Novel coronavirus inhibitor, pharmaceutical composition containing the same and use thereof

Abstract

The present invention relates to a novel coronavirus inhibitor, a pharmaceutical composition containing the same, and uses thereof. The inhibitor of the present invention has better activity in inhibiting the novel coronavirus and lower cytotoxicity, that is, has higher safety, and can be used to prevent and / or treat diseases caused by SARS-CoV-2 infection, such as novel coronavirus pneumonia.

Description

Technical Field

[0001] The present invention relates to compounds for treating novel coronavirus (SARS-CoV-2) infection, pharmaceutical compositions containing the compounds, and uses thereof. Background Art

[0002] Novel coronavirus pneumonia (COVID-19) is caused by infection with the novel coronavirus (SARS-CoV-2). The novel coronavirus spreads quickly, infects a wide range of people, and is difficult to prevent and control. The novel coronavirus is spread through droplet transmission and aerosol transmission. The clinical symptoms after infection generally include fever, dry cough, sore throat, dyspnea, nausea, vomiting, etc., while severe patients are accompanied by acute respiratory distress syndrome, sepsis, and multiple organ failure. Diagnostics have found that mild patients have decreased lymphocytes, decreased leukocytes, and increased CRP, while severe patients have increased transaminase and lactate dehydrogenase.

[0003] Based on phylogenetic and taxonomic considerations and established conventions, the International Committee on Taxonomy of Viruses classifies SARS-CoV-2 as the genus Beta of the family Coronaviridae of the order Nidovirales. The coronaviruses that have been found to infect humans include HCoV-229E and HCoV-NL63 of the alpha genus and HCoV-HKU1, HCoV-OC43, MERS-CoV, SARA-CoV and SARS-CoV-2 of the beta genus. In addition to SARS-CoV, MERS-CoV and SARS-CoV-2, which are highly pathogenic viruses, other human coronaviruses may have been circulating in humans for a long time, but usually only cause relatively mild respiratory diseases.

[0004] SARS-CoV-2 is a single-stranded positive-sense RNA virus with a genome of about 30kbp, the largest genome among RNA viruses. SARS-CoV-2 is spherical or elliptical, with a diameter of 80-120nm. Under an electron microscope, the virus surface has a rod-shaped protrusion, which is composed of a trimeric spike protein (S), divided into a large extracellular domain and a small intracellular domain; the viral envelope is composed of a membrane protein (M) containing three transmembrane structures, interspersed with some transmembrane envelope proteins (E), and the genomic RNA is wrapped by the nucleocapsid protein (N) to form a spiral, which is further surrounded by the envelope. The genome from the 5' end to the 3' end is: 5' cap structure-leader-UTR-replicase-SEMN-URT-3'polyA. The methylated cap structure and polyadenylic acid (Poly adenine, poly A) at both ends allow it to be used as mRNA to directly translate the protein of the replicase domain. There are at least 11 open reading frames (ORFs) on the genome, of which the upstream ORF1a and ORF1b contain replicase domain genes, about 20kbp, accounting for 66% of the entire genome, encoding non-structural proteins, and the downstream is the genome encoding structural proteins and auxiliary proteins, about 10kbp, and the auxiliary protein genes are interspersed in the structural protein genome. The two ends of the open reading frame are the untranslated regions 5'UTR and 3'UTR. The 5'UTR is an important structure for genome replication and transcription, and the 3'UTR can regulate genome replication and transcription. The upstream of the replicase domain gene contains a leader sequence.

[0005] The process of SARS-CoV-2 infecting host cells is divided into five steps: virus entry, expression of replicase genes, replication, transcription and translation of the genome, and assembly and release of progeny viruses. Its host cells are mainly type II lung epithelial cells. The path to enter the target cell is that the S protein specifically binds to the ACE2 receptor on the surface of the host cell, inducing the protease TMPRSS2 to hydrolyze the S protein, the S protein is activated, the viral envelope fuses with the cytoplasmic membrane, and quickly enters the host cell through the endocytosis of the lipid membrane, the fusion of vesicles and virus particles, and the viral genome is released into the cytoplasm. After the virus enters the host cell, the endolysosome digestion of the viral nucleocapsid protein is initiated, and the viral RNA is released. The viral genomic RNA can be used as mRNA, translated and frameshifted to produce precursor polyproteins pp1a and pp1ab, which are further hydrolyzed by the main protease and papain-like protease into non-structural proteins required for viral replication and transcription. Under the action of the viral replicase, the viral genomic RNA uses itself as a template to synthesize full-length antisense RNA, and the antisense RNA uses itself as a template to synthesize new genomic RNA. The polymerase can switch templates during discontinuous transcription at specific sites of genomic RNA, produce 5' nested antisense sgRNA, and use it as a template to synthesize 3' nested positive sgRNA, thereby translating structural proteins and auxiliary proteins. The S protein, E protein and M protein are transferred from the endoplasmic reticulum to the endoplasmic reticulum-Golgi intermediate complex. The N protein forms a nucleocapsid and encapsulates the progeny viral RNA. On the ERGIC, the E protein promotes the M protein to form a viral envelope and assemble into mature virions, which are transported to the cytoplasmic membrane via the Golgi apparatus and secretory vesicles and released outside the host cell by exocytosis.

[0006] The immune response mainly occurs in capillaries. At the innate immune level, the type I interferon response is delayed or suppressed during the initial infection, viral replication triggers hyperinflammatory response and cytokine storm, activated neutrophils and inflammatory monocytes / macrophages increase, and serum neutrophils and elevated proinflammatory cytokines are associated with the severity of the disease. In terms of adaptive immune response, helper T cells Th1 / Th17 are activated, IgA, IgM and IgG are usually detectable within two weeks of infection, and lymphocytopenia may be related to bone marrow suppression.

[0007] Since the beginning of 2020, there have been hopes of finding effective compounds that can inhibit the new coronavirus. Summary of the invention

[0008] The present invention provides an effective inhibitor for the SARS-CoV-2 virus, and also provides a pharmaceutical composition containing the inhibitor and uses thereof.

[0009] According to the first aspect of the present invention, the present invention relates to a compound of the following formula I or a pharmaceutically acceptable salt thereof:

[0010]

[0011] in:

[0012] R1 represents ZYX-,

[0013] X represents a bond; or, O;

[0014] Y represents a bond; or, C 1-10 Straight or branched chain alkylene, C 2-10 Straight or branched chain alkenylene or C 2-10 Straight-chain or branched alkynylene, wherein the alkylene, alkenylene or alkynylene is unsubstituted or substituted with one or more halogens;

[0015] Z stands for H; C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, S, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted by 1 or more independently selected from halogen, C 1-10 Straight or branched alkyl, C 2-10 Straight-chain or branched alkenyl, C 2-10 Straight-chain or branched alkynyl, C 1-10 linear or branched alkyloxy, hydroxyl, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy; or 6-10 Aryl or 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, S, wherein the aryl or heteroaryl is unsubstituted or substituted by 1 or more independently selected from halogen, C 1-10 Straight or branched alkyl, C 2-10 Straight-chain or branched alkenyl, C 2-10 Straight-chain or branched alkynyl, C 1-10 Straight-chain or branched alkyloxy, unsubstituted or C 1-6 Alkyl substituted phenyl, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy;

[0016] Provided that, when Y is a bond, Z is not H;

[0017] R2 represents phenyl, C 1-10 Straight chain or branched chain alkylene phenyl, C 2-10 Straight chain or branched alkenylene phenyl or C 2-10 A straight chain or branched alkynylene phenyl group, wherein the phenyl group is unsubstituted or substituted by one or more independently selected from halogen, C 1-10 Straight or branched alkyl, C 2-10 Straight-chain or branched alkenyl, C 2-10 Straight-chain or branched alkynyl, C 1-10 Substitution with linear or branched alkyloxy, hydroxy, amino, cyano, nitro, trifluoromethyl, or trifluoromethoxy groups;

[0018] R3 represents hydrogen; C 1-10 Straight or branched alkyl, C 2-10 Straight or branched alkenyl or C 2-10 Straight or branched alkynyl, wherein the alkyl, alkenyl or alkynyl is unsubstituted or substituted by one or more halogens; C 3-10 Cycloalkyl, C 1-10 Straight or branched alkylene C 3-10 Cycloalkyl, C 2-10 Straight or branched alkenylene C 3-10 Cycloalkyl, C 2-10 Straight or branched chain alkynylene C 3-10 Cycloalkyl, phenyl, C 1-10 Straight chain or branched chain alkylene phenyl, C 2-10 Straight chain or branched alkenylene phenyl or C 2-10 A straight chain or branched alkynylene phenyl, wherein the cycloalkyl or phenyl is unsubstituted or substituted by one or more independently selected from halogen, C 1-10 Straight or branched alkyl, C 2-10 Straight-chain or branched alkenyl, C 2-10 Straight-chain or branched alkynyl, C 1-10 Substitution with linear or branched alkyloxy, hydroxy, amino, cyano, nitro, trifluoromethyl, or trifluoromethoxy groups;

[0019] R4 represents -CHO.

[0020] In a preferred embodiment, in the compound of formula I:

[0021] R1 represents ZYX-,

[0022] X represents a bond; or, O;

[0023] Y represents a bond; or, C 1-6 Straight or branched chain alkylene, C 2-6 Straight or branched alkenylene, or C 2-6 Straight or branched alkynylene, wherein the alkylene, alkenylene or alkynylene is unsubstituted or substituted with 1 to 3 fluorine groups;

[0024] Z stands for H; C 3-10 Cycloalkyl or 3-10 membered heterocycloalkyl containing 1 heteroatom selected from N, O, S, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted by 1-3 independently selected from halogen, C 1-6 Straight or branched alkyl, C 2-6 Straight-chain or branched alkenyl, C 2-6 Straight-chain or branched alkynyl, C 1-6 linear or branched alkyloxy, hydroxyl, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy; or6-10 aryl or a 5-10 membered heteroaryl containing 1-3 heteroatoms independently selected from N, O, S, wherein the aryl or heteroaryl is unsubstituted or substituted by 1-3 heteroatoms independently selected from halogen, C 1-6 Straight or branched alkyl, C 2-6 Straight-chain or branched alkenyl, C 2-6 Straight-chain or branched alkynyl, C 1-6 Substitution with linear or branched alkyloxy, phenyl, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy groups;

[0025] Provided that, when Y is a bond, Z is not H;

[0026] R2 represents phenyl, C 1-6 Straight chain or branched chain alkylene phenyl, C 2-6 Straight chain or branched alkenylene phenyl or C 2-6 A straight chain or branched alkynylene phenyl group, wherein the phenyl group is unsubstituted or substituted by 1-3 groups independently selected from halogen, C 1-6 Straight or branched alkyl, C 2-6 Straight-chain or branched alkenyl, C 2-6 Straight-chain or branched alkynyl, C 1-6 Substitution with linear or branched alkyloxy, hydroxy, amino, cyano, nitro, trifluoromethyl, or trifluoromethoxy groups;

[0027] R3 represents hydrogen; methyl, n-propyl, C 4-6 Straight or branched alkyl, C 4-6 Straight or branched alkenyl or C 4-6 Straight or branched alkynyl, the alkyl, alkenyl or alkynyl being unsubstituted or substituted by 1-3 fluorine groups; C 3-10 Cycloalkyl, C 1-6 Straight or branched alkylene C 3-10 Cycloalkyl, C 2-6 Straight or branched alkenylene C 3-10 Cycloalkyl, C 2-6 Straight or branched chain alkynylene C 3-10 Cycloalkyl, phenyl, C 1-6 Straight chain or branched chain alkylene phenyl, C 2-6 Straight chain or branched alkenylene phenyl or C 2-6 A straight chain or branched alkynylene phenyl, wherein the cycloalkyl or phenyl is unsubstituted or substituted by 1-3 independently selected from halogen, C 1-6 Straight or branched alkyl, C 2-6 Straight-chain or branched alkenyl, C 2-6 Straight-chain or branched alkynyl, C 1-6 Substitution with linear or branched alkyloxy, hydroxy, amino, cyano, nitro, trifluoromethyl, or trifluoromethoxy groups;

[0028] R4 represents -CHO.

[0029] In a preferred embodiment, in the compound of formula I:

[0030] R1 represents ZYX-,

[0031] X represents a bond; or, O;

[0032] Y represents a bond; or, C1-3 straight chain or branched chain alkylene, C2-3 straight chain or branched chain alkenylene;

[0033] Z represents H; cyclohexyl or a 6-membered heterocycloalkyl containing 1 heteroatom selected from N, O, S, wherein the cycloalkyl or heterocycloalkyl is unsubstituted or substituted by 1-3 groups independently selected from halogen, methyl, methoxy, hydroxyl, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy; or, phenyl, naphthyl, pyrrolyl, furanyl, thienyl, indolyl, pyridyl, isoxazolyl, pyrimidinyl, wherein the substituent is unsubstituted or substituted by 1-3 groups independently selected from halogen, methyl, methoxy, phenyl, hydroxyl, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy;

[0034] Provided that, when Y is a bond, Z is not H;

[0035] R2 means C 1-3 Straight-chain or branched alkylenephenyl, the phenyl being unsubstituted or substituted by one group selected from halogen, methyl, methoxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy;

[0036] R3 represents hydrogen; methyl, n-propyl, C 4-6 Straight or branched chain alkyl; C 1-3 Straight or branched alkylene cyclohexyl or C 1-3 Straight-chain or branched alkylenephenyl, wherein the cyclohexyl or phenyl is unsubstituted or substituted by one group selected from halogen, methyl, methoxy, hydroxy, amino, cyano, nitro, trifluoromethyl, trifluoromethoxy;

[0037] R4 represents -CHO.

