Beta-nucleoside compound for inhibiting coronavirus as well as synthesis and application of beta-nucleoside compound

Abstract

The invention discloses a beta-nucleoside compound for inhibiting coronavirus as well as synthesis and application thereof, the compound has a structure as shown in formula 1, # imgabs0 is used for treating human coronavirus in coronaviridae and coronavirus alpha and beta.

Description

Technical Field

[0001] The present invention relates to a class of β-nucleoside compounds for inhibiting coronaviruses, and their synthesis and application, belonging to the technical field of medicinal chemistry. Background Art

[0002] Coronaviruses belong to the order Nidovirales, family Coronaviridae, and genus Coronavirus. They are a type of RNA virus with an envelope and a linear, single-stranded, positive-sense genome. They are a widespread group of viruses in nature. Under an electron microscope, these viruses have a crown-like shape resembling that of the sun's corona, hence the name Coronavirus (Coronaviridae). In 1975, the Committee on Nomenclature of Viruses officially named the Coronaviridae family. These include rhinoviruses, B814 virus, 229E virus, strain 0C43, as well as those that can infect humans and cause severe respiratory illnesses, such as Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS, a variant of coronavirus), and the novel coronavirus (SARS-CoV-2). Symptoms of infection can range from the common cold to severe lung infections.

[0003] Potential targets for COVID-19 are divided into three categories: structural proteins, non-structural proteins, and other coronavirus treatment-related targets. Structural proteins include spike protein (Surface Glycoprotein, Spike Protein), E protein (Envelope protein, E Protein), membrane protein (M protein) and nucleocapsid phosphoprotein (N protein). Non-structural proteins include replicase polyprotein 1ab, 3C-like protease, papain-like protease, NSP12 (RDRP, RNA-dependent RNA polymerase), helicase, Nsp13 (RNA helicase), Nsp14 (Guanine-N7 methyltransferase), Nsp15 (Uridylate-specific endoribonuclease), and Nsp16 (2'-0-methyl transferase). Other coronavirus treatment-related targets are mainly ACE2 (angiotensin-converting enzyme 2).

[0004] There are three main types of COVID-19 treatments, each with different focuses and applicable populations: small molecule antivirals for mild, moderate, and severe cases; neutralizing antibodies primarily for mild and moderate cases; and immunomodulatory drugs, primarily for severe cases. Currently, small molecule COVID-19 antivirals primarily include RNA polymerase inhibitors and 3CL protease inhibitors, depending on their mechanism of action. Globally, only three new small molecule COVID-19 treatments have been approved: Gilead Sciences' remdesivir, molnupiravir (co-developed by Merck and Ridgeback), Shanghai Wangshi Biopharmaceuticals' VV116 (deuterium-containing remdesivir hydrobromide) and a 3CL protease inhibitor, and Pfizer's Paxlovid. However, to date, no single drug has proven to be a specific treatment for COVID-19 or other coronaviruses.

[0005] The molecular structure of SARS-CoV-2 RNA is a biopolymer primarily composed of four nucleotide monomers (G, C, A, and U) through condensation reactions. It is known that SARS-CoV-2 RNA molecules are composed of over 29,000 nucleotides. This means that the generation of a single daughter SARS-CoV-2 RNA molecule requires over 29,000 nucleotide monomers to undergo condensation reactions between acidic and alcoholic hydroxyl groups and the growing daughter SARS-CoV-2 RNA chain, generating a single daughter SARS-CoV-2 RNA molecule containing over 29,000 nucleotides. Once generated, the daughter SARS-CoV-2 RNA molecule has the ability to direct the synthesis of 29 SARS-CoV-2 proteins, which damage various organs and tissues in the host body, causing the various symptoms and pains of COVID-19 in patients.

[0006] At the same time, the process of generating progeny SARS-CoV-2 RNA also gives us 29,000 opportunities; using appropriate synthetic compounds, "impersonating" normal nucleotides, undergoing condensation reactions with the progeny SARS-CoV-2 RNA growth chain, and embedding into the progeny SARS-CoV-2 RNA growth chain, thereby destroying the normal sequence arrangement of the progeny SARS-CoV-2 RNA growth chain or stopping its growth.

[0007] The information disclosed in this background technology section is only intended to enhance understanding of the overall background of the invention and should not be regarded as an admission or any form of suggestion that the information constitutes the prior art already known to a person skilled in the art. Summary of the Invention

[0008] The object of the present invention is to provide a β-nucleoside compound to overcome the above-mentioned defects in the prior art.

[0009] To achieve the above objectives, the present invention provides a class of β-nucleoside compounds that inhibit coronaviruses, the structure of which is shown in Formula 1: ;

[0010] R1~R 14 and R are selected as follows:

[0011] (C1-C8)alkyl, monosubstituted or polysubstituted (C1-C8)alkyl; (C2-C8)alkenyl, monosubstituted or polysubstituted (C2-C8)alkenyl; (C2-C8)alkynyl, monosubstituted or polysubstituted (C2-C8)alkynyl; (C3-C8)cycloalkyl, monosubstituted or polysubstituted (C3-C8)cycloalkyl; (C3-C8)cycloalkenyl, monosubstituted or polysubstituted (C3-C8)cycloalkenyl; (C6-C 20 ) aryl, monosubstituted or polysubstituted (C6-C 20 ) aryl; 3-8 membered heterocyclic group, monosubstituted or polysubstituted 3-8 membered heterocyclic group, any carbon atom of which can be replaced by -Se-, -NR-, -O- or -S-; (C6-C 20 ) heteroaryl, monosubstituted or polysubstituted (C6-C 20 ) heteroaryl, any carbon atom of which may be replaced by -Se-, -NR-, -O- or -S-; (C6-C 20 ) aryl (C1-C8) alkyl, mono- or polysubstituted (C6-C 20 ) aryl (C1-C8) alkyl; (C6-C 20 ) aryl-monosubstituted or polysubstituted (C1-C8) alkyl; monosubstituted or polysubstituted (C6-C 20 )aryl-monosubstituted or polysubstituted (C1-C8)alkyl; (C1-C8)alkyl-(C6-C 20 )aryl, monosubstituted or polysubstituted (C1-C8)alkyl-(C6-C 20 ) aryl; (C1-C8) alkyl-monosubstituted or polysubstituted-(C6-C 20 ) aryl; monosubstituted or polysubstituted (C1-C8) alkyl-monosubstituted or polysubstituted (C6-C 20 )aryl; HC=O, (C1-C7)alkyl-C=O, monosubstituted or polysubstituted (C1-C7)alkyl-C=O; (C6-C 20 ) aryl-C=O, monosubstituted or polysubstituted (C6-C 20 )Aryl-C=O; (C6-C 20 ) aryloxy, mono- or polysubstituted (C6-C 20 )aryloxy;

[0012] definition:

[0013] (1) Substituents or substitutions include halogen, -OH, -OR, -NO2, -N(R)O, -NR2 (each R can be selected from the same element or different elements in the R set), -NH2, -NHR, -CN, -C=N=N, -CHO, -N3, -COOH, -COOR, -SH, -SR, -COSH, -COSR; thiocyanate, oxycyanate, methylcyanate, urea, and guanidinium.

