP-218: The product was synthesized using CP-02 and methoxyacetic acid as raw materials. The product was a light yellow powder and was purified by recrystallization with a yield of 74%. 1 H NMR (400MHz, CDCl3) δ7.38 (d, J = 8.4Hz, 1H), 7.00 (s, 1H), 6.94 (s, 1H), 6.79 (s, 2H), 6.63 (s,1H),6.36(s,2H),5.65(s,1H),5.62(d,J=1.4Hz,1H),5.45(s,1H),4.33(s,2H),4.20 (s,1H),3.89(s,3H),3.69(s,3H),3.65(s,1H),3.55(s,3H),3.32(d,J=14.0Hz,1H),3.2 2–3.06(m,2H),2.95–2.75(m,5H),2.61(s,3H),2.58(s,3H),2.54–2.32(m,4H).HRMS(ESI + )m / e[M+H] + :695.29520,C 40 H 42 N2O9.

[0135] CP-222, CP-223, CP-224, CP-225, CP-229, CP-230, CP-234, CP-237, CP-239 and CP-240 were synthesized using the synthesis steps described in method 2, and the structural characterizations are as follows:

[0136] CP-222: light yellow powder, yield 76%. 1 H NMR(400MHz, CDCl3)δ7.79(d,J=1.5Hz,1H),7.38(dd,J=8.4,2.2Hz,1H),7.26(s,1H),7.03(s,1H), 6.94(d,J=8.0,Hz,1H),6.78(s,2H),6.65(s,1H),6.36(s,2H),5.63(s,1H),5.61(d,J=1.5Hz,1H),5 .47(s,1H),4.21(d,J=6.3Hz,1H),3.88(s,3H),3.70(s,3H),3.61(s,1H),3.32(d,J=14.0Hz,1H),3. 24–3.03(m,2H),2.95–2.73(m,5H),2.61(s,3H),2.59–2.51(m,4H),2.51–2.36(m,3H),2.32(s,3H). 13C NMR (101MHz, CDCl3) δ159.51,152.26,148.79,148.61,146.61,141.76,138.94,138.66,138. 44,136.73,136.38,134.13,132.35,131.67,131.51,130.63,129.60,128.07,125.70,123.8 1,123.33,122.29,120.92,119.81,118.47,116.69,111.17,110.76,101.57,64.13,61.69,5 5.92,55.11,53.47,51.12,44.12,43.86,41.99,40.80,37.75,28.77,19.52,15.59.HRMS(ESI + )m / e[M+H] + :747.27205,C 43 H 42 N2O8S.

[0137] CP-223: light yellow powder, yield 81%. 1 H NMR (400MHz, CDCl3) δ7.89(d,J=1.6Hz,1H),7.56(d,J=1.6Hz,1H),7.38(dd,J=8.5,2.4Hz,1H),7 .02(s,1H),6.95(s,1H),6.78(s,2H),6.65(s,1H),6.36(s,2H),5.65(s,1H),5.63(d,J=1.5Hz,1 H),5.47(s,1H),4.21(d,J=6.4Hz,1H),3.89(s,3H),3.70(s,3H),3.61(s,1H),3.31(d,J=14.0Hz ,1H),3.24–3.02(m,2H),2.97–2.75(m,5H),2.62(s,3H),2.58–2.49(m,4H),2.48–22.31(m,3H). 13C NMR (101MHz, CDCl3) δ158.24,152.52,148.77,148.58,146.54,141.63,138.30,136.78 ,136.55,134.15,133.03,132.51,131.78,131.66,130.87,130.59,128.10,125.41,123 .81,123.57,122.34,120.92,119.66,118.48,116.60,111.08,110.74,101.64,64.07, 61.60,55.92,55.09,51.07,44.09,43.83,42.02,40.59,37.74,28.80,19.63.HRMS(ESI + )m / e[M+H] + :811.16731,813.16710,C 42 H 39 BrN2O8S.

[0138] CP-224: light yellow powder, yield 71%. 1 H NMR (400MHz, CDCl3) δ7.54(d,J=5.9Hz,1H),7.38(dd,J=8.7,2.3Hz,1H),7.14(d,J=5.9Hz,1H),7. 03(s,1H),6.95(d,J=8.0Hz,1H),6.78(s,2H),6.65(s,1H),6.36(s,2H),5.64(s,1H),5.63(d,J=1. 5Hz,1H),5.47(s,1H),4.22(d,J=6.4Hz,1H),3.89(s,3H),3.70(s,3H),3.62(s,1H),3.32(d,J=14. 0Hz,1H),3.23–3.03(m,2H),3.00–2.73(m,5H),2.62(s,3H),2.59–2.49(m,4H),2.47–2.22(m,3H). 13CNMR (101MHz, CDCl3) δ158.78,152.41,148.79,148.61,146.54,141.71,139.17,138.7 9,138.32,136.38,134.14,132.41,131.67,130.61,129.00,128.08,127.23,125.53,12 3.81,123.42,122.92,122.27,119.53,118.48,116.65,111.16,110.75,101.58,64.08, 61.64,55.92,55.12,51.09,44.14,43.87,42.02,40.60,37.72,28.72,19.76.HRMS(ESI + )m / e[M+H] + :767.21797, C 42 H 39 ClN2O8S.

[0139] CP-225: light yellow powder, yield 77%. 1 H NMR (400MHz, CDCl3) δ7.59(d,J=5.3Hz,1H),7.38(dd,J=8.5,2.3Hz,1H),7.11(d,J=5.3Hz,1H),7.02( s,1H),6.95(s,1H),6.78(s,2H),6.66(s,1H),6.36(s,2H),5.66(s,1H),5.64(d,J=1.5Hz,1H),5.47( s,1H),4.21(d,J=6.1Hz,1H),3.89(s,3H),3.70(s,3H),3.63(s,1H),3.32(d,J=14.0Hz,1H),3.25–3. 02(d,J=14.3Hz,2H),2.97–2.73(m,5H),2.62(s,3H),2.59–2.52(m,4H),2.49–2.32(d,J=25.5Hz,3H). 13C NMR (101MHz, CDCl3) δ157.71,152.41,148.76,148.61,146.61,138.42,134.16,133. 45,132.63,131.71,131.66,130.60,128.23,128.12,128.02,125.37,124.20,123.81 ,122.29,120.86,119.63,118.46,116.73,116.56,111.14,110.73,101.63,64.04,61 .60,55.92,55.11,51.02,44.09,43.87,42.00,40.71,37.69,28.77,19.62.HRMS(ESI + )m / e[M+H] + :767.21775, C 42 H 39 ClN2O8S.

[0140] CP-229: light yellow powder, yield 85%. 1 H NMR (400MHz, CDCl3) δ8.93(d,J=2.1Hz,1H),8.46(d,J=2.1Hz,1H),7.39(d,J=8.4Hz,1H),7. 03(s,1H),6.95(s,1H),6.78(s,2H),6.65(s,1H),6.37(s,2H),5.63(s,1H),5.61(d,J=1.4Hz ,1H),5.47(s,1H),4.23(s,1H),3.88(s,3H),3.70(s,3H),3.62(s,1H),3.32(d,J=14.0Hz,1 H),3.23–3.05(m,2H),2.94–2.76(m,5H),2.69–2.58(m,4H),2.56(s,3H),2.52–2.30(m,3H). 13C NMR (101MHz, CDCl3) δ158.39,153.97,152.37,148.76,148.62,146.64,141.76,138. 70,138.29,136.51,134.17,132.27,131.66,130.59,129.04,128.05,125.67,123.82 ,123.34,122.27,120.90,119.66,118.47,116.67,111.17,110.76,101.60,64.08,61 .71,55.91,55.09,51.07,44.09,43.83,41.95,40.86,37.69,28.70,19.48.HRMS(ESI + )m / e[M+H] + :734.25112,C 41 H 39 N3O8S.

[0141] CP-230: light yellow powder, yield 79%. 1 H NMR (400MHz, CDCl3) δ9.05 (s, 1H), 8.71 (s, 1H), 7.38 (dd, J = 8.5, 2.2Hz, 1H), 7.02 (s, 1H) ,6.95(s,1H),6.78(s,2H),6.65(s,1H),6.36(s,2H),5.66(s,1H),5.64(d,J=1.4Hz,1H), 5.46(s,1H),4.22(s,1H),3.89(s,3H),3.71(s,3H),3.62(s,1H),3.32(d,J=14.0Hz,1H), 3.23–3.03(m,2H),2.97–2.72(m,5H),2.62(s,3H),2.59–2.48(m,4H),2.48–2.29(m,3H). 13C NMR (101MHz, CDCl3) δ159.09,158.45,152.41,150.24,148.75,148.55,146.48,141.63,1 39.07,138.27,138.01,137.82,136.63,134.16,132.42,131.65,130.72,128.24,128.03 ,125.33,123.82,122.26,120.89,119.58,118.49,116.65,111.16,110.75,101.67,64.1 1,61.65,55.92,55.08,51.07,44.07,43.84,42.03,40.60,37.70,28.81,19.66.HRMS(ESI + )m / e[M+H] + :734.25203,C 41 H 39 N3O8S.