[0038] In a preferred embodiment, in the compound of formula I:

[0039] R1 represents ZYX-,

[0040] X represents a bond; or, O;

[0041] Y represents a bond; or, CH2, CH=CH;

[0042] Z represents a cyclohexyl group or a 6-membered heterocycloalkyl group containing 1 O atom, wherein the cyclohexyl group or heterocycloalkyl group is unsubstituted or substituted by 1 or 2 groups independently selected from halogen, methyl, methoxy, and nitro; or, phenyl, naphthyl, pyrrolyl, furanyl, thienyl, indolyl, pyridyl, isoxazolyl, pyrimidinyl, wherein the substituent is unsubstituted or substituted by 1 or 2 groups independently selected from halogen, methyl, vinyl, methoxy, phenyl, and nitro;

[0043] R2 represents methylenephenyl or ethylenephenyl, wherein the phenyl is unsubstituted or substituted by a group selected from halogen, methoxy, nitro, trifluoromethyl at the ortho, meta or para position of the methylene or ethylene;

[0044] R3 represents methyl, n-propyl, n-butyl, isobutyl, sec-butyl, tert-butyl; methylene cyclohexyl or methylene phenyl, wherein the cyclohexyl or phenyl is unsubstituted or substituted by a group selected from halogen at the ortho-position, meta-position or para-position of the methylene;

[0045] R4 represents -CHO.

[0046] In a preferred embodiment, the compound of formula I

[0047] R1 is selected from pentyl, phenyl, vinylene phenyl, methylene phenyl, -O-methylene phenyl, phenylene phenyl, naphthyl, pyrrolyl, furanyl, thienyl, indolyl, methylene indolyl, pyridyl, isoxazolyl, cyclohexane, tetrahydropyran, and the substituents are unsubstituted or substituted with 1 or 2 groups independently selected from fluorine, chlorine, bromine, methyl, vinyl, methoxy, and nitro;

[0048] R2 is selected from methylenephenyl, wherein the phenyl is unsubstituted or substituted by a group selected from fluorine, chlorine, bromine, methoxy, nitro, trifluoromethyl at the ortho, meta or para position of the methylene;

[0049] R3 is selected from isobutyl; methylene cyclohexyl or methylene phenyl, wherein the cyclohexyl or phenyl is unsubstituted or substituted by one fluorine at the ortho, meta or para position of the methylene;

[0050] R4 represents -CHO.

[0051] In a preferred embodiment, the compound of formula I is selected from:

[0052]

[0053]

[0054]

[0055] Definitions of terms in this invention:

[0056] In the present invention, "halogen" refers to fluorine, chlorine, bromine, and iodine;

[0057] In the present invention, “C 1-10 The term "straight-chain or branched alkyl" refers to a straight-chain or branched alkyl group having 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, etc. This definition also applies to the corresponding alkyl groups having fewer carbon atoms, such as C 1-6 Straight-chain or branched alkyl, etc., and the corresponding alkyl in other more complex substituents, such as C 1-10 Straight chain or branched chain alkyloxy, etc.;

[0058] In the present invention, “C 2-10 The term "straight-chain or branched alkenyl" refers to a straight-chain or branched alkenyl group having 2 to 10 carbon atoms, such as vinyl, allyl, propenyl, etc. This definition also applies to the corresponding alkenyl group having fewer carbon atoms, such as C 2-6 Straight chain or branched chain alkenyl, etc.;

[0059] In the present invention, “C 2-10 The term "straight-chain or branched alkynyl" refers to a straight-chain or branched alkynyl group having 2 to 10 carbon atoms, such as ethynyl, propargyl, propynyl, etc. This definition also applies to the corresponding alkynyl groups having fewer carbon atoms, such as C 2-6 Straight chain or branched chain alkynyl, etc.

[0060] In the present invention, “C 1-10 The term "straight-chain or branched alkylene" refers to a straight-chain or branched alkylene group having 1 to 10 carbon atoms, such as methylene, ethylene, n-propylene, isopropylene, and n-butylene. This definition also applies to the corresponding alkylene groups having fewer carbon atoms, such as C 1-6 Straight-chain or branched alkylene, etc., and the corresponding alkylene in other more complex substituents, such as C 1-10 Straight chain or branched chain alkylene phenyl, etc.;

[0061] In the present invention, “C 2-10 The term "straight-chain or branched alkenylene" refers to a straight-chain or branched alkenylene group having 2 to 10 carbon atoms, such as vinylene, allylene, propenylene, etc. This definition also applies to the corresponding alkenylene groups having fewer carbon atoms, such as C 2-6 Straight-chain or branched alkenylene, etc., and the corresponding alkenylene in other more complex substituents, such as C 2-10 Straight-chain or branched alkenylene phenyl, etc.;

[0062] In the present invention, “C 2-10The term "straight-chain or branched alkynylene" refers to a straight-chain or branched alkynylene group having 2 to 10 carbon atoms, such as ethynylene, propargylene, propynylene, etc. This definition also applies to the corresponding alkynylene group having fewer carbon atoms, such as C 2-6 Straight-chain or branched alkynylene, etc., and the corresponding alkynylene in other more complex substituents, such as C 2-10 Straight-chain or branched alkynylene phenyl, etc.;

[0063] In the present invention, “C 3-10 "Cycloalkyl" refers to a cycloalkyl group having 3 to 10 carbon atoms, including a single ring or a condensed ring, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl, etc.;

[0064] In the present invention, "3-10 membered heterocycloalkyl containing 1-3 heteroatoms independently selected from N, O, and S" refers to a 3-10 membered heterocycloalkyl having 1, 2, or 3 heteroatoms independently selected from N, O, and S, including a monocyclic or condensed ring connected through a ring carbon atom or a ring nitrogen atom of the heterocycloalkyl, such as tetrahydrofuranyl, pyrrolidinyl, tetrahydropyranyl, etc.;

[0065] In the present invention, “C 6-10 The term "aryl" refers to an aromatic group having 6 to 10 carbon atoms, including a single ring or a condensed ring, such as phenyl, naphthyl, and the like.

[0066] In the present invention, "a 5-10 membered heteroaryl group containing 1-3 heteroatoms independently selected from N, O, and S" refers to a 5-10 membered heteroaryl group having a single ring or a condensed ring, having 1, 2, or 3 heteroatoms independently selected from N, O, and S, which is connected through a ring carbon atom or a ring nitrogen atom of the heteroaryl group, such as pyrrole, furan, thiophene, imidazole, pyrazole, thiazole, oxazole, isoxazole, 1,2,3-triazole, 1,2-thiadiazole, pyridine, pyrazine, pyrimidine, 1,2,4-triazine, indole, benzoxazole, benzothiazole, quinoline, etc.;

[0067] In the present invention, "alkylenephenyl" refers to a phenyl group connected via an alkylene group. This definition also applies to other similar groups, such as C 1-10 Straight or branched alkylene C 3-10 Cycloalkyl, etc.

[0068] According to the present invention, pharmaceutically acceptable salts refer to pharmaceutically acceptable salts formed by the compound of formula I and inorganic or organic acids. Inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc., and organic acids include formic acid, acetic acid, propionic acid, valeric acid, trifluoroacetic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, naphthalene disulfonic acid, malonic acid, maleic acid, succinic acid, fumaric acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, benzoic acid, etc.

[0069] The compound of formula I of the present invention or a pharmaceutically acceptable salt thereof can inhibit SARS-CoV-2, and thus can be used to prevent and / or treat diseases caused by SARS-CoV-2 infection, such as novel coronavirus pneumonia, and can be used alone or simultaneously with other compounds for treating diseases caused by SARS-CoV-2 infection.

[0070] According to the second aspect of the present invention, the present invention relates to a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0071] In a preferred embodiment, the pharmaceutical composition of the present invention further comprises other compounds for treating diseases caused by SARS-CoV-2 infection.

[0072] According to the third aspect of the present invention, the present invention relates to a method for preventing and / or treating diseases caused by SARS-CoV-2 infection in mammals, by administering a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of the present invention to the mammal.

[0073] In a preferred embodiment, the prevention and / or treatment method of the present invention further administers other compounds for treating diseases caused by SARS-CoV-2 infection to mammals. Other compounds for treating diseases caused by SARS-CoV-2 infection may be administered before, simultaneously with, or after administration of the compounds or compositions of the present invention.

[0074] According to the fourth aspect of the present invention, the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating diseases caused by SARS-CoV-2 infection in mammals.

[0075] According to the fifth aspect of the present invention, the present invention relates to the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating diseases caused by SARS-CoV-2 infection in mammals in combination with other compounds for treating diseases caused by SARS-CoV-2 infection.

[0076] In the present invention, preferably, the mammal is a human.

[0077] In the present invention, preferably, the disease caused by SARS-CoV-2 infection is novel coronavirus pneumonia.

[0078] In the present invention, preferably, other compounds for treating diseases caused by SARS-CoV-2 infection include but are not limited to antiviral agents such as acyclovir, remdesivir, monabivir, etc., anti-infective drugs, immunomodulators such as α, β, δ-interferon, etc., main protease inhibitors, S protease inhibitors, M protein inhibitors, and / or antibiotics, etc.

[0079] Pharmaceutical composition of the present invention can be given by various approaches known in the art, including but not limited to oral, skin, intradermal, subcutaneous, intramuscular, intraperitoneal, intravenous, lung, epidural, intraarticular, intrasynovial, intrasternal, intrathecal, intralesional, eyes, oral mucosa, nasal mucosa, rectal mucosa, bronchial mucosa etc. It can also be administered by implanted storage device or by the stent of loaded medicine. It can be systemic or topical administration. Preferred administration routes are oral, intravenous injection, nasal hydroxy mucosal administration, bronchial spray.

[0080] The pharmaceutical composition of the present invention can be administered in various pharmaceutical forms known in the art. The pharmaceutical carrier used can be solid or liquid.

[0081] The dosage form using solid carriers can be tablets (including but not limited to various coated tablets, sustained-release or controlled-release tablets), powders or pellets placed in hard capsules, lozenges or troches, granules, dispersible powders, etc. The amount of solid carrier varies greatly, but preferably ranges from about 25 mg to about 1.0 g. Typical solid carriers include lactose, gypsum powder, sucrose, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid, and the like. The solid carrier may include one or more substances that may also serve as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrants; it can also be an encapsulating material. In powders, the carrier is a finely pulverized solid, which is mixed with finely pulverized active ingredients. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in a suitable proportion and compressed in the desired shape and size. Powders and tablets preferably contain up to 99% active ingredients.

[0082] The preparation form using liquid carrier can be syrup, emulsion, soft capsule, sterile injection solution or suspension in ampoule or vial or non-aqueous liquid suspension. Typical liquid carriers include syrup, peanut oil, olive oil, water, etc. Liquid carriers are used to prepare solutions, suspensions, emulsions, syrups, tinctures and sealed compositions. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of the two or a pharmaceutically acceptable oil or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickeners, pigments, viscosity modifiers, and stable osmotic pressure-regulating agents. Suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives such as those described above, such as cellulose derivatives, preferably carboxymethyl cellulose sodium salt solutions), alcohols (including monohydric alcohols and polyhydric alcohols, such as ethylene glycol) and their derivatives, and oils (such as fractionated coconut oil and peanut oil). The carrier for parenteral administration can also be oils and fats such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used for sterile liquid compositions for parenteral administration. Liquid carriers for pressurized compositions can be halogenated hydrocarbons or other pharmaceutically acceptable propellants. Sterile solutions or suspension liquid pharmaceutical compositions can be used, for example, for intravenous, intramuscular, intraperitoneal or subcutaneous injection. The suspension can be prepared using appropriate dispersants or wetting agents (such as Tween 80) and suspending agents according to known techniques in the art.

[0083] In order to obtain a stable water-soluble dosage form, the compound or its pharmaceutically acceptable salt can be dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3M succinic acid or citric acid solution. Optionally, acidic derivatives can be dissolved in suitable alkaline solutions. If a soluble form is not available, the compound can be dissolved in a suitable cosolvent or a combination thereof. Examples of such suitable cosolvents include, but are not limited to, ethanol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerol, polyoxyethylene fatty acid esters, fatty alcohols or glycerol hydroxy fatty acid esters, etc., in a concentration range of 0-60% total volume.

[0084] Other suitable excipients or carriers that can be used in the above-mentioned compositions can be found in standard pharmacology textbooks, for example in "Remington's Pharmaceutical Sciences", 19th edition.

[0085] In order to prevent and treat diseases caused by SARS-CoV-2, such as novel coronavirus pneumonia, in monotherapy, the compound of formula I of the present invention or its pharmaceutically acceptable salt is useful in a dosage range of about 0.01 to about 100 mg / kg body weight per day, preferably between 0.5 and 75 mg / kg body weight per day. It will be appreciated by those skilled in the art that when the compound of formula I of the present invention or its pharmaceutically acceptable salt is used in combination with other therapeutic agents, its dosage can be appropriately reduced. Generally, the pharmaceutical composition of the present invention will be administered about 1 to 5 times a day, or another continuous infusion. Such drugs can be used as chronic or acute treatments. Representative preparations will contain about 5% to about 95% active ingredient (weight / weight). Preferably, such preparations contain about 20% to about 80% of active compounds.

[0086] Those skilled in the art will appreciate that a higher or lower dose than mentioned above may be required. The specific dose and treatment for a particular patient should be determined according to various factors, including the activity of the specific compound used, the patient's age, weight, sex, general health status, diet, time of administration, metabolic rate, combination of drugs, and the severity and course of infection, the patient's tendency to infection, and the judgment of the treating physician. In general, treatment is started with a small dose that is substantially lower than the optimal dose of the compound. The dose is then increased by a small amount until the best effect is achieved in this case. In general, it is required to administer the compound at a concentration that is usually sufficient to produce an effective antiviral result but does not cause any harmful or adverse side effects.

[0087] The compounds of the general formula of the present invention can be prepared by the following general synthetic methods. The substituents in these synthetic methods are as defined above.

[0088] Process flow:

[0089]

[0090] In some embodiments of the present invention, the preparation method is as follows:

[0091] Step I-1: Preparation of Compound 1

[0092] At room temperature, L-configuration NH2CHR2COOH (1.0 equivalent) was dissolved in an appropriate amount of methanol, and dichlorothionyl (1.2 equivalent) was slowly added under an ice-water bath. After stirring at room temperature for 10 minutes, the mixture was transferred to a 70°C oil bath for reaction for 3 hours. After the reaction was completed, the solvent was removed under reduced pressure, the product was dissolved with an appropriate amount of dichloromethane, the pH was adjusted to weak alkalinity with TEA under an ice-water bath, and L-configuration Boc-NHCHR3COOH (1.0 equivalent), EDCI (1.2 equivalent), HOBt (1.2 equivalent) and TEA (4.0 equivalent) were added in sequence, and the mixture was transferred to room temperature for reaction for 12 hours. After the reaction was completed, the organic phase was washed with water, saturated citric acid solution, saturated NaHCO3 solution, and saturated sodium chloride in sequence. The combined organic phase was dried over anhydrous sodium sulfate, filtered and the solvent was evaporated under reduced pressure, and the crude product was purified by flash chromatography to obtain the target compound 1.