[0014] (2) Polysubstitution means selecting multiple substituents of the same type or multiple substituents of different types.

[0015] (3) Monosubstitution means that only one substituent is selected.

[0016] Further preferably, R1 and R2 have the following options:

[0017] Class A selection of R1 and R2: R1 and R2 each select OH or OR;

[0018] Category B selection for R1 and R2: select type I, type II, type III, type IV and R or OH;

[0019]

[0020] In the B-type expression, R a 、R b 、R c 、R d and R e Each of them may be H, halogen; (C1-C8) alkyl, mono- or poly-substituted (C1-C8) alkyl; (C3-C8) cycloalkyl, mono- or poly-substituted (C3-C8) cycloalkyl; (C1-C8) alkoxy, mono- or poly-substituted (C1-C8) alkoxy; (C3-C8) cycloalkoxy, mono- or poly-substituted (C3-C8) cycloalkoxy; (C6-C 20 ) aryl, monosubstituted or polysubstituted (C6-C 20 ) aryl.

[0021] R in Type I b and R c This patent gives priority to the use of ethylene, (C3-C8) cycloalkyl, monosubstituted or polysubstituted ethylene, monosubstituted or polysubstituted (C3-C8) cycloalkyl.

[0022] Therefore, from the molecular structures of the four compounds Z10-B, Z10-BA, Z10-BB, and Z10-BC in the Z10-B series that are finally preferred in this patent, it can be seen that they all go beyond the scope of protection of the remdesivir-related patents and are the molecular structures of innovative compounds. However, the molecular structures of the applied compounds finally implemented in some previously approved and published novel coronavirus compound patents, such as the VV116 and shen 26 patents, may not go beyond the scope of protection of the remdesivir-related patents. Therefore, the publication of this patent will help to make up for this shortcoming.

[0023] Further preferably, after appropriately selecting R1 and R2, the specific structure of the compound of Formula 1 is the compound shown in Formula 2, the compound shown in Formula 3, the compound shown in Formula 4, or the compound shown in Formula 5;

[0024] .

[0025] Further preferably, R3, R4, R5, R6, R7 and R8 are each selected from H, a substituent as defined, and (C1-C8)alkyl, mono-substituted or poly-substituted (C1-C8)alkyl; (C1-C8)alkoxy, mono-substituted or poly-substituted (C1-C8)alkoxy; (C3-C8)cycloalkyl, mono-substituted or poly-substituted (C3-C8)cycloalkyl; (C3-C8)cycloalkoxy, mono-substituted or poly-substituted (C3-C8)cycloalkoxy; (C2-C8)alkenyl, mono-substituted or poly-substituted (C1-C8)alkenyl; (C2-C8)alkynyl, mono-substituted or poly-substituted (C1-C8)alkynyl.

[0026] Further preferably, after appropriately selecting R3, R4, R5, R6, R7 and R8, the specific structure of the compound of Formula 2 is the compound shown in Formula 2-A and the compound shown in Formula 2-B, the specific structure of the compound of Formula 3 is the compound shown in Formula 3-A and the compound shown in Formula 3-B, the specific structure of the compound of Formula 4 is the compound shown in Formula 4-A and the compound shown in Formula 4-B, and the specific structure of the compound of Formula 5 is the compound shown in Formula 5-A and the compound shown in Formula 5-B;

[0027] .

[0028] Further preferably, R5 and R7 can also be selected from the following: (C1-C7)alkyl-C(O)O-, monosubstituted or polysubstituted (C1-C7)alkyl-C(O)O-, (C1-C7)alkoxy-C(O)O-, monosubstituted or polysubstituted (C1-C7)alkoxy-C(O)O-, (C1-C7)alkyl-C(O)-NH-, monosubstituted or polysubstituted (C1-C7)alkyl-C(O)-NH-, (C1-C7)alkoxy-C(O)-NH-, monosubstituted or polysubstituted (C1-C7)alkoxy-C(O)-NH-, (C1-C7)alkyl-C(O)-NR-, Mono- or poly-substituted (C1-C7)alkyl-C(O)-NR-, (C1-C7)alkoxy-C(O)-NR-, mono- or poly-substituted (C1-C7)alkoxy-C(O)-NR-, (C6-C 20 ) aryl-C(O)-O-, monosubstituted or polysubstituted (C6-C 20 ) aryl-C(O)-O-, (C6-C 20 ) aryl-C(O)-NH-, monosubstituted or polysubstituted (C6-C 20 ) aryl-C(O)-NH-, (C6-C 20 ) aryl-C(O)-NR-, monosubstituted or polysubstituted (C6-C 20 )aryl-C(O)-NR-, (C1-C7)alkyl-C(O)S-, mono- or poly-substituted (C1-C7)alkyl-C(O)-S-, (C1-C7)alkoxy-C(O)S-, mono- or poly-substituted (C1-C7)alkoxy-C(O)-S-.

[0029] More preferably, R8 can also be selected from: -C(O)-NH2, -C(O)-NHR, -C(O)-NRR.

[0030] Further preferably, R9 and R10 can be H, -NH2, -NHR, -NRR, respectively, and the two Rs can be selected from the same or different groups in the R set, such as -OH, -SeH, -SH, -COOH, -COOR, -COSH, -COSR, -NH2·HX; HX is hydrobromic acid, fumaric acid, or other pharmaceutically acceptable inorganic or organic acids;

[0031] R11 and R12 can be H, D and halogen respectively;

[0032] R13 and R14 can be H, (C1-C8) alkyl, mono-substituted or poly-substituted (C1-C8) alkyl; (C1-C8) alkoxy, mono-substituted or poly-substituted (C1-C8) alkoxy; (C2-C8) alkenyl, mono-substituted or poly-substituted (C2-C8) alkenyl; (C2-C8) alkynyl, mono-substituted or poly-substituted (C2-C8) alkynyl; (C3-C8) cycloalkyl, mono-substituted or poly-substituted (C3-C8) cycloalkyl; (C6-C20) aryl, mono-substituted or poly-substituted (C6-C20) aryl; 3-8 membered heterocyclyl, mono-substituted or poly-substituted 3-8 membered heterocyclyl, any carbon atom of which can be replaced by -Se-, -NR-, -O- or -S-.

[0033] Further preferably, by appropriately selecting R9, R10, R11, R12, R13 and R14, compounds of formula 2-C and formula 2-D can be obtained from compounds of formula 2-A and formula 2-B, respectively;

[0034] From the compounds of formula 3-A and formula 3-B, compounds of formula 3-C and formula 3-D are obtained;

[0035] From the compounds represented by formula 4-A and formula 4-B, compounds represented by formula 4-C and formula 4-D are obtained;

[0036] Formula 5-C and Formula 5-D are obtained from the compounds represented by Formula 5-A and Formula 5-B;

[0037] Among them, formula 2-C is a collection of 32 structural formulas selected from its structural cluster, namely formula 2-Ci, where i = 1, 2, 3…32;

[0038] Formula 2-D is a general term for selecting 5 structural formulas from its structural cluster, formula 2-Di, where i = 1, 2, 3…5;

[0039]

[0040]

[0041]

[0042]

[0043] .