[0142] CP-234: light yellow powder, yield 72%. 1 H NMR (400MHz, CDCl3) δ8.46(d,J=1.0Hz,1H),8.02(d,J=1.0Hz,1H),7.38(dd,J=8.5,2.2Hz,1H),7. 02(s,1H),6.94(s,1H),6.78(s,2H),6.65(s,1H),6.36(s,2H),5.64(s,1H),5.62(d,J=1.4Hz,1H), 5.46(s,1H),4.2(d,J=4.0Hz,1H),3.88(s,3H),3.70(s,3H),3.62(s,1H),3.32(d,J=14.0Hz,1H),3 .22–3.04(s,2H),2.89(dd,J=20.8,8.9Hz,5H),2.61(s,3H),2.58–2.51(m,4H),2.46–2.34(m,3H). 13CNMR (101MHz, CDCl3) δ158.07,152.28,151.81,148.75,148.61,146.58,145.22,141. 69,138.73,138.29,136.55,134.15,132.13,131.65,130.59,128.01,125.23,123.81 ,123.44,122.26,120.90,119.62,118.48,116.65,111.18,110.78,101.62,64.04,61 .63,55.92,55.09,51.09,44.08,43.84,41.96,40.76,37.69,28.72,19.51.HRMS(ESI + )m / e[M+H] + :718.27495, C 41 H 39 N3O9.

[0143] CP-237: light yellow powder, yield 82%. 1 H NMR (400MHz, CDCl3) δ8.12(s,1H),7.99(s,1H),7.38(dd,J=8.4,2.3Hz,1H),7.02(s,1H),6 .95(s,1H),6.78(s,2H),6.65(s,1H),6.36(s,2H),5.66(s,1H),5.63(d,J=1.4Hz,1H),5.46 (s,1H),4.22(d,J=3.2Hz,1H),3.89(s,3H),3.70(s,3H),3.63(s,1H),3.32(d,J=14.0Hz,1H ),3.22–3.04(m,2H),2.94–2.76(m,5H),2.62(s,3H),2.58–2.50(m,4H),2.48–2.31(m,3H). 13C NMR (101MHz, CDCl3) δ154.63,154.08,152.29,148.76,148.58,146.53,141.74,140.79 ,138.71,138.22,136.68,135.00,134.18,132.39,131.64,130.47,128.04,127.99,124 .80,123.83,122.27,120.92,119.55,118.49,116.57,111.14,110.74,101.70,64.06, 61.65,55.91,55.08,51.01,44.06,43.82,42.00,40.55,37.67,28.75,19.65.HRMS(ESI + )m / e[M+H] + :718.27507, C 41 H 39 N3O9.

[0144] CP-239: light yellow powder, yield 81%. 1 H NMR (400MHz, CDCl3) δ8.46 (d, J=5.1Hz, 1H), 7.92 (d, J=5.1Hz, 1H), 7.71–7.63 (m, 1H), 7.39 (dd, J= 8.4,2.2Hz,1H),7.03(s,1H),6.95(s,1H),6.79(s,2H),6.66(s,1H),6.38(s,2H),5.66(s,1H),5.6 4(d,J=1.4Hz,1H),5.46(s,1H),4.25(s,1H),3.89(s,3H),3.72(s,3H),3.65(s,1H),3.34(d,J=14. 0Hz,1H),3.24–3.04(m,2H),2.96–2.77(m,5H),2.64(s,3H),2.59–2.50(m,4H),2.50–2.25(m,3H). 13C NMR (101MHz, CDCl3) δ165.46,163.06,161.26,161.22,152.44,149.10,148.96,148.62,141 .61,141.53,138.46,138.11,136.67,134.26,131.64,128.08,125.38,123.85,122.33,121 .21,121.16,120.85,119.24,118.51,116.62,111.16,110.76,110.55,110.15,101.73,63. 93,61.63,55.91,55.09,50.81,44.00,43.67,41.97,40.38,37.68,28.51,19.74.HRMS(ESI + )m / e[M+H] + :746.28533,C 43 H 40 FN3O8.

[0145] CP-240: light yellow powder, yield 69%. 1 H NMR (400MHz, CDCl3) δ8.99(d,J=4.9Hz,1H),8.41(s,1H),8.23(dd,J=4.9,1.5Hz,1H),7.39(dd,J=8.0,2 .4Hz,1H),7.03(s,1H),6.96(s,1H),6.79(s,2H),6.66(s,1H),6.38(s,2H),5.67(s,1H),5.64(d,J=1.4 Hz,1H),5.46(s,1H),4.26(d,J=4.0Hz,1H),3.89(s,3H),3.72(s,3H),3.64(d,J=10.6Hz,1H),3.35(d,J =14.0Hz,1H),3.24–3.05(m,2H),2.95–2.78(m,5H),2.64(s,3H),2.59–2.51(m,4H),2.51–2.27(m,3H). 13C NMR (101MHz, CDCl3) δ161.31,152.28,151.31,149.46,148.71,148.60,146.68,141.5 9,138.09,138.03,136.74,134.28,131.64,130.44,127.99,126.18,125.34,123.85, 122.52,122.30,120.91,120.28,119.23,118.51,116.62,111.15,110.78,101.75,64 .02,61.61,55.92,55.09,50.78,43.99,43.69,41.97,37.77,28.63,19.75.HRMS(ESI + )m / e[M+H] + :796.28211,C 44 H 40 F3N3O8.

[0146] Example 8: Synthesis of 5-carbamate derivatives

[0147]

[0148] General steps: CP-02 and the corresponding amine are used as raw materials, di(p-nitrobenzene) carbonate is used as a condensing agent, 4-dimethylaminopyridine is used as a catalyst, triethylamine is used as a base, and dichloromethane is used as a solvent. CP-02 reacts with the condensing agent in the presence of the catalyst and triethylamine for 10 minutes to 2 hours. After the reaction is complete, amine is added and the reaction is continued for 10 minutes to 10 hours. After the reaction is completed, the crude product is obtained by washing with water, drying and concentrating, and the product is purified by column chromatography.

[0149] CP-26: Add CP-02 (100 mg, 1 equivalent), 20 mL of dichloromethane, triethylamine (3 equivalents), di(p-nitrobenzene) carbonate (1.2 equivalents) and 4-dimethylaminopyridine (0.1 equivalent) into a three-necked flask, stir at room temperature for 1 hour, add dimethylamine hydrochloride (1.1 equivalents), and continue to react for 4 hours. After the reaction is completed, wash twice with water and once with brine, dry over anhydrous sodium sulfate, and concentrate to obtain a crude product. Purify the product by column chromatography to obtain a light yellow powder with a yield of 73%. 1H NMR (400MHz, CDCl3) δ7.37 (d, J = 7.9Hz, 1H), 7.00 (s, 1H), 6.94 (s, 1H), 6.77 (s, 2H) ),6.63(s,1H),6.34(s,2H),5.63(s,1H),5.62(s,1H),5.47(s,1H),4.17(s,1H),3 .88(s,3H),3.67(s,3H),3.60(s,1H),3.29(d,J=13.6Hz,1H),3.25-3.13(m,4H),3 .09–2.92(m,4H),2.92–2.64(m,6H),2.60(s,3H),2.56(s,3H),2.50–2.32(m,3H). 13 C NMR (101MHz, CDCl3) δ153.87,152.34,148.78,148.60,146.56,141.80,138.89,138. 57,135.97,134.02,132.26,131.68,130.75,128.05,126.70,123.77,123.10,122.1 8,120.85,120.02,118.43,116.68,111.18,110.76,101.40,64.15,61.68,55.91,55 .10,51.17,44.19,43.91,42.01,40.90,37.71,36.96,36.52,28.88,19.33.HRMS(ESI + )m / e[M+H] + :694.30924, C 40 H 43 N3O8.

[0150] Referring to the synthesis method of CP-26, CP-27, CP-28, CP-205, CP-206, CP-214, CP-220 and CP-242 were synthesized. The structural characterization is as follows:

[0151] CP-27: light yellow powder, yield 66%. 1H NMR (400MHz, CDCl3) δ7.37(d,J=8.2Hz,1H),6.97(d,J=19.4Hz,2H),6.77(s ,2H),6.63(s,1H),6.34(s,2H),5.64(s,1H),5.63(s,1H),5.47(s,1H),4.1 8(s,1H),3.88(s,3H),3.85–3.45(m,12H),3.29(d,J=13.6Hz,1H),3.20–3. 03(m,2H),3.00–2.68(m,6H),2.60(s,3H),2.56(s,3H),2.50–2.33(m,3H). 13 C NMR (101MHz, CDCl3) δ152.73,152.32,148.78,148.58,146.62,141.76,138.81,138.51, 136.09,134.07,132.39,131.66,130.70,128.02,126.37,123.78,123.27,122.28,120.9 2,119.90,118.44,116.67,111.15,111.07,110.77,101.47,66.64,64.13,61.72,55.91 ,55.10,51.18,45.10,44.43,44.16,43.90,42.02,40.71,37.67,28.87,19.42.HRMS(ESI + )m / e[M+H] + :736.32020,C 42 H 45 N3O9.