[0093] Step I-2: Preparation of Compound 2

[0094] Compound 1 (1.0 equivalent) was dissolved in anhydrous DCM, TFA (15.0 equivalent) was slowly added dropwise under an ice-water bath, and the mixture was transferred to room temperature for reaction for 3h. After the reaction was completed, DCM and TFA were removed by distillation under reduced pressure. After the product was dissolved in an appropriate amount of anhydrous DCM, the pH was adjusted to weak alkalinity with TEA under an ice-water bath, and the corresponding R1COOH (1.0 equivalent), EDCI (1.2 equivalent), HOBt (1.2 equivalent) and TEA (4.0 equivalent) were added in sequence, and the mixture was transferred to room temperature for reaction for 12h. After the reaction was completed, the organic phase was washed with water, saturated citric acid, saturated NaHCO3, and saturated sodium chloride in sequence. The combined organic phase was dried over anhydrous sodium sulfate, filtered and the solvent was removed under reduced pressure, and the crude product obtained was purified by flash chromatography to obtain compound 2.

[0095] Step I-3: Preparation of Compound 3

[0096] Under an ice-water bath, sodium borohydride (15.0 equivalents) was slowly added to a methanol solution of compound 2 (1.0 equivalents) several times and stirred at room temperature for 2 hours. After the reaction was complete, a saturated aqueous solution of ammonium chloride was added to quench the reaction, and methanol was removed under reduced pressure. DCM and water were used for extraction to remove water-soluble impurities, and the combined organic phase was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated. The crude product was purified by flash chromatography to obtain the target compound 3.

[0097] Step I-4: Preparation of Compound 4

[0098] DMP (1.2 eq.) was added to a solution of compound 3 (1.0 eq.) in anhydrous DCM and stirred for 2 hours. After the reaction was complete, saturated sodium bicarbonate was added to quench the reaction, and sodium thiosulfate (2.0 eq.) was added and stirred until the organic phase was clear. The mixture was extracted with DCM, and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography to obtain the target compound 4.

[0099] As demonstrated in the following examples of the present invention, the compounds of the present invention or pharmaceutically acceptable salts thereof have better activity in inhibiting the novel coronavirus and lower cytotoxicity, that is, have higher safety, and can be used to prevent and / or treat diseases caused by SARS-CoV-2 infection, such as novel coronavirus pneumonia. DETAILED DESCRIPTION

[0100] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and are not intended to limit the scope of the present invention. In addition, it should be understood that after reading the content recorded in the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms fall within the scope limited by the present invention equally.

[0101] The temperatures in the following examples are given in degrees Celsius. Unless otherwise stated, solution percentages represent weight to volume relationships, and solution ratios represent volume to volume relationships. The structures of the compounds in the examples were determined using nuclear magnetic resonance.

[0102] NMR spectroscopy ( 1 H NMR and 13 C NMR) was measured using a Bruker 400 spectrometer at 400 MHz. Chemical shifts are expressed in parts per million (ppm, δ) relative to the internal tetramethylsilane standard. 1 The multiplicity of peaks in H-NMR is expressed as follows: s = singlet; d = doublet; t = triplet; m = multiplet. Coupling constants are expressed in Hz. Solvent peaks refer to internal deuterated reagents. Commercial reagents used were obtained from their respective suppliers and, if necessary, were described in the text. Dichloromethane (DCM) was distilled from calcium hydride before use.

[0103] The present invention uses the following abbreviations: MeOH: methanol; Boc: tert-butyloxycarbonyl; TEA: triethylamine; EA: ethyl acetate; DMP: Dess-martin reagent; PE: petroleum ether; EDCI: 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; HOBT: 1-hydroxybenzotriazole hydrate; DBU: 1,8-diazabicycloundec-7-ene. In addition, "L" represents a naturally occurring amino acid.

[0104] Example 1 Preparation of Compound 4-1

[0105]

[0106] Step 1. Preparation of Compound 1

[0107]

[0108] Take L-phenylalanine (5.00g, 30.3mmol) in a 500mL round-bottom flask, add an appropriate amount of MeOH to dissolve, slowly add dichlorothionyl (2.6mL, 35.8mmol) under an ice-water bath, and reflux at 70°C for 3h. After the reaction is completed, concentrate under reduced pressure, and the resulting white solid is dissolved in an appropriate amount of anhydrous DCM. Adjust the pH value to weak alkalinity with TEA under an ice-water bath. Add Boc-L-leucine (7.42g, 29.8mmol), EDCI (6.84g, 35.7mmol), HOBt (4.82g, 35.7mmol) and TEA (17.0mL, 104.0mmol) in sequence at room temperature and react for 12h. After the reaction is completed, extract with water (2×200mL), saturated citric acid solution (2×200mL), saturated sodium bicarbonate solution (2×200mL), and saturated brine (2×200mL) in sequence. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (PE:EA=6:1) to obtain white solid compound 1 (6.20 g, yield 53.1%).

[0109] 1 H NMR (400MHz, CDCl3) δ7.34–7.16(m,3H),7.11(d,J=7.1Hz,2H),6.72(d,J=6.6Hz,1H),5.03(d,J=6.8Hz,1H),4.84(dd,J=13.0,6. 1Hz,1H),4.11(d,J=7.1Hz,1H),3.70(d,J=10.4Hz,3H),3.10(qd,J=13.8,6.0Hz,2H),1.72–1.52(m,2H),1.38(d,J=38.8Hz,10H), 0.91(t,J=6.0Hz,6H).

[0110] 13 C NMR (101MHz, CDCl3) δ172.30,171.73,155.54,135.83,129.29,128.51,127.06,79.93, 53.19,53.08,52.24,41.24,37.91,28.29,24.65,22.87,21.96.

[0111] Step 2. Preparation of Compound 2

[0112]

[0113] Compound 1 (1.00 g, 2.55 mmol) was dissolved in an appropriate amount of anhydrous DCM, trifluoroacetic acid (3.00 mL, 40.4 mmol) was slowly added, and stirred at room temperature for 2 h. After the reaction was complete, the volatile solvent was removed under reduced pressure. The obtained oily liquid was dissolved in an appropriate amount of anhydrous DCM, and the pH value was adjusted to weak alkalinity with TEA under an ice-water bath. p-Methoxycinnamic acid (0.45 g, 2.55 mmol), EDCI (0.59 g, 3.06 mmol), HOBt (0.41 g, 3.06 mmol) and TEA (1.4 mL, 10.2 mmol) were added in sequence at room temperature and reacted for 12 h. After the reaction was completed, it was extracted with water (2×50 mL), saturated citric acid solution (2×50 mL), saturated sodium bicarbonate solution (2×50 mL), and saturated brine (2×50 mL) in sequence. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (PE:EA=4:1) to obtain white solid compound 2 (0.60 g, yield 52.0%).

[0114] 1 H NMR (400MHz, CDCl3) δ7.63–7.54(m,1H),7.43(t,J=5.8Hz,2H),7.24–7.14(m,3H),7.12–7.07(m,2H),7.02(d,J=7.9Hz,1H),6.84(d ,J=8.8Hz,2H),6.56(d,J=8.4Hz,1H),6.31(t,J=11.9Hz,1H),4.84(dd,J=14.1,6.3Hz,1H),4.68(td,J=8.5,5.6Hz,1H),3.81(d,J= 4.2Hz, 3H), 3.70 (s, 3H), 3.12 (dd, J=13.8, 5.9Hz, 1H), 3.04 (dd, J=13.8, 6.6Hz, 1H), 1.74- 1.54 (m, 3H), 0.93 (dd, J=6.0, 2.7Hz, 6H).

[0115] 13C NMR (101MHz, CDCl3) δ172.14,171.72,166.22,160.96,141.25,135.78,129.46, 129.30,128.56,127.45,127.01,117.85,114.26,55.33,53.43,52.29,51.62,41.11,37.92,24.78,22.89,22.25.

[0116] Step 3. Preparation of compound 3

[0117]

[0118] Compound 2 (0.60 g, 1.33 mmol) was dissolved in an appropriate amount of MeOH, sodium borohydride (0.75 g, 20.0 mmol) was slowly added under an ice-water bath, and the reaction was carried out at room temperature for 1 h. After the reaction was completed, an appropriate amount of saturated ammonium chloride solution was added to quench. The solvent was removed by distillation under reduced pressure, and the mixture was extracted with DCM to remove water-soluble impurities. The DCM layer was collected, dried over anhydrous Na2SO4, and filtered. The crude product was separated and purified by rapid silica gel chromatography (PE: EA = 2: 1) to obtain a white solid compound 3 (0.40 g, yield 70.8%).

[0119] 1 H NMR(400MHz,MeOD)δ7.51(dd,J=12.2,3.4Hz,3H),7.26–7.17(m,4H),7.15–7.07(m,1H),6.93(d,J=8.7Hz,2H),6.52(d,J=15.8Hz ,1H),4.55–4.44(m,1H),4.17–4.03(m,1H),3.81(s,3H),3.52(t,J=7.1Hz,2H),2.90(dt,J=15.1,7.5Hz,1H),2.80–2.70(m,1H), 1.70–1.59(m,1H),1.58–1.48(m,2H),0.91(dt,J=23.5,11.8Hz,6H).

[0120] 13 C NMR(101MHz,MeOD)δ173.13,167.47,161.29,140.71,138.26,129.16,129.03,127.97,127. 44,125.87,117.58,114.00,62.64,54.48,52.82,52.04,40.63,36.51,24.56,22.05,20.73.

[0121] Step 4. Preparation of compound 4-1

[0122]

[0123] Compound 3 (0.10 g, 0.24 mmol) was dissolved in an appropriate amount of anhydrous DCM, and Dess-Martin periodinane (0.12 g, 0.29 mmol) was added at room temperature. After TLC monitoring, the reaction was complete, and an appropriate amount of saturated sodium bicarbonate solution and sodium thiosulfate were added to quench the reaction, and stirred at room temperature for 2 h. Extracted with DCM to remove water-soluble impurities, the DCM layer was collected, dried over anhydrous Na2SO4, and filtered. The crude product was separated and purified by flash silica gel chromatography (PE: EA = 3: 1) to obtain white solid compound 4-1 (800 mg, yield 80.0%).

[0124] 1 H NMR (400MHz, CDCl3) δ9.52 (s, 1H), 7.56–7.43 (m, 1H), 7.36 (d, J = 8.7Hz, 2H), 7.14 (d,J=7.5Hz,3H),7.07(d,J=1.2Hz,4H),6.79(d,J=8.6Hz,2H),6.24–6.17(m,1H),4.65– 4.56(m,1H),4.55–4.46(m,1H),3.75(s,3H),3.11–3.02(m,1H),3.01–2.90(m,1H),1.68– 1.48(m,3H),0.86(dd,J=5.8,4.8Hz,6H).

[0125] 13 C NMR (101MHz, CDCl3) δ197.76,171.62,165.33,160.07,140.56,134.72,128.48, 128.27,127.71,126.25,125.99,116.46,113.29,58.81,54.33,50.55,39.88,33.96,23.80,21.84,21.19.

[0126] Example 2 Preparation of Compound 4-2

[0127]

[0128] The preparation method was the same as compound 4-1 (760 mg, yield 77.0%).

[0129] 1H NMR (400MHz, CDCl3) δ9.59 (s, 1H), 7.82 (d, J = 7.0Hz, 2H), 7.60 (dd, J = 13.3, 7.5Hz, 4H),7.45(t,J=7.1Hz,2H),7.40(d,J=6.3Hz,1H),7.24(d,J=7.1Hz,1H),7.13(dt,J=7.1,5. 7Hz,5H),6.92(d,J=8.1Hz,1H),4.85–4.71(m,1H),4.60(d,J=6.9Hz,1H),3.19–3.08(m,1H), 3.07–2.94(m,1H),1.81–1.63(m,3H),0.96(s,6H).

[0130] 13 C NMR (101MHz, CDCl3) δ198.70,172.59,167.21,144.73,139.87,135.72,132.19, 129.24,128.97,128.71,128.12,127.75,127.22,127.05,59.88,52.00,40.99,34.96,24.96,22.88,22.27.

[0131] Example 3: Preparation of Compound 4-3

[0132]

[0133] The preparation method was the same as compound 4-1 (440 mg, yield 45.0%).

[0134] 1 H NMR(400MHz, CDCl3)δ9.50(s,1H),8.41–8.33(m,1H),7.47–7.41(m,1H),7.40–7.34(m,1H),7.22–7.17(m,2H),7.14–7.04(m,5H),6.85–6. 75(m,1H),5.97–5.85(m,1H),4.55–4.39(m,2H),3.70(s,2H),3.11–3 .03(m,1H),2.96–2.85(m,1H),1.58–1.32(m,3H),0.81–0.72(m,6H).

[0135] 13C NMR (101MHz, CDCl3) δ198.80,172.20,171.98,136.39,135.85,129.27,128.74, 127.08,123.75,122.78,120.17,118.44,111.56,108.42,59.75,51.46,40.06,34.86,33.26,24.61,22.74,21.85.

[0136] Example 4: Preparation of Compound 4-4

[0137]

[0138] The preparation method was the same as compound 4-1 (600 mg, yield 61.0%).

[0139] 1 H NMR (400MHz, CDCl3) δ9.62 (s, 1H), 8.58 (ddd, J=4.7, 1.5, 0.9Hz, 1H), 8.26 (d, J= 8.4Hz,1H),8.14(d,J=7.8Hz,1H),7.88(td,J=7.7,1.7Hz,1H),7.48(ddd,J=7.6,4.8,1.2Hz ,1H),7.09(d,J=6.7Hz,5H),6.98(d,J=6.9Hz,1H),4.67(dt,J=13.7,4.5Hz,2H),3.16(dd,J= 14.1, 6.4Hz, 1H), 3.07 (dd, J = 14.1, 7.1Hz, 1H), 1.82 (dd, J = 10.4, 5.0Hz, 1H), 1.76–1.63 (m, 2H), 0.94 (dd, J = 10.7, 6.3Hz, 6H).

[0140] 13 C NMR (101MHz, CDCl3) δ198.85,172.02,164.61,149.03,148.28,137.41,135.59, 129.22,128.58,126.93,126.58,122.55,59.70,51.54,40.25,34.93,24.81,22.97,21.94.