[0044] More preferably, the -NH2 on the base reacts with an acid to form a salt structure -NH2·HX. Compounds represented by formulas 2-Ci (i = 1, 2, 3, ... 32) and 2-Dj (j = 1, 2, 3, 4, 5) are obtained from compounds represented by formulas 2-Ei (i = 1, 2, 3, ... 32) and 2-Fj (j = 1, 2, 3, 4, 5). For example, compounds represented by formula 2-C1 can be obtained from compounds represented by 2-E1, and compounds represented by formula 2-D1 can be obtained from compounds represented by 2-F1. Compounds represented by formulas 3-C and 3-D can be obtained from compounds represented by formulas 3-E and 3-F. Compounds represented by formulas 4-C and 4-D can be obtained from compounds represented by formulas 4-E and 4-F. Compounds represented by formulas 5-C and 5-D can be obtained from compounds represented by formulas 5-E and 5-F. The molecular structures are as follows:

[0045] .

[0046] More preferably, HX can be selected from HBr, fumaric acid and other pharmaceutically acceptable organic or inorganic acids.

[0047] Further preferably, the ribose structure in Formula 1 can be the following:

[0048] Option a: ,

[0049] wherein R3, R4, R5, R6, R7 and R8 are each a substituent as defined, (C1-C8)alkyl, monosubstituted or polysubstituted (C1-C8)alkyl; (C1-C8)alkoxy, monosubstituted or polysubstituted (C1-C8)alkoxy; (C3-C8)cycloalkyl, monosubstituted or polysubstituted (C3-C8)cycloalkyl; (C3-C8)cycloalkoxy, monosubstituted or polysubstituted (C3-C8)cycloalkoxy; (C2-C8)alkenyl, monosubstituted or polysubstituted (C2-C8)alkenyl; (C2-C8)alkynyl, monosubstituted or polysubstituted (C2-C8)alkynyl; (C6-C 20 ) aryl, monosubstituted or polysubstituted (C6-C 20 ) aryl; R9, R 10 Each is H, deuterium D or halogen, halogen is F or Cl;

[0050] Option b: ,

[0051] wherein X is -O- or -S- or -Se-; R3, R6, R7 and R8 are each a "substituent" as defined, (C1-C8) alkyl, monosubstituted or polysubstituted (C1-C8) alkyl; (C1-C8) alkoxy, monosubstituted or polysubstituted (C1-C8) alkoxy; (C3-C8) cycloalkyl, monosubstituted or polysubstituted (C3-C8) cycloalkyl; (C3-C8) cycloalkoxy, monosubstituted or polysubstituted (C3-C8) cycloalkoxy; (C2-C8) alkenyl, monosubstituted or polysubstituted (C2-C8) alkenyl; (C2-C8) alkynyl, monosubstituted or polysubstituted (C2-C8) alkynyl; (C6-C 20 ) aryl, monosubstituted or polysubstituted (C6-C 20 ) aryl; R9, R 10 Each is H, deuterium D or halogen, halogen is F or Cl;

[0052] Select c: ;

[0053] wherein R4 (except the -OH group in the substituent), R6, R7 and R8 are each a substituent as defined, (C1-C8) alkyl, monosubstituted or polysubstituted (C1-C8) alkyl; (C1-C8) alkoxy, monosubstituted or polysubstituted (C1-C8) alkoxy; (C3-C8) cycloalkyl, monosubstituted or polysubstituted (C3-C8) cycloalkyl; (C3-C8) cycloalkoxy, monosubstituted or polysubstituted (C3-C8) cycloalkoxy; (C2-C8) alkenyl, monosubstituted or polysubstituted (C2-C8) alkenyl; (C2-C8) alkynyl, monosubstituted or polysubstituted (C2-C8) alkynyl; (C6-C 20 ) aryl, monosubstituted or polysubstituted (C6-C 20 ) aryl; R9, R 10 Each is H, deuterium D or halogen, halogen is F or C1; R4 substituents exclude -OH;

[0054] Option d: ,

[0055] wherein R3, R4, R5, R6 and R8 are each a substituent as defined, (C1-C8)alkyl, monosubstituted or polysubstituted (C1-C8)alkyl; (C1-C8)alkoxy, monosubstituted or polysubstituted (C1-C8)alkoxy; (C3-C8)cycloalkyl, monosubstituted or polysubstituted (C3-C8)cycloalkyl; (C3-C8)cycloalkoxy, monosubstituted or polysubstituted (C3-C8)cycloalkoxy; (C2-C8)alkenyl, monosubstituted or polysubstituted (C2-C8)alkenyl; (C2-C8)alkynyl, monosubstituted or polysubstituted (C2-C8)alkynyl; (C6-C 20 ) aryl, monosubstituted or polysubstituted (C6-C 20 ) aryl; R9, R10 Each is H, deuterium D or halogen, halogen is F or C1; R4 and R6 substituents exclude -OH;

[0056] Since ribose has four types, a, b, c, and d, any molecular structure mentioned previously in this patent can be derived into four related molecular structures, including its original structure. The molecular structure of type a is often the original molecular structure. For example, using Formula 2-C1, compounds represented by Formulas 2-C1 / a, 2-C1 / b, 2-C1 / c, and 2-C1 / d can be derived.

[0057] .

[0058] As described above, β-nucleoside compounds have inhibitory effects in treating human coronaviruses and covid-19 viruses in the coronavirus family, coronavirus α and β genera.

[0059] It should be noted that the bases connected to the compounds mentioned in this disclosure are not limited to the bases discussed above. When reading this disclosure, researchers should know that in addition to the bases used in the compounds listed above, they should also include bases existing in nature such as adenine, guanine, cytosine, thymine, uracil, appropriately transformed forms of bases, and other synthetic bases that are not common in nature.

[0060] When the phosphorus atom and the carbon atom are connected to four different groups, the phosphorus atom and the carbon atom have chirality. The above-mentioned compounds involving chiral phosphorus and chiral carbon should include optically active isomers of R and S configurations.

[0061] In the above-mentioned compounds, H, C, O, N, P, S and halogen atoms all have isotopes. When reading this patent, researchers should be aware that the compounds described in this patent should include compounds composed of their isotopes.

[0062] Compared with the prior art, the present invention has the following beneficial effects:

[0063] (a) Before being embedded in the progeny viral RNA growth chain, it has the function of inhibiting polymerase activity. Once embedded in the progeny viral RNA growth chain, it can disrupt the normal sequencing of the gene sequence of the progeny viral RNA growth chain or stop its growth.