[0152] CP-28: light yellow powder, yield 78%. 1 H NMR(400MHz, CDCl3) δ7.37(d,J=8.2Hz,1H),7.00(s,1H),6.94(d,J=3.7Hz,1H),6.7 7(s,2H),6.63(s,1H),6.34(s,2H),5.64(s,1H),5.63(s,1H),5.46(s,1H),4.18(d, J=3.2Hz,1H),3.88(s,3H),3.75-3.55(m,8H),3.29(d,J=13.8Hz,1H),3.23–3.03(m ,2H),2.98–2.68(m,6H),2.60(s,3H),2.56(s,3H),2.53–2.36(m,7H),2.34(s,3H). 13C NMR (101MHz, CDCl3) δ152.61,149.64,148.77,148.59,146.54,141.78,138.97,138.55,136 .03,134.05,132.36,131.66,128.03,126.48,123.76,123.13,122.15,120.89,119.95,118. 42,116.73,111.17,111.00,110.74,106.59,101.44,64.16,61.67,55.91,55.09,54.87,54 .67,51.17,46.21,44.63,44.17,43.89,42.02,40.84,39.04,37.78,28.83,19.36.HRMS(ESI + )m / e[M+H] + :749.35324, C 43 H 48 N4O8.

[0153] CP-205: light yellow powder, yield 72%. 1 H NMR (400MHz, CDCl3) δ7.37 (dd, J=8.5, 2.2Hz, 1H), 7.12–6.97 (m, 1H), 6.96–6.88 (m, 1H), 6.77 (s, 2H), 6.64 (d, J= 2.7Hz,1H),6.33(d,J=6.1Hz,2H),5.63(s,1H),5.63(d,J=1.5Hz,1H),5.47(s,1H),4.18(d,J=5.1Hz,1H),3.88(s ,3H),3.68(s,3H),3.60(s,1H),3.54–3.34(m,4H),3.29(d,J=14.2Hz,1H),3.16(q,J=7.1Hz,2H),3.09–2.95(m,1 H),2.93–2.70(m,5H),2.60(s,3H),2.56(s,3H),2.50–2.35(m,3H),1.28(t,J=8.0Hz,3H),1.21(t,J=7.6Hz,3H). 13C NMR (101MHz, CDCl3) δ153.22,152.34,148.79,148.63,147.03,146.54,141.84,138.93,13 8.64,135.90,134.03,132.80,132.26,131.67,130.70,128.05,126.73,122.18,120.88,1 20.12,118.43,116.64,111.13,110.71,101.38,64.14,61.64,55.91,55.11,51.17,44.19 ,43.89,42.46,42.29,42.02,41.99,,40.95,37.69,28.84,19.44,14.27,13.48.HRMS(ESI + )m / e[M+H] + :722.34152, C 42 H 47 N3O8.

[0154] CP-206: light yellow powder, yield 70%. 1 H NMR (400MHz, CDCl3) δ7.50 (d, J = 12.8Hz, 1H), 7.01 (s, 1H), 6.93 (s, 1H), 6.87 (s, 1H), 6. 79(s,1H),6.65(d,J=4.5Hz,1H),6.36(s,2H),5.78–5.53(m,2H),5.42(s,1H),4.32(s, 1H),3.89(s,3H),3.78-3.60(m,4H),3.47(s,3H),3.37(s,3H),3.30–3.20(m,1H),3.18 –2.99(m,3H),2.99–2.72(m,5H),2.65(s,3H),2.62(s,3H),2.57-2.26(m,3H).HRMS(ESI + )m / e[M+H] + :710.28868,C 40 H 43 N3O7S.

[0155] CP-214: light yellow powder, yield 81%. 1H NMR (400MHz, CDCl3) δ7.37(d,J=9.0Hz,1H),7.00(d,J=8.4Hz,1H),6.94(s,1H),6.77(s,2H),6.6 3(s,1H),6.34(s,2H),5.64(s,1H),5.63(d,J=1.6Hz,1H),5.47(s,1H),4.18(d,J=8.0Hz,1H),3.8 8(s,3H),3.67(s,3H),3.65-3.41(m,3H),3.29(d,J=14.0Hz,1H),3.24-3.12(m,4H),3.08(s,1H) ,2.98–2.72(m,5H),2.60(s,3H),2.56(s,3H),2.40(s,3H),1.70-1.60(m,4H),1.58-1.50(m,2H). 13 C NMR (101MHz, CDCl3) δ164.85,152.70,152.26,148.78,148.61,146.55,141.82,138.63, 135.92,134.05,132.19,131.66,130.66,128.06,126.69,123.77,122.93,122.23,120. 87,119.98,118.41,116.71,111.17,110.70,101.40,64.13,61.63,55.90,55.10,51.14 ,47.93,45.76,45.46,43.88,41.97,40.92,37.73,28.78,25.79,25.58,19.25.HRMS(ESI + )m / e[M+H] + :734.34228, C 43 H 47 N3O8.

[0156] CP-220: light yellow powder, yield 79%. 1H NMR (400MHz, CDCl3) δ7.37 (dd, J = 8.4, 2.4Hz, 1H), 7.00 (s, 1H), 6.93 (s, 1H), 6.77 (s, 2H), 6.64 (s, 1H) ),6.34(s,2H),5.71–5.64(m,1H),5.63(d,J=1.5Hz,1H),5.47(s,1H),4.18(d,J=6.0Hz,1H),3.88(s, 3H),3.68(s,3H),3.64-3.56(m,3H),3.50(t,J=6.6Hz,2H),3.29(d,J=14.0Hz,1H),3.22–3.04(m,2H) ,2.94–2.76(m,5H),2.60(s,3H),2.56(s,3H),2.51(d,J=5.8Hz,1H),2.39(s,3H),2.01–1.91(m,4H). 13 C NMR (101MHz, CDCl3) δ152.41,152.15,148.77,148.62,146.56,144.82,141.83,138.93,1 38.64,135.94,134.02,131.66,130.70,128.04,126.63,123.76,122.97,122.20,120.84, 120.07,118.42,116.66,111.19,110.71,101.39,64.13,61.67,55.91,55.11,51.12,46.6 4,46.40,44.19,43.88,41.98,40.93,37.61,28.81,25.88,25.00,19.33,14.14.HRMS(ESI + )m / e[M+H] + :720.32716, C 42 H 45 N3O8.

[0157] CP-242: light yellow powder, yield 78%. 1H NMR (400MHz, CDCl3) δ7.38(dd,J=8.3,2.2Hz,1H),7.01(s,1H),6.94(d,J=8.8Hz,1H),6.78(s,2 H),6.64(s,1H),6.35(s,2H),5.65(s,1H),5.63(d,J=1.5Hz,1H),5.45(s,1H),4.19(d,J=5.8Hz, 1H),3.88(s,3H),3.82(s,2H),3.76–3.53(m,6H),3.31(d,J=14.0Hz,1H),3.23–3.06(m,2H),2.9 4–2.76(m,5H),2.61(s,3H),2.57–2.48(m,4H),2.46–2.33(m,3H),2.07(tt,J=13.3,5.7Hz,4H). 13 C NMR (101MHz, CDCl3) δ152.47,148.74,148.62,146.61,141.74,138.66,138.49,136.1 4,134.11,132.25,131.65,130.54,128.02,126.33,123.82,122.22,121.42,120.88,1 19.79,118.46,116.62,111.18,110.73,101.52,64.09,61.55,55.91,55.10,53.45,4 4.10,43.81,43.41,43.36,41.97,41.66,35.46,35.24,35.01,28.63,19.37.HRMS(ESI + )m / e[M+H] + :770.32359,C 43 H 45 F2N3O8.

[0158] Example 9: Synthesis of 5-Carbon-Substituted Amine Derivatives

[0159]

[0160] Method 1: CP-03 and amine are used as raw materials, tetrahydrofuran is used as solvent, triethylamine is used as acid-binding agent, and the reaction is carried out at 0-25°C for 5 minutes to 2 hours. After the reaction is completed, the crude product is obtained by concentration, extraction, water washing, drying and concentration, and the product is purified by column chromatography or recrystallization.

[0161] CP-61: Add CP-03 (100 mg, 1 equivalent), 20 mL of dichloromethane, morpholine (2 equivalents), and triethylamine (3 equivalents) into a three-necked flask and stir at room temperature for 0.5 hours. After the reaction is completed, wash with water twice and brine once, dry over anhydrous sodium sulfate, and concentrate to obtain a crude product. Purify by column chromatography to obtain a light yellow powder with a yield of 64%. 1 H NMR (400MHz, CDCl3) δ7.37(d,J=7.9Hz,1H),7.03(s,1H),6.95(d,J=6.8Hz,1H),6.77(s,2H ),6.63(s,1H),6.35(s,2H),5.58(s,1H),5.53(d,J=1.2Hz,1H),5.46(s,1H),4.21(s,1H),3 .88(s,3H),3.73–3.64(m,7H),3.60(s,1H),3.41(s,2H),3.32(d,J=14.0Hz,1H),3.15-3.05 (m,3H),2.95-2.85(m,1H),2.87–2.71(m,4H),2.64(s,3H),2.56(s,3H),2.50-2.35(m,7H). 13 C NMR (101MHz, CDCl3) δ152.24,148.85,148.69,146.75,146.52,141.84,139.26,13 7.24,132.30,131.79,131.72,130.65,127.95,126.85,123.96,123.75,122.28,12 0.97,118.46,116.73,111.11,110.71,110.00,100.22,67.16,64.12,61.94,55.9 1,55.03,53.48,51.22,45.17,43.93,42.30,39.81,37.64,28.88,22.65.HRMS(ESI + )m / e[M+H] + :706.34644, C 42 H 47 N3O7.