[0141] Example 5: Preparation of Compound 4-5

[0142]

[0143] The preparation method was the same as compound 4-1 (810 mg, yield 81.9%).

[0144] 1 H NMR(400MHz, CDCl3)δ9.78–9.36(m,1H),7.84–7.67(m,2H),7.34–6.99(m,9H),4. 90–4.69(m,1H),4.65–4.35(m,1H),3.44–2.82(m,2H),1.69(m,3H),0.93(s,6H).

[0145] 13 C NMR (101MHz, CDCl3) δ198.58,172.70,166.39,135.69,129.63,129.55,129.22, 128.71,127.08,115.71,115.49,59.93,52.06,41.00,34.90,24.92,22.84,22.18.

[0146] Example 6: Preparation of Compound 4-6

[0147]

[0148] The preparation method was the same as compound 4-1 (560 mg, yield 58.2%).

[0149] 1 H NMR (400MHz, CDCl3) δ9.58 (s, 1H), 7.35–7.21 (m, 3H), 7.15 (d, J = 7.2Hz, 2H), 6.95 (d,J=6.8Hz,1H),6.13(d,J=8.1Hz,1H),4.59(d,J=6.8Hz,1H),4.50(d,J=5.7Hz,1H),3.99 (d,J=10.6Hz,2H),3.45–3.33(m,2H),3.14(d,J=6.4Hz,1H),3.09(d,J=7.2Hz,1H),2.32(s, 1H), 1.66 (tdd, J=26.7, 17.4, 12.5Hz, 7H), 0.91 (t, J=6.8Hz, 6H).

[0150] 13 C NMR (101MHz, CDCl3) δ198.52,174.53,172.48,135.65,129.24,128.77,127.16,67.14, 59.79,51.31,41.93,41.06,34.91,29.20,28.95,24.86,22.89,22.15.

[0151] Example 7: Preparation of Compound 4-7

[0152]

[0153] The preparation method was the same as compound 4-1 (660 mg, yield 67.8%).

[0154] 1 H NMR (400MHz, CDCl3) δ9.60 (s, 1H), 7.66 (d, J = 7.5Hz, 2H), 7.38 (d, J = 8.2Hz, 2H), 7.17(s,3H),7.12(s,2H),6.98(s,1H),6.88–6.75(m,1H),4.77–4.66(m,1H),4.65– 4.57(m,1H),3.20–3.10(m,1H),3.10–2.99(m,1H),1.77–1.59(m,3H),0.93(s,6H).

[0155] 13 C NMR (101MHz, CDCl3) δ198.45,172.40,166.35,138.20,135.53,131.90,129.21, 128.84,128.74,128.60,127.14,59.86,52.03,41.05,34.98,24.92,22.83,22.21.

[0156] Example 8: Preparation of Compound 4-8

[0157]

[0158] The preparation method was the same as compound 4-1 (300 mg, yield 31.5%).

[0159] 1 H NMR(400MHz,MeOD)δ9.58(s,1H),8.13(s,1H),7.64–7.61(m,1H),7.46(s,1H),7.31(d,J=2.9Hz,2H),7.17(dd,J=5.8,3.0Hz,5H ), 6.58(d,J=2.9Hz,1H),4.46(s,1H),4.17–4.04(m,1H),3.27–3.18(m,1H),3.00–2.91(m,1H),1.73(s,3H),0.98–0.94(m,6H).

[0160] 13C NMR(101MHz,MeOD)δ199.19,174.05,173.42,173.26,138.21,136.52,129.04,128.32,127.95,127.5 5,126.51,126.05,125.86,120.38,110.85,102.35,60.15,54.88,40.57,34.05,24.70,22.35,21.30.

[0161] Example 9: Preparation of Compound 4-9

[0162]

[0163] The preparation method was the same as compound 4-1 (350 mg, yield 36.0%).

[0164] 1 H NMR(400MHz, CDCl3)δ9.64(s,1H),9.43–9.33(m,1H),7.70–7.61(m,1H),7.48–7.40(m,1H),7.34–7.29(m,1H),7.09(s,7 H),6.97–6.93(m,1H),6.88–6.79(m,1H),4.86–4.66(m,2H),3.21–3.04(m,2H),1.77–1.69(m,3H),0.94(t,J=6.0Hz,6H).

[0165] 13 C NMR (101MHz, CDCl3) δ198.69,161.75,160.66,136.42,135.29,129.20,128.68, 127.10,124.88,122.15,120.83,111.99,103.35,59.79,51.58,41.02,35.10,24.90,22.86,22.21.

[0166] Example 10: Preparation of Compound 4-10

[0167]

[0168] The preparation method was the same as compound 4-1 (510 mg, yield 52.3%).

[0169] 1H NMR (400MHz, CDCl3) δ9.44(s,1H),7.91(t,J=6.2Hz,1H),7.87(s,1H),7.79(d,J=7.5 Hz,1H),7.33(dd,J=4.0,2.3Hz,1H),7.23–7.15(m,3H),7.11–7.03(m,2H),6.64(d,J= 1.1Hz,1H),4.72(dd,J=13.7,8.4Hz,1H),4.27(q,J=7.0Hz,1H),3.06(dd,J=14.1,6.8Hz,1 H),2.97(dd,J=14.1,7.5Hz,1H),1.74–1.67(m,2H),1.57(td,J=9.9,4.9Hz,1H),0.86(dd,J =6.4,3.5Hz,6H).

[0170] 13 C NMR (101MHz, CDCl3) δ198.75,174.00,162.89,145.50,143.58,135.85,129.10, 128.67,127.01,121.78,108.58,60.15,51.96,40.81,34.77,24.71,22.83,21.69.

[0171] Example 11: Preparation of Compound 4-11

[0172]

[0173] The preparation method was the same as compound 4-1 (360 mg, yield 36.8%).

[0174] 1 H NMR (400MHz, CDCl3) δ9.52–9.41(m,1H),9.09–8.94(m,1H),7.27–7.25(m,1 H),7.22–7.19(m,1H),7.08–7.00(m,5H),6.72–6.62(m,1H),6.41–6.34(m, 1H),6.33–6.24(m,1H),4.66–4.55(m,1H),4.52–4.38(m,1H),3.11–2.99(m ,1H),2.99–2.88(m,1H),1.65–1.59(m,2H),1.55–1.50(m,1H),0.84(s,6H).

[0175] 13C NMR (101MHz, CDCl3) δ199.13,173.24,165.27,135.71,129.28,128.71,127.02, 121.56,119.08,107.25,59.94,51.35,40.69,34.90,24.81,22.83,22.10.

[0176] Example 12: Preparation of Compound 4-12

[0177]

[0178] The preparation method was the same as compound 4-1 (810 mg, yield 82.1%).

[0179] 1 H NMR (400MHz, CDCl3) δ9.59 (d, J = 2.4Hz, 1H), 7.74–7.67 (m, 2H), 7.43 (t, J = 8.5Hz, 2H),7.18–7.13(m,3H),7.12–7.04(m,3H),6.80–6.68(m,2H),5.84(dt,J=17.6,3.5Hz,1H), 5.37(dd,J=11.1,5.7Hz,1H),4.79–4.68(m,1H),4.66–4.56(m,1H),3.20–3.09(m,1H),3.03 (dd,J=14.2,7.4Hz,1H),1.79–1.62(m,3H),0.98–0.88(m,6H).

[0180] 13 C NMR (101MHz, CDCl3) δ198.68,172.45,167.06,141.09,135.86,135.64,132.54, 129.23,128.71,127.49,127.07,126.34,116.27,59.84,51.87,40.93,34.97,24.92,22.87,22.25.

[0181] Example 13: Preparation of Compound 4-13

[0182]

[0183] The preparation method was the same as compound 4-1 (750 mg, yield 76.3%).

[0184] 1H NMR (400MHz, CDCl3) δ9.58 (s, 1H), 7.35–7.20 (m, 3H), 7.15 (d, J = 7.1Hz, 2H), 7.00 (d,J=6.5Hz,1H),5.94(d,J=8.0Hz,1H),4.63–4.54(m,1H),4.49(dd,J=8.3,2.7Hz,1H),3. 15(dd,J=14.2,6.4Hz,1H),3.07(dd,J=14.2,7.2Hz,1H),2.06(dd,J=8.7,5.7Hz,1H),1.77 (d,J=9.4Hz,4H),1.70–1.55(m,3H),1.51(dd,J=14.7,6.6Hz,1H),1.44–1.32(m,2H),1.25(dd,J=10.8,7.8Hz,2H),0.90(dd,J=9.4,6.2Hz,6H).

[0185] 13 C NMR (101MHz, CDCl3) δ198.72,176.30,172.58,135.72,129.25,128.74,127.17,59.76, 51.16,45.20,40.82,34.93,29.67,29.40,25.65,25.58,24.83,22.85,22.12.

[0186] Example 14: Preparation of Compound 4-14

[0187]

[0188] The preparation method was the same as compound 4-1 (400 mg, yield 40.5%).

[0189] 1 H NMR (400MHz, CDCl3) δ9.54 (s, 1H), 7.89–7.83 (m, 1H), 7.38 (dd, J = 9.9, 6.1Hz, 2H), 7.31–7.24(m,1H),7.17(d,J=6.5Hz,2H),7.12–7.04(m,3H),4.72(d,J=7.4Hz,1H),4.49(d, J=6.9Hz,1H),3.10(d,J=6.3Hz,1H),3.06–2.93(m,1H),1.74–1.61(m,3H),0.91(dd,J=5.6, 3.7Hz, 6H).

[0190] 13C NMR (101MHz, CDCl3) δ198.73,172.92,163.05,136.54,135.81,129.24,129.09, 128.68,127.04,126.45,126.29,59.99,51.81,40.86,34.89,24.89,22.86,22.11.

[0191] Example 15: Preparation of Compound 4-15

[0192]

[0193] The preparation method was the same as compound 4-1 (760 mg, yield 77.0%).

[0194] 1 H NMR(400MHz, CDCl3)δ9.62(s,1H),7.64–7.53(m,4H),7.26(s,2H),7.13(s,3H),6.92–6.82(m,1H),6.75 –6.61(m,1H),4.74–4.60(m,2H),3.22–3.12(m,1H),3.11–2.99(m,1H),1.73(s,3H),0.98–0.88(m,6H).

[0195] 13 C NMR (101MHz, CDCl3) δ198.37,172.23,166.43,135.44,131.85,129.22,128.62, 127.16,59.82,51.96,41.05,35.01,24.88,22.83,22.22.

[0196] Example 16: Preparation of Compound 4-16

[0197]

[0198] The preparation method was the same as compound 4-1 (780 mg, yield 78.5%).

[0199] 1H NMR (400MHz, CDCl3) δ9.59 (s, 1H), 7.74 (d, J = 8.0Hz, 2H), 7.51 (d, J = 7.3Hz, 1H), 7.42(t,J=7.5Hz,2H),7.15(d,J=5.6Hz,3H),7.11(d,J=7.0Hz,2H),7.06(d,J=6.9Hz,1H), 6.72(d,J=8.1Hz,1H),4.74(s,1H),4.61(d,J=7.0Hz,1H),3.12(d,J=6.2Hz,1H),3.05(d,J= 7.3Hz, 1H), 1.79–1.59 (m, 3H), 0.94 (t, J = 4.8Hz, 6H).

[0200] 13 C NMR (101MHz, CDCl3) δ198.60,172.47,167.28,135.62,133.61,131.96,129.17, 128.45,127.19,59.76,51.66,40.77,34.87,24.99,22.55,21.99.

[0201] Example 17: Preparation of Compound 4-17

[0202]

[0203] The preparation method was the same as compound 4-1 (660 mg, yield 67.1%).

[0204] 1 H NMR (400MHz, CDCl3) δ9.52 (t, J=8.1Hz, 1H), 8.23 ​​(dd, J=6.3, 3.4Hz, 1H), 7.92– 7.79(m,2H),7.50(ddd,J=11.0,7.4,2.3Hz,3H),7.40–7.30(m,1H),7.24(dd,J=15.7,8.0Hz ,1H),7.15(ddd,J=7.6,5.8,4.3Hz,3H),7.09(dd,J=5.0,2.7Hz,2H),6.67(d,J=8.3Hz,1H), 4.95–4.76(m,1H),4.53(td,J=6.8,4.6Hz,1H),3.14–3.02(m,1H),3.01–2.90(m,1H),1.79– 1.58(m,3H),0.99(dd,J=8.7,6.0Hz,6H).

[0205] 13C NMR (101MHz, CDCl3) δ198.64,172.35,169.59,135.75,133.67,133.34,131.08, 130.09,129.22,128.72,128.41,127.33,127.04,126.53,125.34,125.22,124.64,59.85,52.04,41.19,34.84,25.00,22.89,22.26.

[0206] Example 18: Preparation of Compound 4-18

[0207]

[0208] The preparation method was the same as compound 4-1 (480 mg, yield 48.2%).

[0209] 1 H NMR (400MHz, CDCl3) δ9.68–9.56(m,1H),9.27(s,1H),8.98(t,J=19.2Hz,1H),8.25(d,J=8.4Hz,1H),8.11–8.02(m,1H),7.22–7.00 (m,6H),6.78(d,J=6.8Hz,1H),4.73(dd,J=13.6,6.8Hz,1H),4.66(td,J=8.6,5.8Hz,1H),3.14(qd,J=14.2,6.7Hz,2H),1.79–1.63 (m,3H),0.94(dt,J=14.8,7.4Hz,6H).

[0210] 13 C NMR (101MHz, CDCl3) δ198.48,171.40,162.80,159.31,157.88,155.48,135.34, 129.21,128.67,127.08,118.65,59.69,51.74,40.59,34.96,24.83,22.90,21.99.

[0211] Example 19: Preparation of Compound 4-19

[0212]

[0213] The preparation method was the same as compound 4-1 (880 mg, yield 90.0%).

[0214] 1H NMR(400MHz, CDCl3)δ9.58(s,1H),7.52(t,J=12.0Hz,1H),7.46–7.37(m,3H),7.25–7.19(m,2H),7.15(ddd,J=11.3,6.5,4.0Hz,3H) ,7.01–6.88(m,3H),6.39(d,J=15.6Hz,1H),4.79–4.68(m,1H),4.54(dd,J=13.8,7.0Hz,1H),3.13(dd,J=14.2,6.3Hz,1H),3.03(dd, J=14.2,7.4Hz,1H),1.75–1.59(m,3H),0.92(dd,J=15.5,10.2Hz,6H).