[0064] (b) Particularly suitable for human coronavirus 229E and NL63 in the α genus of the Coronaviridae family; particularly suitable for human coronavirus HKU1, OC43, and COVID-COV-2 in the β genus of the Coronaviridae family; pneumonia and respiratory infections caused by severe acute respiratory syndrome (SARS).

[0065] (c) "Double compounds" are usually used. The difference between them is that one compound can destroy the normal genetic sequence of the progeny viral RNA growth chain after insertion, while the other compound can stop the growth of the progeny viral RNA growth chain after insertion. BRIEF DESCRIPTION OF THE DRAWINGS

[0066] Figure 1 Example 1 Compound C;

[0067] Figure 2 Example 1 compound D;

[0068] Figure 3 Example 1 Compound G;

[0069] Figure 4 Example 1 Compound H;

[0070] Figure 5 Example 1 compound 2-C1;

[0071] Figure 6 Example 2 Compound C;

[0072] Figure 7 Example 2 compound D;

[0073] Figure 8 Example 2 compound G;

[0074] Figure 9 Example 2 compound H;

[0075] Figure 10 Example 2 Compound J;

[0076] Figure 11 Example 2 compound K;

[0077] Figure 12 Example 2 Compound M( 1 H NMR);

[0078] Figure 13 Example 2 Compound M( 19 F NMR);

[0079] Figure 14 Example 2 Compound 2-D1( 31 P NMR);

[0080] Figure 15 Example 2 Compound 2-D1( 1H NMR);

[0081] Figure 16 Example 2 Compound 2-D1( 19 F NMR);

[0082] Figure 17 Example 3 compound G (intermediate 1);

[0083] Figure 18 Example 3 compound G (intermediate 2);

[0084] Figure 19 Example 3 compound G;

[0085] Figure 20 Example 3 Compound I;

[0086] Figure 21 Example 3 compound C;

[0087] Figure 22 Example 3 compound D;

[0088] Figure 23 Example 3 compound 2-C3;

[0089] Figure 24 Example 4 Compound F;

[0090] Figure 25 Example 4 Compound G;

[0091] Figure 26 Example 4 Compound H;

[0092] Figure 27 Example 4 Compound J;

[0093] Figure 28 Example 4 Compound K;

[0094] Figure 29 Example 4 compound 2-C7;

[0095] Figure 30 Example 5 compound A (solvent: DMSO-d6);

[0096] Figure 31 Example 5 Compound A (Solvent: DMSO-d6 + D2O);

[0097] Figure 32Example 5 Compound B;

[0098] Figure 33 Example 5 Compound C;

[0099] Figure 34 Example 5 Compound G;

[0100] Figure 35 Example 5 Compound J;

[0101] Figure 36 Example 5 compound 2-C28;

[0102] Figure 37 Example 6 compound 2-C25;

[0103] Figure 38 Example 7 Compound F;

[0104] Figure 39 Example 7 Compound B;

[0105] Figure 40 Example 7 Compound C;

[0106] Figure 41 Example 7 Compound D;

[0107] Figure 42 Example 7 Compound E;

[0108] Figure 43 Example 7 compound 2-C22;

[0109] Figure 44 Example 8 compound 2-C19-1;

[0110] Figure 45 Example 8 compound 2-C19-2;

[0111] Figure 46 Example 9 compound G;

[0112] Figure 47 Example 9 compound 2-C4;

[0113] Figure 48 Example 10 compound C;

[0114] Figure 49 Example 10 compound F;

[0115] Figure 50 Example 10 compound E;

[0116] Figure 51 Example 10 compound G;

[0117] Figure 52 Example 10 compound 2-C2;

[0118] Figure 53 Example 11 compound O;

[0119] Figure 54 Example 11 compound P;

[0120] Figure 55 Example 11 compound B;

[0121] Figure 56 Example 11 compound C;

[0122] Figure 57 Example 11 compound E;

[0123] Figure 58 Example 11 compound H;

[0124] Figure 59 Example 11 compound I;

[0125] Figure 60 Example 11 compound J;

[0126] Figure 61 Example 11 compound K;

[0127] Figure 62 Example 11 compound L;

[0128] Figure 63 Example 11 compound 2-C32;

[0129] Figure 64 Example 12 compound C;

[0130] Figure 65 Example 12 compound D;

[0131] Figure 66 Example 12 compound H;

[0132] Figure 67Example 12 compound 2-C1;

[0133] Figure 68 Example 12 compound 2-E;

[0134] Figure 69 Example 13 compound 2-F. DETAILED DESCRIPTION

[0135] The specific embodiments of the present invention are described in detail below, but it should be understood that the protection scope of the present invention is not limited by the specific embodiments.

[0136] Unless expressly stated otherwise, throughout the specification and claims, the term "comprise" or variations such as "include" or "comprising", etc., will be understood to include the stated elements or components but not to exclude other elements or other components.

[0137] Example 1

[0138]

[0139] Compound A (4.5 g) was mixed with compound B (90 mL), 70 o C, TMSCl (26.5 g) was added under N2, 70 o C overnight, the reaction solution was concentrated and pumped dry, Et2O was added to make a slurry, the insoluble matter was removed by filtration, and the filtrate was concentrated and pumped dry to obtain compound C (8.21 g, light brown glassy solid).

[0140] 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 3H), 4.07 (d, 2H), 1.52 (m, 1H), 1.33 (m, 7H), 1.28 (m, 1H), 0.86 (m, 6H), 0.66 – 0.57 (m, 1H), 0.53 (m, 3H).

[0141]

[0142] Compound C (4.89 g) was dissolved in DCM (100 mL, dry) at -78 o C, add phenyl dichlorophosphate (3.78 g) dropwise under N2, then add Et3N (3.78 g) dropwise, stir at rt for 6 h, 0 oA solution of pentafluorophenol (3 g) in DCM (50 mL, dry) was added dropwise at 4°C, followed by Et3N (1.81 g). The mixture was stirred at rt overnight. The reaction solution was concentrated and purified by column chromatography (PE / EA = 20 / 1) to obtain compound D (5.27 g, colorless oily liquid).

[0143] 1 H NMR (400 MHz, Chloroform-d) δ 7.35 (t, 2H), 7.30 – 7.15 (m, 3H), 4.33 (m, 1H), 4.16 – 4.01 (m, 2H), 1.62 (m, 3H), 1.53 (m, 1H), 1.36 (m, 4H), 1.27 – 1.19 (m, 1H), 0.89 (m, 6H), 0.57 – 0.38 (m, 4H).

[0144]

[0145] Compound E (6 g) was mixed in acetone (100 mL), compound F (10.3 g) was added at rt, and then H2SO4 (2.63 g) was added dropwise, and stirred at rt for 30 min. o C for 30 min, the reaction solution was cooled to rt, and solid NaHCO3 (16.07 g) and H2O (6 mL) were added in sequence and stirred for 15 min. The reaction solution was concentrated, water was added, and extracted with EA. The organic phase was separated and dried over anhydrous Na2SO4. The anhydrous Na2SO4 was removed by filtration, and the filtrate was concentrated and passed through a column (DCM / MeOH=20 / 1) to obtain compound G (7.21 g, white solid).