[0162] CP-62, CP-63 and CP-67 were synthesized by referring to the synthesis steps of CP-61. The structural characterization is as follows:

[0163] CP-62: light yellow powder, yield 66%. 1H NMR (400MHz, CDCl3) δ7.38(d,J=8.0Hz,1H),7.01(s,1H),6.95(d,J=6.8Hz,1H),6.77(s,2H),6.64(s,1H),6 .35(s,2H),5.60(s,1H),5.56(d,J=1.2Hz,1H),5.46(s,1H),4.22(s,1H),3.88(s,3H),3.67(s,3H),3.61(t ,J=5.2Hz,3H),3.50(s,2H),3.32(d,J=13.8Hz,1H),3.20-3.07(m,2H),3.06–2.98(m,1H),2.98–2.85(m,2H ),2.85-2.70(m,4H),2.63(s,3H),2.62-2.58(t,J=5.6Hz,2H),2.56(s,3H),2.50-2.35(m,3H),2.23(s,3H). 13 C NMR (101MHz, CDCl3) δ152.27,148.85,148.66,146.58,141.81,139.10,137.44,132.3 7,132.21,131.69,130.62,127.93,125.93,123.98,123.89,123.74,122.23,120.93,1 18.42,116.73,111.18,111.10,110.74,100.32,64.11,61.88,58.57,58.54,55.91,5 4.98,52.45,51.20,45.11,43.92,42.17,41.53,40.08,37.65,28.86,22.76.HRMS(ESI + )m / e[M+H] + :694.34553,C 41 H 47 N3O7.

[0164] CP-63: light yellow powder, yield 54%. 1H NMR (400MHz, CDCl3) δ7.37(d,J=8.0Hz,1H),7.03(s,1H),6.95(d,J=6.8Hz,1H),6.77(s,2H),6. 62(s,1H),6.35(s,2H),5.58(s,1H),5.53(d,J=1.2Hz,1H),5.46(s,1H),4.21(s,1H),3.88(s,3H ),3.80–3.70(m,1H),3.69–3.55(m,4H),3.42(s,2H),3.32(d,J=13.8Hz,1H),3.18-3.02(m,3H), 2.97–2.89(m,1H),2.89–2.65(m,6H),2.64(s,3H),2.56(s,3H),2.52-2.35(m,8H),2.27(s,3H). 13 C NMR (101MHz, CDCl3) δ152.26,148.85,148.70,146.69,146.49,141.88,139.25,137.15, 132.28,131.81,131.71,130.77,130.63,128.00,126.82,123.74,122.24,120.94,118. 47,116.68,111.11,110.70,110.57,100.21,95.60,64.11,61.94,55.90,55.28,55.03, 52.97,52.89,51.21,46.05,45.18,43.92,42.25,40.01,37.66,28.86,22.50.HRMS(ESI + )m / e[M+H] + :719.37831,C 43 H 50 N4O6.

[0165] CP-67: light yellow powder, yield 62%. 1 H NMR (400MHz, CDCl3) δ7.36 (d, J = 7.6Hz, 1H), 7.26-7.21 (m, 2H), 7.02 (s, 1H), 6.95-6.87 (m, 3H), 6.80 -6.72(m,3H),6.64(s,1H),6.35(s,2H),5.58(s,1H),5.54(d,J=0.8Hz,1H),5.45(s,1H),4.30(ABq,J AB=13.8Hz,2H),4.21(s,1H),3.86(s,3H),3.78–3.47(m,6H),3.34–3.24(m,1H),3.17–2.97( m,2H),2.96–2.76(m,4H),2.79-2.72(m,3H),2.60(s,3H),2.54(s,3H),2.46-2.31(m,3H). 13 C NMR (101MHz, CDCl3) δ152.29,150.80,148.85,148.65,146.64,141.84,139.21,137.44,132 .39(s),132.24.131.71,130.68,129.10,128.03,126.30,124.11,123.78,122.28,120.94, 120.73,118.45,117.32,116.70,113.87,111.17,110.70,110.66,100.44,64.22,61.90,55 .93,55.00,51.23,47.45,44.99,43.95,42.21,40.03,37.66,36.53,28.86,22.68.HRMS(ESI + )m / e[M+H] + :726.35079,C 45 H 47 N3O6.

[0166] Method 2: Using CP-05 and amine as raw materials and sodium triacetoxyborohydride as a reducing agent, the product is prepared by reductive amination reaction at room temperature. CP-05 and amine react with sodium triacetoxyborohydride in a solvent for 10 minutes to 10 hours. After the reaction is completed, the crude product is obtained by quenching, neutralization, concentration, extraction, water washing, drying and concentration, and the product is purified by column chromatography or recrystallization.

[0167] CP-69: CP-05 (100 mg, 1 equivalent), 20 mL of methanol, 4-hydroxypiperidine (1.5 equivalents), sodium triacetoxyborohydride (3 equivalents) were added to a three-necked flask, and the mixture was stirred at room temperature for 0.5 hours. After the reaction was completed, a saturated potassium carbonate solution was added to quench the reaction, and the pH value was adjusted to 8-9. The mixture was concentrated under reduced pressure to remove methanol, extracted with dichloromethane, washed twice with water and once with brine, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography to obtain a light yellow powder with a yield of 89%. 1H NMR (400MHz, CDCl3) δ7.37(d,J=8.0Hz,1H),7.03(s,1H),6.94(d,J=4.8Hz,1H),6.77(s,2H),6.62(s, 1H),6.35(s,2H),5.56(s,1H),5.52(d,J=1.0Hz,1H),5.45(s,1H),4.20(s,1H),3.88(s,3H),3.80–3. 51(m,5H),3.38(s,2H),3.32(d,J=14.2Hz,1H),3.21–3.01(m,3H),2.96–2.67(m,7H),2.63(s,3H),2. 56(s,3H),2.50-2.32(m,3H),2.19-2.06(m,2H),1.83(t,J=13.2Hz,2H),1.54(dt,J=18.9,9.4Hz,2H). 13 CNMR (101MHz, CDCl3) δ152.22,148.84,148.71,146.58,145.93,141.88,139.25,137. 13,132.29,131.79,131.72,130.68,127.99,127.85,123.74,122.27,120.95,118.54, 118.46,116.76,111.11,110.98,110.68,100.16,68.32,64.08,61.89,55.91,55.03,5 2.95,51.26,50.92,45.16,43.91,42.23,39.93,37.67,34.66,28.82,22.49.HRMS(ESI + )m / e[M+H] + :720.36275,C 43 H 49 N3O7.

[0168] CP-70, CP-71 and CP-73 were synthesized by referring to the synthesis steps of CP-69. The structural characterization is as follows:

[0169] CP-70: light yellow powder, yield 83%. 1H NMR (400MHz, CDCl3) δ7.37(d,J=8.1Hz,1H),7.02(s,1H),6.95(s,1H),6.77(s,2H),6.63(s,1 H),6.35(s,2H),5.57(s,1H),5.54(s,1H),5.47(s,1H),4.20(s,1H),3.88(s,3H),3.65(s,3H) ,3.60-3.54(m,2H),3.50(d,J=12.4Hz,1H),3.31(d,J=13.9Hz,1H),3.21–3.01(m,3H),3.00– 2.69(m,6H),2.63(s,3H),2.55(s,3H),2.53(s,3H),2.47-2.35(m,3H),1.76(t,J=5.2Hz,4H). 13 C NMR (101MHz, CDCl3) δ152.23,148.87,148.70,146.55,146.24,141.97,139.28,137.08, 132.24,132.02,131.72,130.69,128.79,128.12,128.00,126.27,123.72,122.21,120. 94,118.42,116.74,112.04,111.18,110.75,100.16,64.10,61.95,55.94,55.91,55.02 ,54.21,51.24,50.37,45.18,43.93,42.26,40.06,37.65,28.87,23.62,22.54.HRMS(ESI + )m / e[M+H] + :690.35178,C 42 H 47 N3O6.

[0170] CP-71: light yellow powder, yield 83%. 1H NMR (400MHz, CDCl3) δ7.37(d,J=7.9Hz,1H),7.03(s,1H),6.95(d,J=4.1Hz,1H),6.77(s, 2H),6.63(s,1H),6.35(s,2H),5.58(s,1H),5.53(s,1H),5.46(s,1H),4.21(s,1H),3.88( s,3H),3.67(s,3H),3.60(s,1H),3.45(s,2H),3.32(d,J=12.8Hz,1H),3.23–3.01(m,3H), 2.93–2.71(m,5H),2.64(s,3H),2.60-2.52(m,7H),2.50–2.29(m,3H),2.03-1.90(m,4H). 13 C NMR (101MHz, CDCl3) δ152.27,148.85,148.68,146.64,146.53,141.79,139.26,137.28,132.40,1 31.84,131.72,130.66,128.08,127.95,126.81,124.08,123.76,122.34,120.94,118.47,116.71, 111.12,110.75,110.43,100.25,64.12,61.93,55.91,55.03,52.19,51.17,49.79(t,J=4.8Hz),48 .14(t,J=5.2Hz),45.16,43.91,42.32,39.73,37.66,34.02(t,J=22.8Hz),28.90,22.62.HRMS(ESI + )m / e[M+H] + :740.34772, C 43 H 47 F2N3O6.