[0215] 13 C NMR (101MHz, CDCl3) δ198.71,172.95,165.91,164.86,162.37,140.42,135.82, 130.86,130.83,129.72,129.64,129.27,128.73,127.04,119.94,116.07,115.85,59.95,51.79,41.21,34.92,24.88,22.84,22.27.

[0216] Example 20: Preparation of Compound 4-20

[0217]

[0218] The preparation method was the same as compound 4-1 (750 mg, yield 76.3%).

[0219] 1 H NMR(400MHz, CDCl3)δ9.61(d,J=12.6Hz,1H),8.99(s,1H),8.71(d,J=4.6Hz,1H), 8.13–8.03(m,1H),7.41–7.34(m,1H),7.33–7.28(m,1H),7.15(dt,J=13.7,7.3Hz,6H),4.80 –4.61(m,2H),3.17(dd,J=14.1,6.3Hz,1H),3.08(dd,J=13.9,7.1Hz,1H),1.70(d,J=5.0Hz, 3H),0.95–0.89(m,6H).

[0220] 13C NMR (101MHz, CDCl3) δ198.45,172.39,165.56,152.37,148.18,135.48,135.41, 129.24,128.74,127.15,123.52,59.87,52.07,40.96,34.96,24.93,22.83,22.13.

[0221] Example 21: Preparation of Compound 4-21

[0222]

[0223] The preparation method was the same as compound 4-1 (730 mg, yield 74.5%).

[0224] 1 H NMR (400MHz, CDCl3) δ9.64 (s, 1H), 8.78–8.66 (m, 2H), 7.57 (ddd, J = 8.3, 5.5, 1.7Hz, 2H),7.23–7.17(m,3H),7.15–7.11(m,2H),7.00(d,J=7.9Hz,1H),6.80(d,J=6.7Hz,1H),4 .75–4.64(m,2H),3.18(dd,J=14.2,6.5Hz,1H),3.11(dd,J=14.2,6.9Hz,1H),1.69(dt,J= 18.0, 6.7Hz, 3H), 0.94 (dt, J = 10.4, 5.2Hz, 6H).

[0225] 13 C NMR (101MHz, CDCl3) δ198.22,172.01,165.35,150.56,140.68,135.27,129.23, 128.81,127.27,120.98,59.86,52.07,41.21,35.02,24.92,22.82,22.19.

[0226] Example 22: Preparation of Compound 4-22

[0227]

[0228] The preparation method was the same as compound 4-1 (790 mg, yield 79.1%).

[0229] 1H NMR (400MHz, CDCl3) δ9.60 (s, 1H), 8.23 ​​(d, J = 11.3Hz, 1H), 7.84 (t, J = 9.8Hz, 3H), 7.79(dd,J=8.6,1.5Hz,1H),7.54(ddd,J=15.0,10.8,3.7Hz,2H),7.21(d,J=7.1Hz,1H),7.17 –7.04(m,5H),6.98(d,J=8.2Hz,1H),4.92–4.75(m,1H),4.62(dd,J=13.8,7.0Hz,1H),3.1 4(dd,J=14.2,6.3Hz,1H),3.02(dd,J=14.2,7.4Hz,1H),1.82–1.66(m,3H),1.02–0.90(m, 6H).

[0230] 13 C NMR (101MHz, CDCl3) δ198.70,172.59,167.57,135.66,134.91,132.54,130.74, 129.22,129.01,128.70,128.52,127.90,127.85,127.77,127.03,126.88,123.57,59.86,52.03,41.03,34.97,24.97,22.90,22.30.

[0231] Example 23: Preparation of Compound 4-23

[0232]

[0233] The preparation method was the same as compound 4-1 (680 mg, yield 67.8%).

[0234] 1 H NMR(400MHz, CDCl3)δ9.61(d,J=12.6Hz,1H),8.99(s,1H),8.71(d,J=4.6Hz,1H), 8.13–8.03(m,1H),7.41–7.34(m,1H),7.33–7.28(m,1H),7.15(dt,J=13.7,7.3Hz,6H),4.80 –4.61(m,2H),3.17(dd,J=14.1,6.3Hz,1H),3.08(dd,J=13.9,7.1Hz,1H),1.70(d,J=5.0Hz, 3H),0.95–0.89(m,6H).

[0235] 13C NMR (101MHz, CDCl3) δ198.72,172.24,171.28,135.79,134.43,129.28,129.04, 128.74,127.49,127.10,59.75,51.58,43.43,40.56,34.88,24.76,22.76,22.12.

[0236] Example 24: Preparation of Compound 4-24

[0237]

[0238] The preparation method was the same as compound 4-1 (540 mg, yield 53.9%).

[0239] 1 H NMR (400MHz, CDCl3) δ9.55 (s, 1H), 7.31–7.22 (m, 5H), 7.17 (ddd, J = 16.5, 9.2, 7.2 Hz,5H),6.89(d,J=6.9Hz,1H),5.93(t,J=22.9Hz,1H),4.55(q,J=6.9Hz,1H),4.51–4.38(m, 1H),3.13(dd,J=14.2,6.4Hz,1H),3.08–2.97(m,1H),2.96–2.85(m,2H),2.50–2 .40(m,2H),1.62–1.49(m,1H),1.48–1.32(m,2H),0.84(dd,J=15.4,8.5Hz,6H).

[0240] 13 C NMR (101MHz, CDCl3) δ198.67,172.41,172.27,140.45,135.74,129.29,128.76, 128.59,128.30,127.14,126.37,59.79,51.36,40.81,38.01,34.94,31.48,24.60,22.83,22.09.

[0241] Example 25: Preparation of Compound 4-25

[0242]

[0243] The preparation method was the same as compound 4-1 (420 mg, yield 43.6%).

[0244] 1H NMR (400MHz, CDCl3) δ9.71 (s, 1H), 9.58 (d, J = 1.6Hz, 1H), 7.32–7.25 (m, 1H), 7.11 (t,J=5.7Hz,5H),6.93(s,1H),6.68–6.57(m,1H),6.43(d,J=8.3Hz,1H),6.29–6.18(m,1H), 4.78–4.61(m,2H),3.11(dd,J=14.1,6.5Hz,1H),3.04(dd,J=14.0,7.0Hz,1H),1.74–1.59(m, 3H), 0.91 (dd, J=11.8, 5.7Hz, 6H).

[0245] 13 C NMR (101MHz, CDCl3) δ198.96,172.58,161.04,135.56,129.21,128.63,127.03, 125.08,122.13,110.13,110.06,59.79,51.24,40.96,35.12,24.85,22.88,22.16.

[0246] Example 26: Preparation of Compound 4-26

[0247]

[0248] The preparation method was the same as compound 4-1 (450 mg, yield 46.0%).

[0249] 1 H NMR(400MHz, CDCl3)δ9.61(s,1H),7.47(s,1H),7.20–7.13(m,3H),7.13–7.08(m, 3H),6.94(t,J=16.7Hz,1H),6.65(t,J=16.8Hz,1H),6.53(dd,J=3.3,1.6Hz,1H),4.73–4.60 (m,2H),3.16(dd,J=14.1,6.4Hz,1H),3.05(dd,J=14.1,7.2Hz,1H),1.78–1.56(m,3H),0.98– 0.88(m,6H).

[0250] 13C NMR (101MHz, CDCl3) δ198.68,171.98,158.30,147.21,144.36,135.57,129.25, 128.65,127.01,115.03,112.32,59.78,51.03,40.77,35.00,24.77,22.89,22.09.

[0251] Example 27: Preparation of Compound 4-27

[0252]

[0253] The preparation method was the same as compound 4-1 (720 mg, yield 72.3%).

[0254] 1 H NMR (400MHz, CDCl3) δ9.59 (s, 1H), 7.51–7.42 (m, 2H), 7.36 (td, J = 8.0, 5.6Hz, 1H), 7.23–7.14(m,4H),7.11(dt,J=11.6,5.4Hz,3H),7.02(d,J=8.2Hz,1H),4.72(dd,J=15.2,7.1 Hz,1H),4.60(q,J=6.9Hz,1H),3.15(dd,J=14.2,6.4Hz,1H),3.06(dd,J=14.2,7.3Hz,1H),1.75–1.62(m,3H),0.99–0.86(m,6H).

[0255] 13 C NMR (101MHz, CDCl3) δ198.54,172.52,166.14,163.93,161.47,135.78,135.71, 135.58,130.26,130.19,129.22,128.74,127.13,122.64,122.61,118.98, 118.77,114.74,114.51,59.90,52.11,40.98,34.94,24.93,22.85,22.18.

[0256] Example 28: Preparation of Compound 4-28

[0257]

[0258] The preparation method was the same as compound 4-1 (750 mg, yield 75.6%).

[0259] 1H NMR (400MHz, CDCl3) δ9.62 (s, 1H), 8.01 (td, J = 7.9, 1.6 Hz, 1H), 7.50 (tt, J = 14.5, 7.2 Hz,1H),7.31–7.22(m,1H),7.20–7.06(m,6H),7.01(t,J=9.3Hz,2H),4.78–4.61(m,2H) ,3.17(dd,J=14.2,6.3Hz,1H),3.11–2.98(m,1H),1.84–1.56(m,3H),1.01–0.89(m,6H).

[0260] 13 C NMR (101MHz, CDCl3) δ198.78,171.99,163.49,161.95,159.49,135.59,133.86, 133.77,132.05,129.21,128.64,127.01,124.88,124.85,120.36,120 .25,116.27,116.03,59.73,51.99,40.53,34.94,24.84,22.91,22.08.

[0261] Example 29: Preparation of Compound 4-29

[0262]

[0263] The preparation method was the same as compound 4-1 (820 mg, yield 83.2%).

[0264] 1 H NMR (400MHz, CDCl3) δ9.58 (s, 1H), 7.32–7.18 (m, 3H), 7.15 (d, J = 6.9Hz, 2H), 7.07 (d,J=6.8Hz,1H),6.11(d,J=8.2Hz,1H),4.63–4.46(m,2H),3.15(dd,J=14.2,6.4Hz, 1H), 3.10–2.98 (m, 1H), 2.12 (t, J = 7.5Hz, 2H), 1.67–1.49 (m, 5H), 0.96–0.86 (m, 9H).

[0265] 13C NMR (101MHz, CDCl3) δ198.71,173.24,172.62,135.79,129.26,128.72,127.09,59.81, 51.33,40.92,38.33,34.93,24.80,22.81,22.15,19.05,13.69.

[0266] Example 30: Preparation of Compound 4-30

[0267]

[0268] The preparation method was the same as compound 4-1 (780 mg, yield 79.6%).

[0269] 1 H NMR (400MHz, CDCl3) δ9.57 (s, 1H), 7.32–7.20 (m, 3H), 7.15 (dd, J = 7.3, 2.9Hz, 3H), 6.18(d,J=8.2Hz,1H),4.62–4.45(m,2H),3.15(dd,J=14.2,6.4Hz,1H),3.09–2.99(m,1H), 2.19–2.09(m,2H),1.67–1.46(m,5H),1.30(ddd,J=13.6,9.1,2.3Hz,4H),0.90(dd,J=13.8,7.5Hz,9H).

[0270] 13 C NMR (101MHz, CDCl3) δ198.73,173.42,172.68,135.83,129.26,128.71,127.07,59.81, 51.35,40.94,36.42,34.92,31.39,25.31,24.80,22.80,22.37,22.17,13.94.

[0271] Example 31: Preparation of Compound 4-31

[0272]

[0273] The preparation method was the same as compound 4-1 (750 mg, yield 76.2%).

[0274] 1H NMR(400MHz, CDCl3)δ9.61(s,1H),7.69(d,J=15.8Hz,1H),7.53–7.43(m,1H),7.33(dtd,J=11.7,7.6,4.0Hz,1H),7.28–7.23(m,2H) ,7.20–7.03(m,5H),6.97(d,J=7.0Hz,1H),6.55(t,J=17.9Hz,1H),6.30(t,J=15.3Hz,1H),4.65(dt,J=8.4,4.5Hz,2H),3.16(dd,J= 14.1, 6.4Hz, 1H), 3.06 (dd, J=14.2, 7.3Hz, 1H), 1.76–1.64 (m, 3H), 0.93 (dt, J=14.5, 7.3Hz, 6H).

[0275] 13 C NMR (101MHz, CDCl3) δ198.64,172.35,165.84,162.92,160.02,135.59,135.04, 131.31,131.22,129.68,129.28,128.77,127.10,124.48,124.44,122.77,122.70,116.32,116.10, 59.81,51.65,40.88,35.02,24.83,22.85,22.19.

[0276] Example 32: Preparation of Compound 4-32

[0277]

[0278] The preparation method was the same as compound 4-1 (620 mg, yield 65.4%).

[0279] 1 H NMR (400MHz, CDCl3) δ9.61 (s, 1H), 7.60–7.46 (m, 1H), 7.30 (tt, J = 9.1, 4.6Hz, 1H), 7.27–7.20(m,3H),7.20–7.11(m,4H),7.08–7.00(m,2H),6.47(dd,J=24.2,6.4Hz,1H),6.42 (dd,J=15.6,8.4Hz,1H),4.73–4.55(m,2H),3.15(dd,J=14.2,6.4Hz,1H),3.07(dd,J=14.2, 7.2Hz,1H),1.75–1.55(m,3H),0.99–0.90(m,6H).

[0280] 13 C NMR (101MHz, CDCl3) δ198.56,172.49,165.54,164.25,161.79,140.58,136.92, 135.60,130.46,130.38,129.28,128.77,127.10,123.89,121.35,116.88, 116.66,114.23,114.02,59.85,51.73,41.08,35.01,24.85,22.85,22.21.

[0281] Example 33: Preparation of Compound 4-33

[0282]

[0283] The preparation method was the same as compound 4-1 (510 mg, yield 49.5%).

[0284] 1 H NMR(400MHz, CDCl3)δ9.61(s,1H),7.24–7.15(m,3H),7.14–7.06(m,3H),6.70(t,J =20.0Hz,1H),6.41(d,J=0.8Hz,1H),4.70(q,J=6.8Hz,1H),4.62(td,J=8.7,5.5Hz, 1H), 3.21–3.06 (m, 2H), 2.50 (d, J = 0.7Hz, 3H), 1.77–1.56 (m, 3H), 0.99–0.87 (m, 6H).