[0146] 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 2H), 7.96 (s, 1H), 6.95 – 6.87(m, 2H), 5.38 (d, 1H), 5.03 (t, 1H), 4.90 (dd, 1H), 4.32 (td, 1H), 3.61 –3.45 (m, 2H), 1.64 (s, 3H), 1.37 (s, 3H).

[0147]

[0148] Compound G (500 mg), compound D (1.13 g) and MgCl2 (144 mg) were mixed in MeCN (30 mL, dry). oC, stirred under N2 for 10 min, then DIEA (488 mg), 90 o The mixture was stirred at 400 °C for 6 h, then compound D (162 mg) and MgCl₂ (144 mg) were added. The mixture was stirred for 10 min, followed by the addition of DIEA (488 mg). The mixture was stirred for another 2 h, cooled to room temperature, diluted with EA, and washed sequentially with 5% citric acid solution, saturated ammonium chloride solution, saturated NaHCO₃ solution, and saturated NaCl. The organic phase was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and filtered through a column chromatography (DCM / MeOH = 80 / 1) to afford product H (953 mg, white solid).

[0149] 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (d, 3H), 7.29 (m, 2H), 7.19 – 7.06(m, 3H), 6.91 (d, 1H), 6.84 (m, 1H), 5.64 (m, 1H), 5.36 (t, 1 / 2H), 5.18 (t,1 / 2H), 5.00 – 4.91 (m, 1 / 2H), 4.86 (m, 1 / 2H), 4.53 (m, 1H), 4.13 (m, 2H), 3.98 – 3.83 (m, 2H), 1.63 (d, 3H), 1.48 – 1.12 (m, 12H), 0.81 (t, 6H), 0.40 –0.23 (m, 4H).

[0150]

[0151] Compound H (799 mg) was dissolved in HCOOH (20 mL, v / v = 80% in water) and stirred at rt for 3 h. The reaction solution was concentrated and filtered through a column (DCM / MeOH = 50 / 1-30 / 1) to obtain the product 2-C1 (634 mg, white solid).

[0152] 1H NMR (400 MHz, DMSO-d6) δ 7.91 (d, 3H), 7.38 – 7.26 (m, 2H), 7.22 –7.10 (m, 3H), 6.89 (m, 1H), 6.82 (d, 1H), 6.31 (m, 1H), 5.64 – 5.53 (m, 1H),5.38 (d, 1H), 4.66 (m, 1H), 4.25 (m, 2H), 4.20 – 4.07 (m, 1H), 3.95 (m, 2H),3.92 – 3.84 (m, 1H), 1.44 (m, 1H), 1.37 – 1.11 (m, 8H), 0.80 (m, 6H), 0.47 –0.21 (m, 4H).

[0153] Example 2

[0154]

[0155]

[0156] Compound A (4.5 g) was mixed with compound B (90 mL), 70 o C, TMSCl (26.5 g) was added under N2, 70 o C overnight, the reaction solution was concentrated and pumped dry, Et2O was added to make a slurry, the insoluble matter was removed by filtration, and the filtrate was concentrated and pumped dry to obtain compound C (8.21 g, light brown glassy solid).

[0157] 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 3H), 4.07 (d, 2H), 1.52 (m, 1H), 1.33 (m, 7H), 1.28 (m, 1H), 0.86 (m, 6H), 0.66 – 0.57 (m, 1H), 0.53 (m, 3H).

[0158]

[0159] Compound C (4.89 g) was dissolved in DCM (100 mL, dry) at -78 o C, add phenyl dichlorophosphate (3.78 g) dropwise under N2, then add Et3N (3.78 g) dropwise, stir at rt for 6 h, 0 oA solution of pentafluorophenol (3 g) in DCM (50 mL, dry) was added dropwise at 4°C, followed by Et3N (1.81 g). The mixture was stirred at rt overnight. The reaction solution was concentrated and purified by column chromatography (PE / EA = 20 / 1) to obtain compound D (5.27 g, colorless oily liquid).

[0160] 1 H NMR (400 MHz, Chloroform-d) δ 7.35 (t, 2H), 7.30 – 7.15 (m, 3H), 4.33 (m, 1H), 4.16 – 4.01 (m, 2H), 1.62 (m, 3H), 1.53 (m, 1H), 1.36 (m, 4H), 1.27 – 1.19 (m, 1H), 0.89 (m, 6H), 0.57 – 0.38 (m, 4H).

[0161]

[0162] Compound E (1 g) was dissolved in Pyridine (50 mL, dry), 0 o C, TIPDSCl (1.62 g) was added dropwise under N2, and stirred at rt overnight. o The reaction mixture was quenched by adding water dropwise at 4°C, and the reaction solution was concentrated and passed through a column (DCM / MeOH = 20 / 1) to obtain product G (1.05 g, light yellow solid).

[0163] 1 H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.56 (s, 1H), 8.10 (s, 1H), 7.16 (d, J = 4.5 Hz, 1H), 6.86 (d, J = 4.5 Hz, 1H), 6.54 (s, 1H), 4.54 (d, J = 3.4 Hz, 1H), 4.19 – 4.11 (m, 2H), 3.92 (d, J = 12.9 Hz, 1H), 1.24 (s, 1H), 1.11 – 0.79 (m, 28H).

[0164]

[0165] Compound G (2 g) was dissolved in DCM (100 mL, dry). AgNO (2.55 g), collidine (1.82 g), and MMTrCl (3.47 g) were added sequentially at rt under N. The mixture was stirred overnight at rt and quenched with MeOH dropwise. The mixture was filtered through a layer of Celite. The filtrate was concentrated and purified by column chromatography (PE / EA = 30 / 1-15 / 1) to afford product H (2.99 g, white solid).

[0166]

[0167] Compound H (2.86 g) was dissolved in THF (100 mL, dry). TBAF (5.30 mL, 1 M in THF) was added dropwise at 0°C under N2. The mixture was stirred at rt for 6 h. The reaction solution was quenched with water and extracted with EA. The organic phase was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and passed through a column chromatography (PE / EA = 10 / 1-1 / 1) to obtain product J (2.15 g, white solid).

[0168] 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 7.41 – 7.16 (m, 18H), 7.12 – 6.83 (m, 11H), 6.80 – 6.72 (m, 2H), 5.32 (d, 1H), 4.67 – 4.56 (m, 2H), 3.97(t, 1H), 3.73 (d, 6H), 3.24 (h, 2H), 2.88 (dd, 1H).

[0169]

[0170] Compound J (4 g), AgNO3 (2.44 g) and Collidine (2.90 g) were dissolved in DCM (200 mL, dry). MMTrCl (4.43 g) was added batchwise at rt under N2. The mixture was stirred overnight at rt. The reaction solution was filtered, and the filtrate was concentrated and passed through a column chromatography (PE / EA = 10 / 1-5 / 1) to obtain product K (2.47 g, white solid).