[0171] CP-73: light yellow powder, yield 81%. 1H NMR (400MHz, CDCl3) δ7.37(d,J=8.0Hz,1H),7.03(s,1H),6.95(s,1H),6.77(s,2H),6.63(s,1H) ,6.35(s,2H),5.58(s,1H),5.53(s,1H),5.46(s,1H),4.21(s,1H),3.88(s,3H),3.66(s,3H),3.6 0(s,1H),3.39(s,2H),3.32(d,J=14.7Hz,1H),3.23–3.01(m,3H),2.99-2.72(m,6H),2.64(s,3H ),2.56(s,3H),2.50–2.28(m,3H),2.20–1.88(m,4H),1.81(t,J=14.7Hz,2H),1.69–1.48(m,2H). 13 C NMR (101MHz, CDCl3) δ152.21,148.85,148.79,148.69,146.61,141.87,139.28,137.21,132. 27,131.77,131.74,130.73,128.09,127.93,126.93,124.02,123.74,122.25,120.93,118.47 ,116.74,111.11,110.74,110.51,100.18,64.12,61.96,55.91,55.00,53.12,52.56,52.02,5 1.26,45.18,43.91,42.32,40.70(q,J=27.0Hz),39.83,37.67,28.93,24.76,22.59.HRMS(ESI + )m / e[M+H] + :772.35377, C 44 H 48 F3N3O6.

[0172] Example 10: Synthesis of 5-carbon substituted ether derivatives

[0173]

[0174] CP-03 and alcohol, sodium alcoholate and sodium phenolate are used as raw materials, and the reaction is carried out at room temperature to 60°C for 30 minutes to 10 hours. After the reaction is completed, the crude product is obtained by concentration, extraction, water washing, drying and concentration, and the product is purified by column chromatography or recrystallization.

[0175] CP-64: CP-03 (100 mg, 1 equivalent), 10 mL of methanol, and sodium methoxide (5 equivalents) were added to a three-necked flask and stirred at room temperature for 0.5 hours. After the reaction was completed, the crude product was concentrated under reduced pressure and purified by column chromatography to obtain a light yellow powder with a yield of 68%. 1 H NMR (400MHz, CDCl3) δ7.37(d,J=8.0Hz,1H),7.01(s,1H),6.95(dd,J=7.8,5.4Hz,1H),6.77(s ,2H),6.64(s,1H),6.34(s,2H),5.62(s,1H),5.57(d,J=1.2Hz,1H),5.45(s,1H),4.43(ABq,J AB =10.4Hz,2H),4.19(s,1H),3.88(s,3H),3.78–3.72(m,1H),3.71–3.53(m,5H),3.38(s,3H),3.31(d,J=13 .8Hz,1H),3.18–2.87(m,4H),2.77(dd,J=14.0,6.5Hz,3H),2.64(s,3H),2.56(s,3H),2.45–2.36(m,2H). 13 C NMR (101MHz, CDCl3) δ152.24,148.83,148.70,146.69,146.50,141.69,139.28,137. 95,132.45,132.47,132.11,131.72,130.70,127.98,126.49,123.87,123.75,122.2 4,120.93,118.50,116.70,110.98,110.74,110.11,100.51,65.51,64.10,61.98,57 .98,55.90,54.97,51.20,44.95,43.92,42.18,40.23,37.70,28.91,22.11.HRMS(ESI + )m / e[M+H] + :651.30450,C 39 H 42 N2O7.

[0176] CP-65: Synthesized from CP-03 and sodium p-methoxyphenol, light yellow powder, yield 53%. 1H NMR(400MHz, CDCl3) δ7.37(d,J=8.0Hz,1H),7.03(s,1H),7.00–6.90(m,3H),6.84(d,J=9.1Hz, 2H),6.77(s,2H),6.63(s,1H),6.35(s,2H),5.63(s,1H),5.58(s,1H),5.45(s,1H),4.96(ABq,J AB =10.6Hz,2H),4.19(s,1H),3.88(s,3H),3.77(s,3H),3.76–3.72(m,1H),3.72–3.64(m,3H),3.60(s,1H),3.32(d,J=13.9Hz,1H ),3.21-2.97(m,3H),2.89(dd,J=11.9,6.9Hz,1H),2.79(dd,J=14.0,6.4Hz,3H),2.64(s,3H),2.56(s,3H),2.49–2.28(m,3H). 13 C NMR (101MHz, CDCl3) δ154.04,152.98,152.23,148.85,148.75,146.66,146.52,141.62,139.2 9,138.27,132.60,132.22,131.76,130.62,128.00,126.87,124.17,123.78,122.28,120.94,1 18.57,116.74,115.99,115.96,114.62,111.01,110.72,109.06,100.62,64.11,62.44,62.02, 55.91,55.75,55.03,51.23,44.96,43.94,42.16,40.20,37.69,28.95,25.63,22.36.HRMS(ESI + )m / e[M+H] + :743.32939,C 45 H 46 N2O8.

[0177] CP-72: Synthesized from CP-03 and isopropanol, light yellow powder, yield 57%. 1H NMR (400MHz, CDCl3) δ7.37(d,J=8.0Hz,1H),7.02(s,1H),6.94(d,J=6.3Hz,1H),6.76 (s,2H),6.62(s,1H),6.34(s,2H),5.60(s,1H),5.56(s,1H),5.45(s,1H),4.46(ABq,J AB =12.0Hz,2H),4.18(s,1H),3.88(s,3H),3.82–3.61(m,4H),3.60(s,1H),3.30(d,J=14.0Hz,1H),3.24 –2.99(m,3H),2.99–2.74(m,5H),2.63(s,3H),2.55(s,3H),2.48–2.27(m,3H),1.23(d,J=6.0Hz,6H). 13 C NMR (101MHz, CDCl3) δ152.19,148.83,148.80,146.54,141.69,139.43,139.32,137.8 2,132.46,132.08,131.76,130.67,128.06,127.97,126.74,123.89,123.75,122.24,1 20.90,118.59,116.69,110.97,110.72,110.62,100.42,70.98,64.14,62.06,61.33,5 5.90,55.00,51.18,45.01,43.94,42.17,40.38,37.77,28.92,22.32,22.03.HRMS(ESI + )m / e[M+H] + :679.33624, C 41 H 46 N2O7.

[0178] Example 11: Synthesis of 5-Carbon-substituted Thioether Derivatives

[0179]

[0180] CP-68: Add CP-03 (100 mg, 1 equivalent), 10 mL of tetrahydrofuran, furfurylthiol (1.5 equivalents), and triethylamine (3 equivalents) into a three-necked flask and stir at room temperature for 5 hours. After the reaction is completed, concentrate under reduced pressure to obtain the crude product, which is purified by column chromatography to obtain a light yellow powder with a yield of 66%. 1H NMR (400MHz, CDCl3) δ7.40-7.33(m,2H),7.02(s,1H),6.94(dd,J=5.6Hz,1H),6.77(s,2H),6.63( s,1H),6.35(s,2H),6.32(s,1H),6.23(d,J=2.9Hz,1H),5.61(s,1H),5.57(s,1H),5.45(s,1H),4. 19(s,1H),3.88(s,3H),3.80-3.71(m,5H),3.70–3.62(m,4H),3.31(d,J=13.6Hz,1H),3.23–3.03 (m,2H),3.01-2.89(m,2H),2.88–2.73(m,3H),2.72–2.59(s,3H),2.56(s,3H),2.48-2.32(m,3H). 13 C NMR (101MHz, CDCl3) δ152.25,151.91,148.86,148.67,146.55,145.98,142.03,141.81,139. 11,137.35,132.38,132.16,131.68,130.66,128.00,125.42,124.03,123.77,122.28,120.8 9,118.50,116.72,111.09,110.79,110.46,109.99,107.37,100.46,96.67,64.13,61.95,55 .92,55.05,51.15,44.79,43.90,42.06,40.39,37.72,28.79,28.71,26.94,21.89.HRMS(ESI + )m / e[M+H] + :733.29170,C 43 H 44 N2O7S.

[0181] Example 12: Synthesis of 5-carbon substituted ester derivatives

[0182]

[0183] General steps: CP-04 and the corresponding acyl chloride are used as raw materials, triethylamine is used as an acid-binding agent, and the reaction is carried out in dichloromethane at a temperature of -10 to 10°C for a reaction time of 1 minute to 2 hours. After the reaction is completed, the crude product is washed with water and dried, and concentrated to obtain the crude product, which is then purified by recrystallization or column chromatography to obtain the products CP-76, CP-79, CP-82 and CP-83. The structural characterization is as follows:

[0184] CP-76: light yellow powder, yield 89%. 1 H NMR (400MHz, CDCl3) δ7.38(d,J=8.0Hz,1H),7.03(s,1H),6.95(d,J=6.4Hz,1H),6.78(s,2H),6. 63(s,1H),6.36(s,2H),5.65(s,1H),5.60(d,J=1.3Hz,1H),5.44(s,1H),5.11(s,2H),4.21(d,J =3.8Hz,1H),3.89(s,3H),3.70(s,3H),3.63(s,1H),3.34(d,J=13.9Hz,1H),3.24–3.06(m,2H), 3.02–2.92(m,2H),2.91–2.71(m,4H),2.66(s,3H),2.57(s,3H),2.48-2.35(m,3H),2.10(s,3H). 13 C NMR (101MHz, CDCl3) δ171.17,152.37,152.29,148.83,148.72,147.06,146.58,141.60 ,139.03,138.39,132.56,132.42,131.72,130.52,127.94,126.31,123.79,122.32,12 0.97,118.56,116.62,111.06,111.00,110.69,107.95,100.78,64.06,61.92,57.96,5 5.90,55.04,51.00,44.81,43.85,42.11,39.94,37.66,28.76,22.41,21.05.HRMS(ESI + )m / e[M+H] + :679.30045,C 40 H 42 N2O8.