[0285] 13 C NMR (101MHz, CDCl3) δ198.52,171.44,171.39,159.28,158.07,135.41,129.26, 128.73,127.12,101.43,59.72,51.58,40.58,35.03,24.77,22.87,21.92,12.35.

[0286] Example 34: Preparation of Compound 4-34

[0287]

[0288] The preparation method was the same as compound 4-1 (640 mg, yield 65.5%).

[0289] 1H NMR (400MHz, CDCl3) δ9.63(d,J=7.3Hz,1H),8.35–8.14(m,2H),7.96–7.80(m,2H),7.25–7.18(m,3H),7.16–7.10(m,2H),6.90( t,J=11.5Hz,1H),6.68(d,J=7.0Hz,1H),4.77–4.63(m,2H),3.15(qd,J=14.2,6.7Hz,2H),1.72–1.68(m,3H),1.00–0.90(m,6H).

[0290] 13 C NMR (101MHz, CDCl3) δ198.14,171.96,165.24,149.82,139.12,135.24,129.23, 128.83,128.35,127.29,123.80,59.86,52.25,41.37,35.07,24.95,22.82,22.22.

[0291] Example 35: Preparation of Compound 4-35

[0292]

[0293] The preparation method was the same as compound 4-1 (560 mg, yield 57.8%).

[0294] 1 H NMR(400MHz, CDCl3)δ9.59(s,1H),7.77–7.64(m,2H),7.18–7.13(m,3H),7.10(dd, J=7.0,2.6Hz,2H),7.06(d,J=7.1Hz,1H),6.96–6.85(m,2H),6.54(d,J=8.2Hz,1H),4.76– 4.65(m,1H),4.61(dd,J=13.6,7.1Hz,1H),3.85(d,J=5.8Hz,3H),3.14(dd,J=14.1,6.2Hz, 1H), 3.02 (dd, J=14.1, 7.4Hz, 1H), 1.78–1.59 (m, 3H), 0.92 (dt, J=8.9, 4.2Hz, 6H).

[0295] 13C NMR (101MHz, CDCl3) δ198.71,172.54,166.98,162.57,135.67,129.23,129.00, 128.69,127.03,125.80,113.81,59.81,55.46,51.78,40.84,34.99,24.91,22.88,22.22.

[0296] Example 36: Preparation of Compound 4-36

[0297]

[0298] The preparation method was the same as compound 4-1 (300 mg, yield 80.0%).

[0299] 1 H NMR (400MHz, DMSO-d6) δ9.54–9.42(m,1H),8.51(d,J=7.1Hz,1H),8.23(d,J=8.1Hz,1H),7.57(d,J=7.4Hz,2H),7.50–7.35(m,4H),7 .21(tt,J=13.2,6.7Hz,5H),6.74(d,J=15.8Hz,1H),4.48(dd,J=14.3,8.1Hz,1H),4.35–4.23(m,1H),3.16(dd,J=14.1,4.2Hz,1H), 2.84(dd,J=13.8,9.7Hz,1H),1.67–1.55(m,1H),1.45(dt,J=20.8,7.4Hz,2H),0.99–0.79(m,6H).

[0300] 13 C NMR(101MHz,DMSO-d6)δ200.71,173.16,165.23,139.42,138.10,135.40,129.93, 129.69,129.43,128.65,127.96,126.73,122.51,60.07,51.39,41.59,33.75,24.74,23.41,22.08.

[0301] Example 37: Preparation of Compound 4-37

[0302]

[0303] The preparation method was the same as compound 4-1 (260 mg, yield 75.6%).

[0304] 1H NMR(400MHz, CDCl3)δ9.62(d,J=12.3Hz,1H),7.30–7.23(m,3H),7.15(t,J=8.0 Hz,2H),6.74(d,J=6.6Hz,1H),4.85(d,J=7.6Hz,1H),4.66(d,J=5.6Hz,1H),4.12(s,1H),3 .20–3.09(m,2H),1.70–1.60(m,2H),1.50(d,J=7.2Hz,1H),1.43(s,9H),0.93(dd,J=11.0, 5.1Hz,6H).

[0305] 13 C NMR (101MHz, CDCl3) δ198.35,172.84,155.59,135.49,129.33,128.77,127.17,59.66, 53.13,41.12,35.12,28.29,24.75,22.90,21.91.

[0306] Example 38: Preparation of Compound 4-38

[0307]

[0308] The preparation method was the same as compound 4-1 (430 mg, yield 75.0%).

[0309] 1 H NMR(400MHz, CDCl3)δ9.58(s,1H),7.39–7.29(m,5H),7.28–7.20(m,3H),7.12(d, J=6.9Hz,2H),6.69(d,J=5.4Hz,1H),5.24(t,J=16.4Hz,1H),5.13–5.02(m,2H),4.71–4.5 7(m,1H),4.21(d,J=4.2Hz,1H),3.20–3.03(m,2H),1.71–1.54(m,2H),1.53–1.41(m,1H), 0.90 (dd, J=12.1, 8.6Hz, 6H).

[0310] 13 C NMR (101MHz, CDCl3) δ198.55,172.44,156.18,136.11,135.51,129.32,128.77, 128.59,128.30,128.08,127.18,67.19,59.70,53.44,41.20,35.03,24.69,22.88,21.95.

[0311] Example 39: Preparation of Compound 4-39

[0312]

[0313] The preparation method was the same as compound 4-1 (450 mg, yield 68.0%).

[0314] 1 H NMR(400MHz, CDCl3) δ9.58(d,J=5.9Hz,1H),7.32–7.23(m,3H),7.15(d,J=6.8Hz,2H),6.86(d,J=6.8Hz,1H),6.16(t,J=10.1Hz,1H),4.65–4 .56(m,1H),4.54–4.43(m,1H),3.23–3.03(m,2H),2.15(d,J=7.5Hz,3H),1.87–1.68(m,6H),1.65–1.51(m,3H),0.91(dd,J=7.8,6.3Hz,6H).

[0315] 13 C NMR (101MHz, CDCl3) δ198.44,174.28,172.44,135.57,129.23,128.80,127.20,59.82, 51.35,42.50,41.12,34.93,32.97,32.76,32.49,25.95,25.86,25.69,25.60,24.87,22.81,22.14.

[0316] Example 40: Preparation of Compound 4-40

[0317]

[0318] The preparation method was the same as compound 4-1 (320 mg, yield 55.0%).

[0319] 1H NMR (400MHz, CDCl3) δ9.58 (d, J=2.8Hz, 1H), 7.33–7.24 (m, 3H), 7.16 (dd, J=5.2, 3.1Hz,2H),6.81(d,J=6.6Hz,1H),5.87(t,J=9.8Hz,1H),4.65–4.57(m,1H),4.46(td,J=8.8, 5.7Hz,1H),3.20–3.04(m,2H),1.86–1.65(m,16H),1.63–1.48(m,2H),0.91(dt,J=10.0,5.1Hz,6H).

[0320] 13 C NMR (101MHz, CDCl3) δ198.73,178.22,172.51,135.66,129.24,128.81,127.15,59.69, 51.10,40.58,39.09,36.41,35.00,28.02,24.91,22.93,22.08.

[0321] Example 41: Preparation of Compound 4-41

[0322]

[0323] The preparation method was the same as compound 4-1 (550 mg, yield 68.2%).

[0324] 1 H NMR (400MHz, CDCl3) δ9.55 (s, 1H), 7.80 (t, J = 5.0Hz, 1H), 7.59 (d, J = 15.6Hz, 1H), 7.42(d,J=6.7Hz,2H),7.26(dt,J=13.4,8.3Hz,4H),6.54(d,J=15.6Hz,1H),4.93–4.71(m, 1H), 4.06 (ddd, J=45.3, 19.5, 5.2Hz, 2H), 1.82–1.65 (m, 3H), 0.94 (dt, J=12.5, 5.6Hz, 6H).

[0325] 13 C NMR (101MHz, CDCl3) δ197.01,173.53,166.29,141.60,134.61,129.81,128.80, 127.89,120.30,51.86,50.02,41.31,24.89,22.91,22.21.

[0326] Example 42: Preparation of Compound 4-42

[0327]

[0328] The preparation method was the same as compound 4-1 (320 mg, yield 65.0%).

[0329] 1 H NMR(400MHz, CDCl3) δ9.61(d,J=14.5Hz,1H),7.60(d,J=15.0Hz,1H),7.47(s,2H),7.40–7.21(m,5H),7.13(d,J=26.7Hz,3H),6.5 6–6.37(m,2H),4.67(t,J=17.2Hz,2H),3.37(d,J=13.8Hz,1H),3.08(d,J=6.0Hz,1H),1.77–1.45(m,3H),0.90(d,J=32.5Hz,6H).

[0330] 13 C NMR (101MHz, CDCl3) δ198.09,172.64,165.95,141.90,134.55,134.10,133.89, 131.81,129.95,129.72,128.89,128.59,127.90,127.04,120.01,58.76,51.66,41.11,32.67,24.86,22.87,22.29.

[0331] Example 43: Preparation of Compound 4-43

[0332]

[0333] The preparation method was the same as compound 4-1 (340 mg, yield 55.0%).

[0334] 1 H NMR(400MHz, CDCl3)δ9.64(d,J=19.1Hz,1H),7.93(t,J=14.8Hz,1H),7.66–7.59 (m,1H),7.50(t,J=11.5Hz,3H),7.35(dd,J=14.9,9.5Hz,5H),6.43–6.35(m,1H),4.87–4.69 (m,1H),4.60(dd,J=30.5,22.2Hz,1H),3.77–3.52(m,1H),3.17–2.97(m,1H),1.64–1.49(m, 3H), 0.92 (dd, J=15.3, 9.2Hz, 6H).

[0335] 13 C NMR (101MHz, CDCl3) δ197.80,172.53,165.93,142.10,134.45,133.41,130.03, 128.90,128.24,127.92,125.27,119.80,58.97,51.63,40.73,32.15,24.77,22.84,21.88.

[0336] Example 44: Preparation of Compound 4-44

[0337]

[0338] The preparation method was the same as compound 4-1 (800 mg, yield 90.0%).

[0339] 1 H NMR(400MHz, CDCl3)δ9.64(s,1H),7.59(t,J=17.2Hz,1H),7.52–7.41(m,2H),7.33(dd,J=5.8,4.0Hz,4H),6.86(d,J=8.3Hz,1H),6 .50(d,J=15.6Hz,1H),4.83(dd,J=13.9,8.1Hz,1H),4.47(dd,J=7.8,4.8Hz,1H),2.35–2.18(m,1H),1.84–1.61(m,3H),1.02–0.95 (m,9H),0.92(d,J=6.9Hz,3H).

[0340] 13 C NMR (101MHz, CDCl3) δ199.62,173.05,165.90,141.51,134.52,129.66,128.81, 128.66,127.89,127.73,120.02,63.35,51.77,41.15,28.78,24.73,22.72,22.19,18.95,17.68.

[0341] Example 45: Preparation of Compound 4-45

[0342]

[0343] The preparation method was the same as compound 4-1 (400 mg, yield 49.0%).

[0344] 1H NMR (400MHz, CDCl3) δ9.56 (d, J = 24.7Hz, 1H), 7.58 (t, J = 15.2Hz, 1H), 7.48 (d, J = 6.3H z,3H),7.39–7.26(m,3H),7.14(t,J=9.3Hz,2H),7.04(d,J=7.9Hz,2H),6.66(d,J=8.0 Hz,1H),6.46(d,J=15.6Hz,1H),4.69(t,J=15.9Hz,1H),4.63–4.37(m,1H),3.13(dd,J=14.1, 5.6Hz,1H),2.93(dd,J=14.0,7.8Hz,1H),1.63(ddd,J=34.5,19.3,6.0Hz,3H),1.05–0.86(m, 6H).

[0345] 13 C NMR (101MHz, CDCl3) δ198.42,172.80,166.07,142.03,134.45,134.36,132.87, 130.65,130.02,128.90,128.79,127.96,119.91,59.67,51.74,40.94,34.18,24.87,22.83,22.31.

[0346] Example 46: Preparation of Compound 4-46

[0347]

[0348] The preparation method was the same as compound 4-1 (850 mg, yield 80.0%).

[0349] 1 H NMR(400MHz, CDCl3)δ9.58(d,J=14.7Hz,1H),7.62(d,J=15.6Hz,1H),7.52–7.43 (m,2H),7.34(dd,J=5.0,1.6Hz,3H),7.09–6.96(m,3H),6.77(dd,J=16.0,8.6Hz,2H),6.43 (dt,J=18.9,8.9Hz,2H),4.75–4.65(m,1H),4.63–4.55(m,1H),3.68(d,J=24.1Hz,3H),3.08 (dt,J=12.7,6.3Hz,1H),3.04–2.92(m,1H),1.77–1.55(m,3H),0.99–0.89(m,6H).

[0350] 13 C NMR (101MHz, CDCl3) δ198.89,172.46,165.94,158.62,141.93,134.55,130.32, 129.96,128.88,127.92,119.93,114.15,59.95,55.10,51.63,40.98,34.15,24.84,22.89,22.23.

[0351] Example 47: Preparation of Compound 4-47

[0352]

[0353] The preparation method was the same as compound 4-1 (150 mg, yield 43.0%).

[0354] 1 H NMR (400MHz, CDCl3) δ9.65 (s, 1H), 7.60 (dd, J = 15.6, 8.8Hz, 1H), 7.53–7.45 (m, 3H),7.39–7.29(m,3H),7.24–7.10(m,3H),7.09–6.98(m,1H),6.42(ddd,J=38.7,24.8,8.2H z,2H),4.70(td,J=14.5,8.4Hz,2H),3.40(dd,J=14.1,5.7Hz,1H),3.08(dt,J=14.1,9.3Hz, 1H),1.73–1.54(m,3H),0.97–0.88(m,6H).

[0355] 13 C NMR (101MHz, CDCl3) δ198.05,172.54,165.95,141.98,135.64,134.53,133.06, 131.78,129.99,128.91,128.80,127.91,127.68,124.65,119.94,58.79,51.63,41.02,35.20,34.93,24.85,22.88,22.26.