[0171] 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 7.49 – 6.99 (m, 39H), 6.89 (s, 2H), 6.78 (d, 2H), 6.67 (d, 3H), 5.50 (d, 1H), 4.49 (d,1H), 3.73 (s, 3H), 3.65 (d, 6H), 2.90 (dd, 1H), 2.74 (q, 2H).

[0172]

[0173] Compound K (1.99 g) and pyridine (1.42 g) were dissolved in DCM (50 mL, dry). DAST (1.45 g) was added dropwise at 0°C under N2 and stirring was continued for 5 min. The temperature was then raised to rt and stirring was continued for 4 h. The mixture was cooled to 0°C and quenched by adding saturated NaHCO3 solution dropwise. The mixture was extracted with DCM, and the organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and passed through a column (PE / EA=10 / 1-5 / 1) to obtain product L (1.03 g, light brown solid, impure).

[0174]

[0175] At rt, compound L (1.03 g) was dissolved in HCOOH (20 mL, V / V = 80% in water) and stirred for 1 h. The reaction solution was concentrated and separated on a reverse phase column (C18 column) to obtain product M (65 mg, white solid).

[0176] 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (m, 3H), 7.06 (d, 1H), 6.90 (t, 1H), 6.74 (d, 1H), 5.18 – 4.99 (m, 2H), 4.92 (dd, 1H), 4.44 (dtd, 1H), 3.70 (s,2H).

[0177] 19 F NMR (377 MHz, DMSO-d6) δ -198.15.

[0178]

[0179] Compound M (1.24 g) was dissolved in NMP (40 mL, dry). t-BuMgCl (6.34 mL, 1 Min THF) was added dropwise at 0°C under N2. Stirring was continued for 30 min. A solution of compound D (3.11 g) in THF (40 mL, dry) was added dropwise. The mixture was stirred at rt overnight. The reaction solution was quenched by adding MeOH dropwise, diluted with water, and extracted with DCM. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and passed through a column (DCM / MeOH = 40 / 1-20 / 1) to obtain the product 2-D1 (1.0 g, light yellow solid).

[0180] 1 H NMR (400 MHz, DMSO-d6) δ 8.08-7.80 (m, 3H), 7.41 – 7.31 (m, 2H), 7.22 (dt, 2H), 7.19 – 7.12 (m, 2H), 6.90 (d, 1H), 6.79 (q, 1H), 5.72 (dd,1H), 5.30 – 5.06 (m, 1H), 4.99 (dd, 1H), 4.83 – 4.60 (m, 1H), 4.32 (ddd, 2H),4.02 – 3.86 (m, 2H), 1.46 (dq, 1H), 1.37 – 1.18 (m, 8H), 0.82 (dd, 6H), 0.42 (dd, 1H), 0.34 (td, 3H).

[0181] 19 F NMR (377 MHz, DMSO-d6) δ -197.92.

[0182] 31 P NMR (162 MHz, DMSO-d6) δ 2.59, 2.26.

[0183] Example 3

[0184]

[0185] Compound A (2 g) and compound B (3.43 g) were mixed in acetone (100 mL), concentrated sulfuric acid (875 mg, 0.5 mL) was added dropwise at room temperature, stirred at room temperature for 30 min, and then heated to 45 oThe mixture was stirred at 40°C for 30 min, cooled to rt, and solid sodium bicarbonate (2.02 g) and water (1.98 g) were added. The mixture was stirred for 15 min, and the reaction solution was concentrated, water was added, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered to remove the anhydrous sodium sulfate. The filtrate was concentrated and filtered through a column chromatography (DCM / MeOH = 50 / 1-20 / 1) to obtain compound C (2.5 g, white solid).

[0186] 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 2H), 7.96 (s, 1H), 6.95 – 6.87(m, 2H), 5.38 (d, 1H), 5.03 (t, 1H), 4.90 (dd, 1H), 4.32 (td, 1H), 3.61 –3.45 (m, 2H), 1.64 (s, 3H), 1.37 (s, 3H).

[0187]

[0188] Compound F (2 g) and Et3N (4 g) were dissolved in dioxane / H2O (100 mL, V / V = 1 / 1). Boc2O (4.32 g) was added at rt and stirred overnight at rt. The reaction mixture was concentrated and extracted with EA. The organic phase was washed with saturated NaCl, separated, dried over anhydrous sodium sulfate, and filtered to remove the anhydrous sodium sulfate. The filtrate was concentrated, slurried with petroleum ether, filtered, and the filter cake was washed with petroleum ether. The filter cake was dried to obtain intermediate compound 1 (2.8 g, white solid).

[0189] 1 H NMR (400 MHz, DMSO-d6) δ 12.26 (s, 1H), 7.40 (s, 1H), 1.37 (s, 9H), 1.25 (q, 2H), 0.94 (q, 2H).

[0190] Intermediate compound 1 (2 g), 2-ethyl-1-butanol (1.32 g), EDCI (2.29 g), and DMAP (1.46 g) were dissolved in DCM (50 mL, dry). Et3N (1.11 g) was added at room temperature and stirred at room temperature for 3 h. The reaction mixture was concentrated and filtered through a column chromatography (PE / EA = 10 / 1) to afford intermediate 2 (2.13 g, colorless liquid).

[0191] 1H NMR (400 MHz, DMSO-d6) δ 7.52 (s, 1H), 3.92 (d, 2H), 1.38 (s, 9H), 1.35-1.26 (m, 6H), 1.00-0.98 (m, 2H), 0.86-0.82 (m, 7H).

[0192] The intermediate product 2 (1 g) was dissolved in toluene (30 mL), and toluenesulfonic acid crystalline hydrate (666 mg) was added. The water separator was added back to (135 o The reaction solution was concentrated and pumped dry to obtain the PTSA salt of compound G, which (1.25 g) was used directly in the next step without further treatment.

[0193] 1 H NMR (400 MHz, DMSO-d6) δ 8.65 (s, 3H), 7.52 – 7.45 (m, 2H), 7.12(d, 2H), 4.06 (d, 2H), 2.29 (s, 3H), 1.48 (h, 1H), 1.43 – 1.24 (m, 8H), 0.84(t, 6H).

[0194]

[0195] The PTSA salt of compound G (1.25 g) was dissolved in DCM (10 mL, dry). o Compound H (738 mg) was added dropwise at C and N2, stirred for 45 min, and then Et3N (780 mg) was added dropwise. The mixture was stirred at rt for 3 h. o p-Nitrophenol (487 mg) was added at 4°C, followed by Et3N (355 mg) dropwise. The mixture was stirred at rt overnight, washed with water, and then with saturated brine. The organic phase was dried over anhydrous sodium sulfate and filtered to remove the anhydrous sodium sulfate. The filtrate was concentrated and filtered through a column chromatography (PE / EA = 5 / 1-4 / 1) to obtain Compound I (1.26 g, colorless liquid).