[0185] CP-79: off-white powder, yield 86%. 1H NMR (400MHz, CDCl3) δ7.37(d,J=8.2Hz,1H),7.03(s,1H),6.95(d,J=6.5Hz,1H),6.77(s,2H),6.63(s,1H),6.3 5(s,2H),5.63(s,1H),5.58(d,J=1.0Hz,1H),5.45(s,1H),5.11(s,2H),4.19(d,J=2.4Hz,1H),3.88(s,3H),3.6 9(s,3H),3.60(s,1H),3.32(d,J=14.3Hz,1H),3.24–3.02(m,2H),3.01-2.87(m,2H),2.87–2.68(m,4H),2.65( s,3H),2.56(s,3H),2.46–2.26(m,5H),1.63(dd,J=14.3,7.2Hz,2H),1.33–1.25(m,8H),0.88(t,J=6.8Hz,3H). 13 C NMR (101MHz, CDCl3) δ173.94,152.30,148.83,148.67,146.98,146.51,141.58,139.15,138.35,1 32.59,132.37,131.72,130.62,128.05,127.93,126.38,124.16,123.78,122.28,120.96,118.53 ,116.71,111.02,110.71,108.11,100.73,64.10,61.93,57.78,55.89,55.04,51.20,44.90,43.9 3,42.18,40.03,37.66,34.31,31.69,29.70,29.12,28.95,25.02,22.61,22.43,14.10.HRMS(ESI + )m / e[M+H] + :763.39219, C 46 H 54 N2O8.

[0186] CP-82: white powder, yield 88%. 1H NMR (400MHz, CDCl3) δ7.58 (s, 1H), 7.37 (d, J = 8.8Hz, 1H), 7.20 (d, J = 3.3Hz, 1H), 7.03 (s, 1H), 6.96 (d, J = 5. 5Hz,1H),6.77(s,2H),6.63(s,1H),6.50(dd,J=3.4,1.6Hz,2H),6.36(s,1H),5.66(s,1H),5.61(d,J=1.1H z,1H),5.45(s,1H),5.34(s,2H),4.20(s,1H),3.89(s,3H),3.71(s,3H),3.62(s,1H),3.33(d,J=13.5Hz,1 H),3.21–3.08(m,2H),3.08–2.85(m,4H),2.84–2.74(m,3H),2.66(s,3H),2.56(s,3H),2.48–2.31(m,2H). 13 C NMR (101MHz, CDCl3) δ158.81,155.22,152.53,152.21,148.84,148.71,147.25,146.36,14 4.62,141.51,138.50,132.54,132.42,131.76,130.60,127.94,126.64,124.19,123.79,12 2.27,120.99,118.58,118.15,116.70,111.86,111.02,110.73,107.58,100.82,64.07,61. 94,58.42,55.90,55.06,51.14,44.90,43.89,42.20,39.76,37.72,28.84,22.70.HRMS(ESI + )m / e[M+H] + :731.29408,C 43 H 42 N2O9.

[0187] CP-83: light yellow powder, yield 78%. 1H NMR (400MHz, CDCl3) δ9.24(s,1H),8.77(d,J=4.4Hz,1H),8.31(d,J=7.8Hz,1H),7.46–7.33(m,2H),7.05 (s,1H),6.96(d,J=5.6Hz,1H),6.77(s,2H),6.64(s,1H),6.37(s,2H),5.67(s,1H),5.62(s,1H),5.46(s, 1H),5.41(s,2H),4.22(s,1H),3.88(s,3H),3.71(s,3H),3.61(s,1H),3.34(d,J=14.0Hz,1H),3.21-3.0 7(m,2H),3.04(dd,J=17.1,10.2Hz,1H),2.96–2.75(m,5H),2.67(s,3H),2.56(s,3H),2.50-2.35(m,3H). 13 C NMR (101MHz, CDCl3) δ165.31,153.45,152.30,151.05,148.83,148.65,147.16,146.51,141.53 ,139.10,138.55,137.20,132.64,132.47,131.75,130.59,128.08,127.92,126.47,126.15,12 4.43,123.78,123.32,122.31,121.00,118.53,116.70,111.03,110.71,107.56,100.85,64.09 ,61.90,58.96,55.89,55.06,51.18,44.91,43.92,42.24,39.66,37.66,28.92,22.85.HRMS(ESI + )m / e[M+H] + :742.30943,C 44 H 43 N3O8.

[0188] Example 13: Synthesis of 5-Carbon Substituted Carbamate Derivatives

[0189]

[0190] CP-04 and the corresponding amine are used as raw materials, di(p-nitrobenzene) carbonate is used as a condensing agent, 4-dimethylaminopyridine is used as a catalyst, triethylamine is used as a base, and dichloromethane is used as a solvent. CP-04 reacts with the condensing agent in the presence of the catalyst and triethylamine for 10 minutes to 1 hour. After the reaction is complete, amine is added, and the reaction is continued for 10 minutes to 2 hours. After the reaction is completed, the crude product is obtained by washing with water, drying and concentrating, and the product is purified by column chromatography.

[0191] CP-80: Add CP-04 (100 mg, 1 equivalent) and 20 mL of dichloromethane into a three-necked flask, add triethylamine (3 equivalents), add di(p-nitrobenzene) carbonate (1.2 equivalents) and 4-dimethylaminopyridine (0.1 equivalents), stir at room temperature for 0.5 hours, add morpholine (1.1 equivalents), continue to react for 1 hour, wash with water twice and brine once after the reaction, dry over anhydrous sodium sulfate, concentrate to obtain a crude product, and purify by column chromatography to obtain a light yellow powder with a yield of 80%. 1 H NMR(400MHz, CDCl3) δ7.36(d,J=7.6Hz,1H),7.03(s,1H),6.95(d,J=6.3Hz,1H),6.77 (s,2H),6.62(s,1H),6.35(s,2H),5.63(s,1H),5.58(s,1H),5.45(s,1H),5.16(ABq,J AB =12Hz,2H),4.20(d,J=1.2Hz,1H),3.88(s,3H),3.69(s,3H),3.64(s,5H),3.47(s,4H),3.33(d,J=14.1Hz, 1H),3.18-3.05(m,2H),3.01-2.87(m,2H),2.85-2.70(m,4H),2.66(s,3H),2.56(s,3H),2.48-2.32(m,3H). 13 CNMR (101MHz, CDCl3) δ155.47,152.25,148.82,148.65,146.95,146.50,141.56,139.16 ,138.24,132.59,132.36,131.74,130.63,128.05,127.87,126.48,124.25,123.78,122. 27,120.98,118.52,116.67,111.02,110.72,108.44,100.71,66.60,64.09,61.90,59.09 ,55.89,55.05,51.23,45.03,44.17,43.94,42.27,39.58,37.64,28.93,22.87.HRMS(ESI+ )m / e[M+H] + :750.33589,C 43 H 47 N3O9.

[0192] CP-81: CP-04 (100 mg, 1 equivalent), 20 mL of dichloromethane, triethylamine (3 equivalents), di(p-nitrobenzene) carbonate (1.2 equivalents) and 4-dimethylaminopyridine (0.1 equivalents) were added to a three-necked flask, stirred at room temperature for 0.5 hours, N-methylpiperazine (1.2 equivalents) was added, and the reaction was continued for 1 hour. After the reaction was completed, the mixture was washed with water twice and with brine once, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product, which was purified by column chromatography to obtain a light yellow powder with a yield of 83%. Light yellow powder, yield 78%. 1 H NMR (400MHz, CDCl3) δ7.36(d,J=8.4Hz,1H),7.04(s,1H),6.95(d,J=6.1Hz,1H),6.77(s,2 H),6.63(s,1H),6.36(s,2H),5.64(s,1H),5.59(d,J=1.1Hz,1H),5.45(s,1H),5.14(ABq,J AB =12.0,2H),4.20(s,1H),3.88(s,3H),3.69(s,3H),3.61(s,1H),3.50(s,4H),3.33(d,J=14.1Hz,1H),3.21–3 .03(m,2H),2.99–2.87(m,2H),2.86–2.69(m,4H),2.66(s,3H),2.56(s,3H),2.48-2.31(m,7H),2.29(s,3H). 13 C NMR (101MHz, CDCl3) δ155.43,152.32,148.83,148.68,146.93,146.51,141.57,139.14,13 8.19,132.57,132.34,131.74,130.60,128.07,127.90,126.51,124.17,123.76,122.30,1 20.99,118.51,116.72,111.02,110.69,108.61,100.70,64.11,61.94,58.97,55.89,55.0 5,54.74,51.22,46.22,45.04,43.91,43.73,42.26,39.68,37.64,28.92,22.81.HRMS(ESI + )m / e[M+H] +:763.36884, C 44 H 50 N4O8.

[0193] 2. Activity Evaluation

[0194] 1. Experimental methods

[0195] 1) Cell virus culture

[0196] Vero E6, an African green monkey kidney cell line, was obtained from the American Type Culture Collection (ATCC, 1586) and cultured in a 37°C, 5% CO2 incubator using DMEM medium (Gibco) containing 10% fetal bovine serum (FBS; Gibco Invitrogen).