[0356] Example 48: Preparation of Compound 4-48

[0357]

[0358] The preparation method was the same as compound 4-1 (230 mg, yield 65.3%).

[0359] 1H NMR (400MHz, CDCl3) δ9.54(d,J=9.6Hz,1H),7.62(d,J=15.6Hz,1H),7.50–7.39 (m,2H),7.35–7.22(m,4H),6.90(d,J=8.4Hz,1H),6.53(dd,J=17.5,7.3Hz,1H),4.83–4.72( m,1H),4.37(tt,J=34.8,6.6Hz,1H),1.86–1.50(m,10H),1.44(ddd,J=15.2,9.8,6.4Hz,1H), 1.41–1.25(m,2H),1.17–1.02(m,3H),1.01–0.93(m,6H).

[0360] 13 C NMR (101MHz, CDCl3) δ199.75,172.88,166.10,141.82,134.59,129.87,128.84, 127.89,120.17,56.86,51.71,41.17,36.00,33.88,33.63,32.50,26.24,26.05,25.95,24.90,22.88,22.42.

[0361] Example 49: Preparation of Compound 4-49

[0362]

[0363] The preparation method was the same as compound 4-1 (230 mg, yield 56.0%).

[0364] 1 H NMR (400MHz, CDCl3) δ9.60 (t, J=7.3Hz, 1H), 7.59 (dd, J=15.6, 6.7Hz, 1H), 7.52– 7.43(m,2H),7.39–7.29(m,3H),7.23(t,J=7.0Hz,1H),7.18–7.10(m,2H),7.06–6.92(m, 2H),6.51(d,J=8.3Hz,1H),6.45(dd,J=15.6,6.1Hz,1H),4.76–4.57(m,2H),3.24(dd,J= 14.0, 6.3Hz, 1H), 3.08 (dd, J=14.2, 7.4Hz, 1H), 1.75–1.51 (m, 3H), 0.91 (ddd, J=9.5, 6.3, 3.9Hz, 6H).

[0365] 13C NMR (101MHz, CDCl3) δ198.04,172.64,165.92,141.84,134.59,131.91,131.87, 129.91,129.05,128.97,128.88,127.89,124.36,124.33,122.87,120.03 ,115.56,115.34,59.04,51.66,41.11,29.71,28.30,24.84,22.86,22.25.

[0366] Example 50: Preparation of Compound 4-50

[0367]

[0368] The preparation method was the same as compound 4-1 (780 mg, yield 85.0%).

[0369] 1 H NMR (400MHz, CDCl3) δ9.47 (d, J=6.4Hz, 1H), 7.59 (t, J=10.6Hz, 2H), 7.40 (d, J= 7.5Hz,2H),7.27(dt,J=13.2,6.6Hz,3H),7.15(dt,J=11.7,7.0Hz,3H),7.08(t,J=6.1Hz,2H), 7.00(d,J=8.3Hz,1H),6.52(d,J=15.6Hz,1H),4.84(dd,J=14.0,7.6Hz,1H),4.37–4.23(m, 1H),2.69–2.53(m,2H),2.15(td,J=14.0,6.9Hz,1H),1.95–1.82(m,1H),1.82–1.64(m,3H), 0.97 (dd, J=16.0, 10.2Hz, 6H).

[0370] 13 C NMR (101MHz, CDCl3) δ199.00,173.11,166.21,141.85,140.41,134.55,129.86, 128.82,128.55,128.45,127.91,126.30,120.18,58.52,51.92,41.30,31.50,30.26,24.94,22.86,22.42.

[0371] Example 51: Preparation of Compound 4-51

[0372]

[0373] The preparation method was the same as compound 4-1 (500 mg, yield 46.0%).

[0374] 1 H NMR (400MHz, CDCl3) δ9.57 (s, 1H), 7.65–7.53 (m, 2H), 7.44 (t, J = 8.4Hz, 2H), 7.35 –7.27(m,3H),7.21–7.15(m,1H),7.12(d,J=5.6Hz,2H),7.01(d,J=4.0Hz,1H),6.75(d,J= 8.0Hz,1H),6.48(dd,J=15.6,5.7Hz,1H),4.79–4.65(m,1H),4.45(dd,J=13.7,7.0Hz,1H), 3.17(td,J=14.6,5.6Hz,1H),3.03–2.87(m,1H),1.76–1.60(m,2H),1.53(dd,J=15.1,6.4Hz,1H),0.98–0.85(m,6H).

[0375] 13 C NMR (101MHz, CDCl3) δ198.35,173.06,166.17,141.93,138.26,134.53,129.91, 129.35,128.87,127.92,127.47,127.18,119.96,59.78,51.79,40.93,34.31,24.89,22.83,22.28.

[0376] Example 52: Preparation of Compound 4-52

[0377]

[0378] The preparation method was the same as compound 4-1 (600 mg, yield 68.0%).

[0379] 1H NMR (400MHz, DMSO-d6) δ9.50(d,J=21.4Hz,1H),8.58(t,J=9.4Hz,1H),8.23(d,J =8.0Hz,1H),7.58(t,J=7.0Hz,4H),7.43(dt,J=11.7,10.5Hz,7H),6.74(t,J=13.4Hz,1H),4 .40(ddd,J=21.5,15.5,9.9Hz,2H),3.26(dd,J=13.9,3.8Hz,1H),2.89(dt,J=26.6,13.2Hz, 1H), 1.55 (dd, J=12.6, 6.2Hz, 1H), 1.50–1.30 (m, 2H), 0.91–0.77 (m, 6H).

[0380] 13 C NMR(101MHz,DMSO-d6)δ200.43,173.21,165.23,139.46,135.35,130.63,129.95, 129.40,127.94,125.36,122.41,59.57,51.47,41.41,33.54,24.69,23.28,22.04.

[0381] Example 53: Preparation of Compound 4-53

[0382]

[0383] The preparation method was the same as compound 4-1 (350 mg, yield 72.0%).

[0384] 1 H NMR (400MHz, CDCl3) δ9.60–9.49(m,1H),7.77(t,J=6.6Hz,1H),7.64–7.55(m,1H),7.47–7.37(m,2H),7.30(ddd,J=14.4,5.9,1.6Hz,3 H),6.89(dddd,J=23.1,19.1,14.6,5.1Hz,5H),6.53–6.43(m,1H),4.73(dt,J=22.6,7.8Hz,1H),4.66–4.56(m,1H),3.18(td,J=14.1, 5.7Hz, 1H), 3.02–2.91 (m, 1H), 1.70–1.44 (m, 3H), 0.85 (qdd, J = 16.8, 10.7, 6.1Hz, 8H).

[0385] 13C NMR (101MHz, CDCl3) δ198.75,173.19,166.19,141.87,134.54,130.18,130.09, 129.90,128.86,128.84,127.92,124.92,120.09,116.44,116.23,114.00,11 3.79,59.56,51.98,51.72,41.31,34.24,29.71,24.76,22.77,22.67,22.29.

[0386] Example 54: Preparation of Compound 4-54

[0387]

[0388] The preparation method was the same as compound 4-1 (550 mg, yield 69.0%).

[0389] 1 H NMR (400MHz, CDCl3) δ9.61 (s, 1H), 7.61 (d, J = 15.6Hz, 1H), 7.49 (d, J = 6.7Hz, 2H), 7.36(s,3H),7.16(d,J=7.0Hz,1H),7.13–7.05(m,2H),6.90(t,J=8.2Hz,2H),6.42(d,J=15. 6Hz,1H),6.35(d,J=8.0Hz,1H),4.72–4.57(m,2H),3.14(dd,J=14.2,6.0Hz,1H),2.99(dd,J= 14.2,7.4Hz,1H),1.75–1.55(m,3H),0.94(t,J=5.5Hz,6H).

[0390] 13 C NMR (101MHz, CDCl3) δ198.48,172.51,166.03,142.15,134.45,130.87,130.79, 130.06,128.93,127.93,119.75,115.70,115.49,59.78,51.67,40.78,34.13,24.84,22.85,22.22.

[0391] Example 55: Preparation of Compound 4-55

[0392]

[0393] The preparation method was the same as compound 4-1 (820 mg, yield 76.0%).

[0394] 1 H NMR (400MHz, CDCl3) δ9.41 (s, 1H), 7.56 (d, J = 15.4Hz, 1H), 7.46 (s, 2H), 7.34 (s, 3H),7.23(d,J=20.4Hz,9H),7.02(s,3H),6.72(s,1H),6.42(d,J=15.6Hz,1H),4.95(s,1H),4.51(s,1H),3.15–2.86(m,4H).

[0395] 13 C NMR (101MHz, CDCl3) δ198.56,171.39,165.82,141.98,136.32,135.56,134.50, 130.00,129.37,129.23,128.90,128.76,127.95,127.16,127.09,119.88,59.78,54.47,38.46,34.95.

[0396] Example 56: Preparation of Compound 4-56

[0397]

[0398] The preparation method was the same as compound 4-1 (660 mg, yield 62.0%).

[0399] 1 H NMR(400MHz, CDCl3)δ9.63(d,J=10.5Hz,1H),7.62(d,J=14.8Hz,1H),7.49(s,2H),7.35(s,3H),7.28–7.13(m,5H),6.92(s,1H),6 .47(d,J=13.9Hz,2H),4.70(d,J=5.6Hz,1H),4.53(s,1H),3.12(d,J=6.5Hz,2H),1.56(s,1H),1.22(d,J=29.4Hz,2H),0.94(dd,J= 16.1,6.6Hz,6H).

[0400] 13 C NMR (101MHz, CDCl3) δ198.31,167.68,159.72,134.65,129.90,129.27,128.82, 127.89,127.16,120.21,59.69,57.67,37.36,35.33,24.69,15.35,11.00.

[0401] Example 57: Preparation of Compound 4-57

[0402]

[0403] The preparation method was the same as compound 4-1 (740 mg, yield 77.0%).

[0404] 1 H NMR (400MHz, CDCl3) δ9.61 (s, 1H), 7.66 (d, J = 7.5Hz, 1H), 7.58 (dd, J = 15.1, 8.3Hz, 1H),7.47(dd,J=9.0,6.8Hz,2H),7.30(dd,J=10.4,5.0Hz,3H),7.24–7.03(m,6H),6.71(d,J= 9.5Hz,1H),6.58–6.50(m,1H),4.71(ddd,J=20.8,16.3,9.1Hz,2H),3.09(dd,J=14.1,6.6Hz, 1H),3.04–2.93(m,1H),1.07(s,9H).

[0405] 13 C NMR (101MHz, CDCl3) δ198.76,171.05,165.76,141.65,135.84,134.61,129.85, 129.20,128.86,128.82,128.69,127.91,127.00,120.53,60.39,59.76,35.27,34.91,26.69.

[0406] Example 58: Preparation of Compound 4-58

[0407]

[0408] The preparation method was the same as compound 4-1 (350 mg, yield 72.0%).

[0409] 1H NMR (400MHz, CDCl3) δ9.62 (s, 1H), 7.59 (dd, J=15.6, 5.1Hz, 1H), 7.48 (dd, J=6.6, 2.6Hz,2H),7.36–7.30(m,4H),7.17(ddd,J=12.3,10.4,7.1Hz,5H),6.71(d,J=8.1Hz,1H), 6.51–6.44(m,1H),4.72–4.62(m,2H),3.15(dd,J=14.1,6.3Hz,1H),3.10–3.00(m,1H),0.97 (t,J=7.4Hz,3H),0.92–0.84(m,4H).

[0410] 13 C NMR (101MHz, CDCl3) δ198.68,172.18,165.95,141.75,135.71,134.62,129.90, 129.25,128.88,128.76,127.91,127.07,120.16,59.85,54.28,35.02,31.95,29.72,29.68,29.38,25.89,22.71,14.14,9.93.

[0411] Example 59: Preparation of Compound 4-59

[0412]

[0413] The preparation method was the same as compound 4-1 (260 mg, yield 60.0%).

[0414] 1 H NMR (400MHz, CDCl3) δ9.60 (s, 1H), 7.62 (d, J = 15.5Hz, 1H), 7.48 (s, 2H), 7.35 (s, 3H), 7.28–7.16 (m, 6H), 7.05 (s, 1H), 6.50 (d, J = 14.5Hz, 1H), 4.67 (s, 1H), 4.03 (t, J = 38.2Hz, 3H), 3.06 (t, J = 32.6Hz, 2H).

[0415] 13 C NMR (101MHz, CDCl3) δ198.70,169.71,166.69,141.98,135.66,134.55,129.99, 129.24,128.89,128.81,127.96,127.15,119.75,59.94,43.39,34.91.

[0416] Example 60: Preparation of Compound 4-60

[0417]

[0418] The preparation method was the same as compound 4-1 (230 mg, yield 45.0%).

[0419] 1 H NMR (400MHz, CDCl3) δ9.52 (s, 1H), 7.57 (d, J = 15.7Hz, 1H), 7.48 (s, 2H), 7.37 (s, 3H),7.25–7.15(m,5H),7.10–6.98(m,4H),6.84(d,J=6.0Hz,1H),6.36(dd,J=15.5,6.2Hz, 2H), 4.86 (dd, J=14.4, 7.2Hz, 1H), 4.62 (q, J=6.6Hz, 1H), 3.18 (d, J=6.9Hz, 2H), 3.14–3.06 (m, 1H), 3.02 (dd, J=13.8, 7.2Hz, 1H).

[0420] 13 C NMR (101MHz, CDCl3) δ198.47,170.88,165.94,142.17,135.42,134.47,131.69, 130.04,129.26,128.91,128.80,127.95,127.13,124.48,119.62,115.34,59.77,53.66,35.07,31.27.

[0421] Example 61: Preparation of Compound 4-61

[0422]

[0423] The preparation method was the same as compound 4-1 (600 mg, yield 75.0%).

[0424] 1H NMR(400MHz, CDCl3)δ9.61(s,1H),7.59(d,J=15.6Hz,1H),7.50–7.45(m,2H),7.42(d,J=7.2Hz,1H),7.36–7.28(m,3H),7.24–7.1 8(m,2H),7.14(dd,J=10.4,7.7Hz,3H),6.80(d,J=8.0Hz,1H),6.53–6.44(m,1H),4.74(dd,J=14.4,7.5Hz,1H),4.62(q,J=7.1Hz, 1H), 3.15 (dd, J=14.1, 6.3Hz, 1H), 3.04 (dd, J=14.1, 7.4Hz, 1H), 1.93–1.79 (m, 1H), 1.77–1.63 (m, 1H), 1.47–1.34 (m, 2H), 0.99–0.87 (m, 3H).