[0196] 1H NMR (400 MHz, DMSO-d6) δ 8.35 – 8.26 (m, 2H), 7.52 – 7.45 (m, 2H), 7.41 (dd, 2H), 7.27 – 7.14 (m, 4H), 3.89 (d, 2H), 1.42 – 1.14 (m, 7H), 1.18 –1.04 (m, 2H), 0.77 (t, J = 7.4 Hz, 6H).

[0197]

[0198] Compound A (900 mg), Compound I (1.26 g) and MgCl2 (259 mg) were dissolved in MeCN (30 mL, dry). o The mixture was stirred at 40 °C for 10 min, DIEA (878 mg) was added, and stirred for 20 min. The mixture was cooled to room temperature, diluted with EA, and washed sequentially with 5% citric acid, saturated ammonium chloride, saturated sodium bicarbonate, and saturated brine, then dried over anhydrous sodium sulfate. Anhydrous sodium sulfate was removed by filtration, and the filtrate was concentrated and filtered through a column (DCM / MeOH = 40 / 1 to 20 / 1) to obtain compound D (1.18 g, white solid).

[0199] 1H NMR (400 MHz, Chloroform-d) δ 7.91 (d, J = 4.2 Hz, 1H), 7.26 (ddd,J = 15.8, 8.3, 6.5 Hz, 2H), 7.23 – 7.08 (m, 3H), 6.89 (dd, J = 10.3, 4.6 Hz,1H), 6.59 (dd, J = 7.3, 4.6 Hz, 1H), 6.09 (s, 2H), 5.41 (t, J = 7.1 Hz,0.5H), 5.23 (t, J = 6.6 Hz, 0.5H), 4.89 (ddd, J = 14.6, 6.8, 3.8 Hz, 1H),4.58 (q, J = 5.1 Hz, 1H), 4.54 – 4.30 (m, 3H), 4.00 – 3.89 (m, 2H), 1.75 (d,J = 2.2 Hz, 3H), 1.49 – 1.39 (m, 1H), 1.43 – 1.31 (m, 5H), 1.28 (tt, J = 7.1,5.8 Hz, 4H), 1.25 – 1.14 (m, 2H), 0.82 (td, J = 7.5, 1.7 Hz, 6H).

[0200]

[0201] Compound D (1.18 g) was dissolved in formic acid (20 mL, V / V = 80%) and stirred at room temperature overnight. The reaction mixture was concentrated and purified by column chromatography (DCM / MeOH = 20 / 1) to afford compound 2-C3 (775 mg, white solid).

[0202] 1H NMR (400 MHz, DMSO-d6) δ 7.92 (m, 3H), 7.38 – 7.27 (m, 2H), 7.21 –7.09 (m, 3H), 6.89 (t, 1H), 6.82 (d, 1H), 6.48 (dd, 1H), 6.33 (dd, 1H), 5.46– 5.35 (m, 1H), 4.65 (ddd, 1H), 4.25 (q, 2H), 4.14 (dt, 1H), 3.94 (dt, 1H), 3.89 (d, 2H), 1.39 (h, 1H), 1.24 (dq, 6H), 1.12 – 1.00 (m, 1H), 1.03 – 0.92 (m, 1H), 0.83 – 0.74 (m, 6H).

[0203] Example 4

[0204] ;

[0205] Compound A (6 g) was mixed in acetone (100 mL), compound a (10.3 g) was added at rt, and then H2SO4 (2.63 g) was added dropwise, and stirred at rt for 30 min. o C for 30 min, the reaction solution was cooled to rt, and solid NaHCO3 (16.07 g) and H2O (6 mL) were added in sequence and stirred for 15 min. The reaction solution was concentrated, water was added, and extracted with EA. The organic phase was separated and dried over anhydrous Na2SO4. The anhydrous Na2SO4 was removed by filtration, and the filtrate was concentrated and passed through a column (DCM / MeOH=20 / 1) to obtain compound B (7.21 g, white solid).

[0206] 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 2H), 7.96 (s, 1H), 6.95 – 6.87(m, 2H), 5.38 (d, 1H), 5.03 (t, 1H), 4.90 (dd, 1H), 4.32 (td, 1H), 3.61 –3.45 (m, 2H), 1.64 (s, 3H), 1.37 (s, 3H);

[0207] ;

[0208] Compound C (1 g), compound D (909 mg) and DMAP (848 mg) were dissolved in THF (20 mL, dry). A solution of DCC (1.79 g) in THF (20 mL, dry) was added dropwise at rt under N2. The mixture was refluxed with stirring overnight. The reaction solution was concentrated, EA was added with stirring, and the insoluble matter was removed by filtration. The filtrate was concentrated and passed through a column (PE / EA=10 / 1) to obtain compound F (1.28 g, colorless, transparent, oily liquid).

[0209] 1 H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 7.88 (m, 1H), 7.51 (m, 1H), 7.01 – 6.89 (m, 2H), 5.37 (p, 1H), 2.59 – 2.48 (m, 2H), 2.36 (d, 1H), 2.36 –2.28 (m, 1H), 2.13 (t, 4H).

[0210] ;

[0211] Compound E (10 g), compound b (19.82 g), and PTSA∙H₂O (18.45 g) were mixed in toluene (200 mL) and refluxed with a water trap for 24 h. The mixture was cooled to room temperature, concentrated, pumped dry, and slurried with Et₂O. The mixture was filtered, and the filter cake was washed with Et₂O and pumped dry to obtain compound G (26.09 g, as the PTSA salt, a white solid).

[0212] 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 3H), 7.51 – 7.44 (m, 2H), 7.12(d, 2H), 4.11 (d, 2H), 2.29 (s, 3H), 1.53 (m, 1H), 1.46 (s, 6H), 1.39 – 1.27 (m, 4H), 0.87 (t, 6H);

[0213] ;

[0214] Compound F (10 g) was dissolved in DCM (100 mL, dry) at -78 o C, POCl3 (7.2 g) was added under N2, and then Et3N (4.75 g) was added dropwise. o C for 4 h, then cooled to -78 oC, a solution of compound G (10.51 g) in DCM (100 mL, dry) was added dropwise, followed by Et3N (9.5 g), stirred at rt overnight, and cooled to 0 o C, add pentafluorophenol (9.43 g) in DCM (100 mL, dry) dropwise, followed by Et3N (9.5 g), and stir at room temperature until the reaction is complete. The reaction solution is concentrated and filtered through a column (PE / EA = 10 / 1 to 5 / 1) to obtain compound H (14.31 g, colorless, transparent, oily liquid).