[0197] Pangolin coronavirus xCoV (GX_P2V) (GISAID: EPI_ISL_410539) is a strain of the novel coronavirus xCoV isolated and cultured by the inventor from a dead pangolin seized by customs. GX_P2V was propagated in Vero E6 cells, and the virus titer was determined by plaque assay. All infection experiments were performed in a biosafety level 2 (BLS-2) laboratory.

[0198] 2) Cephalothin and its derivatives inhibit the EC of pangolin coronavirus xCoV (GX_P2V) 50 and CC 50 Determination

[0199] EC 50 Detection: 2.5×10 per well 4 Vero E6 cells were inoculated in a 96-well plate and cultured in an incubator at 37°C and 5% CO2 for 24 hours. Then, different final concentrations of cephalothin or cephalothin derivatives (2-fold gradient dilution) were added to the cell culture wells, and the cells were infected with viruses (MOI = 0.01). After 2 hours of infection, the cells were washed 3 times with PBS and the medium containing the same concentration of cephalothin or cephalothin derivatives was added, and cultured in an incubator at 37°C and 5% CO2. At 48 hours after virus infection, the cell supernatant was discarded, the cells were washed with PBS, cell lysis solution was added to the cells, the nucleic acid in the cells was collected, and the expression of viral RNA and the reference gene GAPDH in the cells was quantitatively detected by qRT-PCR. GraphPad-Prism 8 software was used for data analysis and calculation of EC 50 .

[0200] CC 50 Detection: CC using CellTiter-Blue method 50Vero E6 cells were inoculated into 96-well cell culture plates and the test was performed when the cell density reached 60%-80%. After the Vero E6 cells were replaced with diluted drugs (with a concentration similar to EC 50 The cells were cultured at 37°C and 5% CO2 for 48 h, and the fluorescence intensity was detected using CellTiter-Blue reagent, with an excitation wavelength of 554 nm and an emission wavelength of 593 nm. GraphPad-Prism 8 software was used to analyze the data and calculate CC 50 .

[0201] 3) Virus sample processing and detection

[0202] Total RNA was extracted using a cell / tissue RNA extraction kit (Beijing Nobel Biotechnology Co., Ltd., R11202109JN) according to the manufacturer's instructions. Reverse transcription used the Hifair II 1st strand cDNA synthesis kit that can digest gDNA (Shanghai Yisheng Biotechnology, Cat. No.: 11121ES60), qRT-PCR used Quantstudio real-time PCR detection reagent (Applied biosystems, Foster City, CA, USA), and SYBR-Green method qPCR amplification: 95°C 5min, 40 cycles, 95°C 10s, 55°C 20s, 72°C 31s. Normalization was achieved by detecting the GAPDH gene.

[0203] (II) Experimental results

[0204] The antiviral activity and cytotoxicity of the derivatives and cepharanthin in Examples 1-13 were tested, and the results are shown in Figure 1-13 .

[0205] Depend on Figure 1 It can be seen that the cephalothin derivatives CP-01, CP-02, CP-04 and CP-05 synthesized in Examples 1, 2, 4 and 5 have good inhibitory effects on the GX_P2V virus and have a dose-dependent effect.

[0206] Depend on Figure 2 It can be seen that the cephalothin derivatives CP-43, CP-44, CP-45, CP-46, CP-47, CP-50, CP-51 and CP-52 synthesized in Example 6 have good inhibitory effects on the GX_P2V virus and have a dose-dependent effect.

[0207] Depend on Figure 3It can be seen that the cephalothin derivatives CP-21, CP-22, CP-23, CP-24, CP-25, CP-204, CP-207, CP-208, CP-209, CP-210, CP-211, CP-212, CP-213, CP-215 and CP-221 synthesized by method 1 in Example 7 have good inhibitory effects on GX_P2V virus and have a dose-dependent effect.

[0208] Depend on Figure 4 It can be seen that the cephalothin derivatives CP-201, CP-202, CP-203, CP-216, CP-217 and CP-218 synthesized according to method 2 using CP-02 and the corresponding organic acid as raw materials in Example 7 have good inhibitory effects on GX_P2V virus and have a dose-dependent effect.

[0209] Depend on Figure 5 It can be seen that the cephalothin derivatives CP-222, CP-223, CP-224, CP-225, CP-229, CP-230, CP-234, CP-237, CP-239 and CP-240 synthesized by method 2 in Example 7 have good inhibitory effects on GX_P2V virus and have a dose-dependent effect.

[0210] Depend on Figure 6 It can be seen that the cephaladin derivatives CP-26, CP-27, CP-28, CP-205, CP-206, CP-214 and CP-242 synthesized with CP-02 and the corresponding amine as raw materials in Example 8, and CP-206 synthesized with CP-02 and dimethylthiocarbamoyl chloride as raw materials have good inhibitory effects on the GX_P2V virus and have a dose-dependent effect.

[0211] Depend on Figure 7 It can be seen that the cephalothin derivatives CP-61, CP-62, CP-63 and CP-67 synthesized according to method 1 in Example 9 have good inhibitory effects on the GX_P2V virus and have a dose-dependent effect.

[0212] Depend on Figure 8 It can be seen that the cephaladin derivatives CP-69, CP-70, CP-71 and CP-73 synthesized according to method 2 in Example 9 have good inhibitory effects on the GX_P2V virus and have a dose-dependent effect.

[0213] Depend on Fig. 9 It can be seen that the 5-carbon substituted ether cephalaenopsis derivatives CP-65 and CP-72 synthesized in Example 10 have good inhibitory effects on the GX_P2V virus and have a dose-dependent effect.

[0214] Depend on Fig.10 It can be seen that the 5-carbon substituted thioether cephalaenopsis derivative CP-68 synthesized in Example 11 has a good inhibitory effect on the GX_P2V virus and has a dose-dependent effect.

[0215] Depend on Fig.11 It can be seen that the 5-carbon substituted ester cephaladin derivatives CP-82 and CP-83 synthesized in Example 12 have good inhibitory effects on the GX_P2V virus and have a dose-dependent effect.

[0216] Depend on Fig.12 It can be seen that the 5-carbon substituted carbamate cephaladin derivatives CP-80 and CP-81 synthesized in Example 13 have good inhibitory effects on the GX_P2V virus and have a dose-dependent effect.

[0217] Depend on Fig.13 It can be seen that the raw material cephalothin has a good inhibitory effect on GX_P2V virus and has a dose-dependent effect.

[0218] Research on live SARS-CoV-2 virus requires higher-level biocontainment facilities, which conflicts with the urgent need of current research. In this application, the inventor used the pangolin coronavirus strain GX_P2V to evaluate the activity of cephalothin derivatives, and also achieved the study of the anti-SARS-CoV-2 activity of cephalothin derivatives while ensuring safety. The reliability of the drug evaluation model has been verified by a large amount of experimental data, ensuring the authenticity of the content of the present invention.

[0219] In the present application, experimental data show that the synthesized various cephalaenopsis derivatives all have significant inhibitory activity against coronaviruses, among which compounds CP-01, CP-02, CP-04, CP-05, CP-22, CP-24, CP-25, CP-26, CP-27, CP-28, CP-43, CP-47, CP-63, CP-69, CP-70, CP-71, CP-72, CP-203, CP-205, CP-206, CP-209, CP-210, CP-214, CP-216, CP-234, CP-239 and CP-240 have better antiviral activity than cephalaenopsis.

[0220] The cytotoxicity of compounds CP-21, CP-22, CP-23, CP-24, CP-25, CP-26, CP-27, CP-28, CP-44, CP-45, CP-50, CP-51, CP-52, CP-61, CP-62, CP-65, CP-67, CP-68, CP-72, CP-81, CP-82, CP-83, CP-201, CP-202, CP-203, CP-204, CP-207, CP-212, CP-214, CP-215, CP-216, CP-217, CP-221, CP-222, CP-223, CP-224, CP-225, and CP-240 are lower than that of cephalothin.

[0221] The selectivity index of compounds CP-22, CP-24, CP-25, CP-26, CP-27, CP-28, CP-45, CP-65, CP-70, CP-72, CP-82, CP-201, CP-202, CP-203, CP-204, CP-206, CP-207, CP-210, CP-214, CP-215, CP-216, CP-222, CP-225, and CP-240 is higher than that of cephalothin, and the above drugs have higher drug potential than cephalothin.

[0222] In addition, the present application also selected two derivatives, CP-25 and CP-26, whose antiviral activity and cytotoxicity are less than that of cephalothin and whose selectivity index is greater than that of cephalothin, to verify their in vivo antiviral activity. They still have a significant effect of inhibiting GX_P2V virus infection in vivo.

[0223] The above results indicate that the above-mentioned cephalothin derivatives are all potential drugs for treating SARS-CoV-2 infectious diseases. The cephalothin derivatives have potential clinical application value for the currently popular new coronavirus and other coronavirus infections caused by the disease. In view of the fact that a large number of cephalothin derivatives have been observed to have a strong inhibitory effect on the virus, the inventors believe that the cephalothin derivatives of the present invention have significant medicinal value as potential drugs for treating SARS-CoV-2 and other coronavirus infections, and are a promising candidate drug for treating SARS-CoV-2 virus and other coronavirus infectious diseases.