[0425] 13 C NMR (101MHz, CDCl3) δ198.73,172.44,165.93,141.72,135.80,134.61,129.89, 129.25,128.88,128.73,127.90,127.03,120.19,59.89,53.01,34.98,34.77,18.87,13.86.

[0426] Example 62: Preparation of Compound 4-62

[0427]

[0428] The preparation method was the same as compound 4-1 (400 mg, yield 75.0%).

[0429] 1 H NMR(400MHz, CDCl3)δ9.62(d,J=8.2Hz,1H),7.60(d,J=15.6Hz,1H),7.53–7.45 (m,2H),7.39–7.32(m,3H),7.27–7.12(m,6H),6.51(d,J=7.5Hz,1H),6.43(dd,J=15.6,8. 1Hz, 1H), 4.78–4.60 (m, 2H), 3.23–3.13 (m, 1H), 3.06 (dd, J=14.1, 7.4Hz, 1H), 1.40 (dd, J= 30.9,6.9Hz,3H).

[0430] 13C NMR (101MHz, CDCl3) δ198.69,172.69,165.81,141.94,135.67,134.56,129.98, 129.26,128.91,128.76,127.91,127.08,119.91,59.88,48.75,34.94,18.24.

[0431] Example 63: Preparation of Compound 4-63

[0432]

[0433] The preparation method was the same as compound 4-1 (420 mg, yield 65.0%).

[0434] 1 H NMR (400MHz, CDCl3) δ9.64–9.55(m,1H),7.61(d,J=15.6Hz,1H),7.49(dd,J=6.5, 2.9Hz,2H),7.37–7.33(m,3H),7.25(d,J=5.2Hz,1H),7.22(d,J=7.5Hz,2H),7.20–7.09(m,4 H),6.42(dt,J=8.0,6.9Hz,2H),4.69(dd,J=14.7,8.5Hz,1H),4.61(dd,J=13.7,7.0Hz,1H), 3.20–3.11(m,1H),3.05(dd,J=14.1,7.3Hz,1H),1.87–1.49(m,10H),0.91(ddd,J=20.5,18.6,10.5Hz,3H).

[0435] 13 C NMR (101MHz, CDCl3) δ198.72,165.98,141.92,135.71,129.95,129.29,128.90, 128.75,127.92,127.05,119.96,59.84,51.02,39.49,35.02,34.12,33.55,32.83,26.34,26.13,26.00.

[0436] Example 64: Preparation of Compound 4-64

[0437]

[0438] The preparation method was the same as compound 4-1 (250 mg, yield 42.0%).

[0439] 1H NMR (400MHz, DMSO-d6) δ9.55–9.38(m,1H),8.65(dd,J=12.1,7.4Hz,1H),8.40(dd,J=15.2,8.5Hz,1H),7.55(d,J=6.9Hz,2H),7.45 –7.35(m,4H),7.26(s,4H),7.19(dd,J=13.6,6.9Hz,3H),7.15–7.07(m,2H),7.05–6.97(m,2H),6.69(dd,J=15.8,10.3Hz,1H),4.74 (td,J=9.3,4.9Hz,1H),4.36(dddd,J=21.0,9.1,7.5,4.7Hz,1H),3.24–3.11(m,1H),3.08–2.97(m,1H),2.90–2.67(m,2H).

[0440] 13 C NMR(101MHz,DMSO-d6)δ200.64,172.05,165.24,139.63,137.99,135.26,130.36, 130.01,129.78,129.68,129.42,128.72,128.02,126.80,125.79,122.19,60.21,54.09,37.98,33.81.

[0441] Example 65: Preparation of Compound 4-65

[0442]

[0443] The preparation method was the same as compound 4-1 (220 mg, yield 40.0%).

[0444] 1 H NMR (400MHz, DMSO-d6) δ9.47 (dd, J=36.7, 18.8Hz, 1H), 8.74–8.54 (m, 1H), 8.40 (dd,J=18.3,8.0Hz,1H),7.56(dd,J=18.0,6.9Hz,2H),7.47–7.33(m,4H),7.33–7.15(m,7H), 7.13–7.04(m,2H),6.69(dd,J=18.7,16.1Hz,1H),4.69(s,1H),4.32(s,1H ), 3.16 (t, J = 14.1Hz, 1H), 3.01 (t, J = 13.5Hz, 1H), 2.85 (d, J = 20.7Hz, 2H).

[0445] 13 C NMR(101MHz,DMSO-d6)δ200.67,172.13,165.28,139.64,131.46,131.39,130.03, 129.66,129.42,128.71,128.01,126.80,115.38,115.17,60.18,54.39,33.77.

[0446] Example 66: Preparation of Compound 4-66

[0447]

[0448] The preparation method was the same as compound 4-1 (200 mg, yield 30.0%).

[0449] 1 H NMR (400MHz, CDCl3) δ9.63 (t, J = 10.2 Hz, 1H), 7.94 (s, 1H), 7.72 (dd, J = 15.4, 4.0 Hz,1H),7.47(dt,J=26.4,14.1Hz,6H),7.24–7.09(m,5H),6.74–6.56(m,1H),4.78(d,J=4. 5Hz,1H),4.72–4.61(m,1H),3.60–3.49(m,2H),3.28–3.15(m,1H),3.01–2.86(m,1H),2.46 (d,J=4.3Hz,1H),1.98(s,2H),1.86–1.75(m,1H).

[0450] 13 C NMR (101MHz, CDCl3) δ199.49,143.59,130.14,129.34,128.98,128.49,128.04, 126.75,117.55,59.68,47.30,34.99,26.57.

[0451] Example 67: Preparation of Compound 4-67

[0452]

[0453] Diethyl phosphonoacetate (57uL, 0.30mmol) was dissolved in an appropriate amount of anhydrous tetrahydrofuran and filled with argon. It was added dropwise to a tetrahydrofuran solution of sodium di(trimethylsilyl)amide at -78°C and stirred for 30min. Then the aldehyde (100mg, 0.25mmol) was dissolved in tetrahydrofuran and added dropwise to the above reaction solution, and stirring was continued for 2h. After the reaction was complete, 1M hydrochloric acid solution was added to quench the reaction. The solvent was removed by vacuum rotary evaporation, dissolved in an appropriate amount of dichloromethane, washed with water, saturated citric acid, saturated sodium bicarbonate and saturated brine in turn, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was spin-dried to obtain a crude product. The crude product was separated by silica gel column chromatography to obtain a white solid (80mg, 78%).

[0454] 1 H NMR (400MHz, CDCl3) δ7.61 (d, J=15.6Hz, 1H), 7.49 (dd, J=6.6, 2.9Hz, 2H), 7.39– 7.33(m,3H),7.20–7.15(m,2H),7.12(dd,J=12.8,7.8Hz,3H),7.05(d,J=8.5Hz,1H),6.94 (dd,J=15.7,5.2Hz,1H),6.39(dd,J=15.6,6.2Hz,1H),6.33(d,J=8.4Hz,1H),5.95–5.85(m, 1H),5.01–4.82(m,1H),4.70–4.55(m,1H),3.71(d,J=3.3Hz,3H),2.93–2.75(m,2H),1.74–1.51(m,3H),0.93(dt,J=13.0,6.5Hz,6H).

[0455] 13 C NMR (101MHz, CDCl3) δ171.64,166.54,166.06,147.06,141.88,136.30,134.56, 129.98,129.33,128.92,128.54,127.90,126.76,121.02,120.05,51.83,51.69,51.15,40.66,40.52,24.84,22.89,22.32.

[0456] Example 68: Preparation of Compound 4-68

[0457]

[0458] Aldehyde (100 mg, 0.25 mmol) was dissolved in acetonitrile, and diethyl cyanomethylphosphonate (50 uL, 0.30 mmol), lithium chloride (13 mg, 0.30 mmol) and DBU (58 uL, 0.38 mmol) were added in sequence, and stirred at room temperature for 2 h. After the reaction was complete, saturated ammonium chloride solution was added to quench. The solvent was removed by rotary evaporation under reduced pressure, dissolved with an appropriate amount of dichloromethane, washed with water, saturated citric acid, saturated sodium bicarbonate and saturated brine in sequence, the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was dried to obtain a crude product. The crude product was separated by silica gel column chromatography to obtain a white solid (60 mg, 59%).

[0459] 1 H NMR (400MHz, CDCl3) δ7.61 (dd, J=9.9, 5.7Hz, 1H), 7.51–7.45 (m, 2H), 7.39–7.33 (m,3H),7.18(dt,J=23.4,7.4Hz,5H),7.09(d,J=7.0Hz,1H),6.66(dd,J=16.4,5.2Hz,1H), 6.41–6.29(m,2H),4.91–4.73(m,1H),4.69–4.50(m,1H),3.64–3.47(m, 1H), 3.07 (dd, J=17.2, 9.7Hz, 1H), 1.76–1.56 (m, 3H), 0.96–0.87 (m, 6H).

[0460] 13 C NMR (101MHz, CDCl3) δ171.89,166.51,166.36,153.28,142.27,137.46,134.38, 130.18,129.19,128.99,128.94,128.76,128.68,127.94,127.12,119 .68,110.67,100.41,51.88,41.81,40.03,24.87,22.86,22.18,16.64.

[0461] Example 69: Preparation of Compound 4-69

[0462]

[0463] Aldehyde (100 mg, 0.25 mmol) was dissolved in 50.0 mL of anhydrous tetrahydrofuran solution. The system was placed under an argon atmosphere, and ethyl magnesium bromide (1.25 mL, 1 M, 1.25 mmol) was added dropwise using a constant pressure dropping funnel at -20°C. After the addition, the reaction system was stirred at -20°C for 4 h. After the reaction was complete, the solvent was evaporated under reduced pressure to obtain a crude product. The crude product was used to prepare compound 4-69 (70 mg, 68%) by the Dess-Martin oxidation method.

[0464] 1 H NMR (400MHz, CDCl3) δ7.64 (dd, J=15.6, 6.8Hz, 1H), 7.51–7.42 (m, 2H), 7.35–7.31 (m,3H),7.24–7.18(m,2H),7.18–7.14(m,1H),7.13–7.07(m,3H),6.49(d,J=8.3Hz,1H),6 .44(d,J=15.6Hz,1H),4.85–4.75(m,1H),4.68(td,J=8.5,5.6Hz,1H),3.12–3.03(m,1H), 2.99–2.92(m,1H),2.48–2.28(m,2H),1.67(tt,J=12.8,6.3Hz,2H),1.58(dd,J=8.7,7.5Hz,1H),1.00(t,J=7.2Hz,3H),0.92(t,J=7.6Hz,6H).

[0465] 13 C NMR (101MHz, CDCl3) δ209.03,172.04,165.83,141.73,136.02,134.68,129.84, 129.21,128.85,128.65,127.89,126.99,120.16,58.94,51.74,41.30,37.60,34.21,24.85,22.90,22.24,7.34.

[0466] Example 70: Preparation of Compound 4-70

[0467]

[0468] The preparation method was the same as compound 4-69 (70 mg, 68%).

[0469] 1H NMR (400MHz, CDCl3) δ7.63 (dd, J=15.6, 7.3Hz, 1H), 7.48 (dd, J=6.5, 2.8Hz, 2H), 7.36–7.29(m,3H),7.23–7.11(m,4H),7.08(d,J=6.9Hz,2H),6.56(d,J=8.4Hz,1H),6.51–6.32(m,3H),5.84(dd,J=9.8,1.7Hz,1H),5 .20–5.08(m,1H),4.71(td,J=8.4,5.7Hz,1H),3.15(dd,J=13.9,6.3Hz,1H),3.04–2.93(m,1H),1.73–1.55(m,3H),0.96–0.88(m,6H).

[0470] 13 C NMR (101MHz, CDCl3) δ197.11,172.01,165.75,141.64,135.67,134.74,133.33, 130.45,129.79,129.47,128.84,128.51,127.89,126.96,120.28,57.14,51.79,41.49,37.55,24.85,22.88,22.27.

[0471] Example 71: Inhibitor cytotoxicity in vitro (CC 50 )experiment

[0472] RD cells were seeded in 96-well plates and incubated in a 37°C 5% CO2 incubator for 24 hours. The inhibitors to be tested were diluted into working solutions of 100μM, 33.33μM, 11.11μM, 3.70μM, 1.23μM, 0.41μM, 0.14μM, 0.046μM and 0.015μM, respectively. The cell supernatant in the 96-well plate was aspirated, and 100μL of inhibitor working solution of different concentrations was added to each well. Each concentration was repeated 3 times. A cell control group was set up at the same time and cultured at 37°C 5% CO2 for 24 hours. The cytotoxicity of the inhibitor was detected using the WST-1 cell proliferation and cytotoxicity detection kit (Roche). 10μL WST-1 was added to each well for live cell staining. After 1 hour, the fluorescence value was read at 490nM on an ELISA reader, and the data were analyzed using GraphPad Prism 7.0. The results are shown in the following table.

[0473] Example 72: In vitro cell activity of inhibitors (EC 50 )experiment

[0474] For the evaluation of SARS-CoV-2 cell activity inhibition, the P3 laboratory of the Wuhan Institute of Virology, Chinese Academy of Sciences, infected cells with SARS-CoV-2 virus (GISAID accession no.EPI_ISL_402124) at a certain MOI, added different test compounds to the cells, and preliminarily screened out compounds that may inhibit virus proliferation by observing the cell pathological changes. The inhibitory effect of the drug on the virus was further clarified by testing the cytotoxicity of the candidate drug and the effect of the drug on the virus titer, and the EC value of the test drug on the virus was determined. 50 (half effective concentration) to evaluate the inhibitory effect of the drug on the virus. The results are shown in the following table.

[0475]

[0476]

[0477]

[0478]

[0479]

[0480] 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 compound of the following formula or a pharmaceutically acceptable salt thereof:

2. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

3. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating diseases caused by SARS-CoV-2 infection in mammals.

4. The use according to claim 3, wherein: Mammals are humans.

5. The use according to claim 3, wherein: The disease caused by SARS-CoV-2 infection is novel coronavirus pneumonia.

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