[0224] The above is an explanation of the embodiments of the present invention. However, the present invention is not limited to the above embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A cephalaenopsis derivative or a pharmaceutically acceptable salt thereof represented by formula I: R is selected from halogen, R1 is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 1-8 Alkyl, C 3-6 Cycloalkyl, -C 1-8 Alkyl OC 1-8 Alkyl, halogenated C 1-8 Alkyl, halogenated C 1-8 Alkoxy, C 2-6 Alkenyl, cyano C 1-8 Alkyl-, C 3-6 Cycloalkyl C 1-8 Alkyl-, 3-6 membered heterocyclic group C 1-8 Alkyl-, C 6-14 Aryl and 5-14 membered heteroaryl; said R b The same or different, independently selected from the following groups: C 1-8 Alkoxy, halogen, hydroxyl, halogenated C 1-8 alkyl; R2 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: C 1-8 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-8 Alkyl, C 1-8 Alkoxy, -C 1-8 Alkyl OC 1-8 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, N(C 1-8 Alkyl)2, C 6-14 Aryl and 5-14 membered heteroaryl; said R c The same or different, independently selected from the following groups: C 1-8 Alkyl, halogen, halogenated C 1-8 Alkyl, amino, cyano, aldehyde, carboxyl, NHC 1-8 Alkyl, N(C 1-8 Alkyl)2, nitro, C 1-8 Alkoxy, hydroxyl, -SO3H, -SO3C 1-8 Alkyl, -COC 1-8 alkyl; R3 and R4 are the same or different and are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, N(C 1-8 Alkyl)2, C 6-14 Aryl and 5-14 membered heteroaryl; R5 is selected from C 1-8 alkyl; R6 is selected from unsubstituted or optionally substituted with one, two or more R d Substituted with the following groups: C 1-8 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-8 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, N(C 1-8 Alkyl)2, C 6-14 Aryl or 5-14 membered heteroaryl; said R d The same or different, independently selected from the following groups: C 1-8 Alkyl, halogen, halogenated C 1-8 Alkyl, amino, cyano, aldehyde, carboxyl, NHC 1-8 Alkyl, N(C 1-8 Alkyl)2, nitro, C 1-8 Alkoxy, hydroxyl, -SO3H, -SO3C 1-8 Alkyl, -COC 1-8 alkyl; R7 and R8 are the same or different and are independently selected from C 1-8 alkyl; R9 is selected from halogen, OH, unsubstituted or optionally substituted by one, two or more R e Substituted with the following groups: C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 1-8 Alkoxy, -COO-C 1-8 Alkyl, -COO-C 3-6 Cycloalkyl, -COO-3-6 membered heterocyclic group, -COO-C 6-14 Aryl or -COO-5-14 membered heteroaryl, R 10 , R 11 The same or different, each independently selected from C 1-8 Alkyl, -C 1-8 Alkyl-OH or C 6-14 Aryl; R 12 Selected from C 1-8 Alkyl, C 6-14 Aryl; R 13 Selected from C 1-8 Alkyl, C 6-14 Aryl, -C 1-8 Alkyl-C 6-14 Aryl; R 14 , R 15 The same or different, each independently selected from C 1-8 alkyl.

2. The cephalaenopsis derivative of formula I or a pharmaceutically acceptable salt thereof according to claim 1, wherein: R is selected from halogen, R1 is selected from unsubstituted or optionally substituted with one, two or more R b Substituted with the following groups: C 1-6 Alkyl, C 3-6 Cycloalkyl, -C 1-6 Alkyl OC 1-6 Alkyl, halogenated C 1-6 Alkyl, halogenated C 1-6 Alkoxy, C 2-6 Alkenyl, cyano C 1-6 Alkyl-, C 3-6 Cycloalkyl C 1-6 Alkyl-, 3-6 membered heterocyclic group C 1-6 Alkyl-, C 6-14 Aryl and 5-14 membered heteroaryl; said R b The same or different, independently selected from the following groups: C 1-6 Alkoxy, halogen, hydroxyl, halogenated C 1-6 alkyl; R2 is selected from unsubstituted or optionally substituted with one, two or more R c Substituted with the following groups: C 1-6 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 1-6 Alkoxy, -C 1-6 Alkyl OC 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, N(C 1-6 Alkyl)2, C 6-14 Aryl and 5-14 membered heteroaryl; said R c The same or different, independently selected from the following groups: C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, amino, cyano, aldehyde, carboxyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, nitro, C 1-6 Alkoxy, hydroxyl, -SO3H, -SO3C 1-6 Alkyl, -COC 1-6 alkyl; R3 and R4 are the same or different and are independently selected from C 1-6 Alkyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, N(C 1-6 Alkyl)2, C 6-14 Aryl and 5-14 membered heteroaryl; R5 is selected from C 1-6 alkyl; R6 is selected from unsubstituted or optionally substituted with one, two or more R d Substituted with the following groups: C 1-6 Alkyl, C 3-6 Cycloalkyl, halogenated C 1-6 Alkyl, C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, N(C 1-6 Alkyl)2, C 6-14 Aryl or 5-14 membered heteroaryl; said R d The same or different, independently selected from the following groups: C 1-6 Alkyl, halogen, halogenated C 1-6 Alkyl, amino, cyano, aldehyde, carboxyl, NHC 1-6 Alkyl, N(C 1-6 Alkyl)2, nitro, C 1-6 Alkoxy, hydroxyl, -SO3H, -SO3C 1-6 Alkyl, -COC 1-6 alkyl; R7 and R8 are the same or different and are independently selected from C 1-6 alkyl; R9 is selected from halogen, OH, unsubstituted or optionally substituted by one, two or more R e Substituted with the following groups: C 3-6 Cycloalkyl, 3-6 membered heterocyclic group, C 1-6 Alkoxy, -COO-C 1-6 Alkyl, -COO-C 3-6 Cycloalkyl, -COO-3-6 membered heterocyclic group, -COO-C 6-14 Aryl or -COO-5-14 membered heteroaryl, R 10 , R 11 The same or different, each independently selected from C 1-6 Alkyl, -C 1-6 Alkyl-OH or C 6-14 Aryl; R 12 Selected from C 1-6 Alkyl, C 6-14 Aryl; R 13 Selected from C 1-6 Alkyl, C 6-14 Aryl, -C 1-6 Alkyl-C 6-14 Aryl; R 14 , R 15 The same or different, each independently selected from C 1-6 alkyl.

3. The cephalaenopsis derivative of formula I or a pharmaceutically acceptable salt thereof according to claim 1 or 2, wherein: R1 is selected from trifluoroethyl, methyl, isopropyl, CH3OC2H4-, 2-fluoroethyl, 3-propenyl, fluoromethyl, ethyl, CNCH2-, cyclopropylmethyl; R2 is selected from methyl, n-heptyl, vinyl, cyclopropyl, 2-thienyl, N,N-dimethyl, N-morpholinyl, 4-methylpiperazinyl, 3-pyridyl, 2-furyl, 3-chloro-2-thienyl, 3-thienyl, 2-benzothiophene, N,N-diethyl, 4-N,N-dimethylphenyl, 3-pyridyl, 4-pyridyl, 4-tetrahydro-2H-pyranyl, 2-bromoisopropyl, cyclobutyl, piperidinyl, phenyl, 2-trifluoromethoxyphenyl, 2,5-ditrifluoromethoxyphenyl, CH3OCH2-, N-pyrrolidinyl, 4-methyl-2-thienyl, 4-bromo-2-thienyl, 3-chloro-2-thienyl, 2-chloro-3-thienyl, or the following radicals: R5 is selected from n-pentyl; R6 is selected from methyl, 4-methylphenyl, 2-thienyl; R7 and R8 are selected from methyl; R9 is selected from halogen, hydroxyl, methoxy, or the following groups:

4. The cephalaenopsis derivative or a pharmaceutically acceptable salt thereof represented by formula I according to any one of claims 1 to 3, wherein: The cephalaenopsis derivative or its pharmaceutically acceptable salt shown in formula I is selected from the following structures:

5. The cephalaenopsis derivative of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein: The pharmaceutically acceptable salt is selected from the acid addition salt of the nitrogen atom with sufficient basicity in the structure of the cepharanthin derivative, and the acid addition salt includes the cepharanthin derivative and an inorganic acid such as hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, pyrosulfuric acid, phosphoric acid or nitric acid; an organic acid such as formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, salts formed by succinic acid, pectinic acid, persulfuric acid, 3-phenylpropionic acid, picric acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, sulfamic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, hemisulfuric acid or thiocyanic acid.

6. Use of at least one of the cephalaenopsis derivatives of formula I or pharmaceutically acceptable salts thereof according to any one of claims 1 to 5 in the preparation of a medicament for preventing, alleviating and / or treating diseases caused by coronavirus infection.

7. The use according to claim 6, wherein The disease caused by the coronavirus infection is the new coronavirus infection.

8. A composition comprising at least one of the cephalaenopsis derivatives or pharmaceutically acceptable salts thereof according to any one of claims 1 to 5.

9. The composition according to claim 8, wherein The composition is configured into tablets, capsules, granules, syrups for oral administration or powder injections and solutions for injection.

10. The composition according to claim 8, wherein The composition is medicine, food, skin care product, cosmetics, daily necessities and health care products.

Images