[0215] 51 H NMR (400 MHz, Chloroform-d) δ 7.91 – 7.85 (m, 1H), 7.61 – 7.49 (m,2H), 7.30 (m, 1H), 5.57 (d, 1H), 5.45 (m, 1H), 4.08 – 3.99 (m, 2H), 2.64 (m,2H), 2.45 (m, 2H), 2.25 (m, 4H), 1.64 (s, 3H), 1.46 (s, 3H), 1.42 – 1.25 (m,4H), 1.25 (d,1H), 0.87 (t, 6H);

[0216] ;

[0217] Compound B (170 mg) was dissolved in THF (5 mL, dry). t-BuMgCl (1.08 mL, 1 M in THF) was added dropwise under N2 at rt. The mixture was stirred at rt for 30 min, and then a solution of compound H (400 mg) in THF (5 mL, dry) was added dropwise. The mixture was stirred at rt for 5 h. The reaction solution was quenched by adding MeOH dropwise, concentrated, and filtered through a column (DCM / MeOH = 50 / 1-20 / 1) to obtain compound I (279 mg, white solid).

[0218] 1H NMR (400 MHz, DMSO-d6) δ 7.94 (m, 3H), 7.82 (q, 1H), 7.58 – 7.49(m, 1H), 7.45 (d, 1H), 7.28 (q, 1H), 6.90 (d, 1H), 6.85 (m, 1H), 5.85 (m,1H), 5.36 (m, 1H), 5.28 – 5.19 (m, 1H), 4.95 (m, 1H), 4.59 – 4.50 (m, 1H), 4.19 (s, 2H), 3.92 – 3.81 (m, 2H), 2.49 – 2.41 (m, 1H), 2.33 (q, 2H), 2.08(q, 3H), 1.64 (s, 3H), 1.38 (m, 3H), 1.31 (d,6H), 1.30 – 1.18 (m, 6H), 0.79(m, 7H);

[0219] ;

[0220] Compound J (347 mg) was dissolved in aqueous formic acid (15 mL, V / V = 80%) and stirred for 2 h. The reaction solution was concentrated and filtered to obtain compound K (257 mg, white solid).

[0221] 1 H NMR (400 MHz, DMSO-d6) δ 8.02 – 7.85 (m, 3H), 7.85 – 7.79 (m, 1H), 7.60 – 7.46 (m, 2H), 7.28 (m, 1H), 6.93 – 6.78 (m, 2H), 6.33 (m, 1H), 5.80(d, J = 9.5 Hz, 1H), 5.37 (m, 1H), 5.33 – 5.25 (m, 1H), 4.67 (m, 1H), 4.44 –4.13 (m, 2H), 3.95 (m, 1H), 3.87 (m, 2H), 2.50 – 2.42 (m, 1H), 2.33 (m, 2H), 2.10 (m, 4H), 1.45 – 1.25 (m, 7H), 1.28 – 1.18 (m, 6H), 0.79 (m, 6H);

[0222] ;

[0223] Compound K (1.36 g) was dissolved in MeOH (50 mL), 0o NaBH4 (102 mg) was added at 400 °C, and the mixture was stirred at rt for 2 h. The mixture was quenched with water, and the reaction solution was concentrated and separated by reverse phase column to obtain compound 2-C7 (725 mg, white solid).

[0224] 1 H NMR (400 MHz, DMSO-d6) δ 8.04 – 7.80 (m, 3H), 7.79 – 7.68 (m, 1H), 7.57 – 7.45 (m, 2H), 7.27 (d, 1H), 6.92 – 6.79 (m, 2H), 6.33 (d,1H), 5.77 (m,1H), 5.39 (d, J = 5.5 Hz, 1H), 4.94 (s, 1H), 4.68 (d,1H), 4.56 (m, 1H), 4.36– 4.13 (m, 3H), 4.01 – 3.88 (m, 1H), 3.87 (m, 2H), 3.55 (d, 1H), 2.08 (s,1H), 2.01 – 1.94 (m, 1H), 1.92 – 1.79 (m, 2H), 1.69 – 1.53 (m, 4H), 1.44 –1.15 (m, 11H), 0.79 (m, 6H).

[0225] Example 5

[0226]

[0227] ;

[0228] Salicylic acid (1 g), 4-hydroxycyclohexanone (909 mg), and DMAP (848 mg) were dissolved in THF (20 mL, dry). A solution of DCC (1.79 g) in THF (20 mL, dry) was added dropwise at rt under N2. The mixture was refluxed with stirring overnight. The reaction solution was concentrated, and EA was added to dissolve the crude product. The insoluble matter was removed by filtration. The filtrate was concentrated and passed through a column chromatography (PE / EA=10 / 1) to give compound A (1.28 g, colorless, transparent, oily liquid).

[0229] 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 7.88 (dt, 1H), 7.51 (ddd,1H), 7.01 – 6.89 (m, 2H), 5.37 (p, 1H), 2.59 – 2.48 (m, 2H), 2.36 (d, 1H),2.36 – 2.28 (m, 1H), 2.13 (t, 4H);

[0230] ;

[0231] 2-Methylalanine (5 g) and 2-ethyl-1-butanol (50 g) were mixed in toluene (150 mL). p-Toluenesulfonic acid monohydrate (9.22 g) was added at rt. The mixture was refluxed for 25 h after a water separator was installed. After the reaction was completed, the mixture was cooled to rt. The reaction solution was concentrated, slurried with ether, filtered, and the filter cake was washed with ether. The filter cake was dried to obtain compound B (8.82 g, white solid, in the form of p-toluenesulfonate).

[0232] 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 3H), 7.47 (d, 2H), 7.11 (d, 2H), 4.10 (d, 2H), 2.29 (s, 3H), 1.55-1.50 (m, 1H), 1.46 (s, 6H), 1.37-1.30 (m,4H), 0.87 (t, 6H).

[0233]

[0234] Compound A (4 g) was dissolved in DCM (50 mL, dry). Phosphorus oxychloride (2.62 g) was added dropwise at -78°C under N₂. Et₃N (1.73 g) was then added dropwise. The mixture was stirred at -20°C to -30°C for 4 h. A solution of the p-toluenesulfonate salt of compound B (6.14 g) in DCM (20 mL, dry) was then added dropwise at -78°C, followed by Et₃N (3.63 g). The mixture was stirred at rt overnight. p-Nitrophenol (2.38 g) was added at 0°C, followed by Et₃N (1.73 g), and the reaction was stirred at rt until complete. Saturated NaHCO₃ solution was added dropwise at 0°C, and the mixture was extracted with DCM. The organic phase was separated, washed with brine, dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated and passed through a column chromatography (PE / EA = 5 / 1) to afford product C (3.9 g, a colorless, transparent oil).

[0235] 1 H NMR (400 MHz, DMSO-d6) δ 8.32 – 8.23 (m, 2H), 7.83 (d, 1H), 7.62(td, 1H), 7.56 (d, 1H), 7.46 (d, 2H), 7.32 (t, 1H), 6.53 (d, 1H), 5.23 (tt,1H), 3.84 (d, 2H), 2.46 – 2.24 (m, 4H), 2.15 – 1.92 (m, 4H), 1.38 (s, 6H),1.37 – 1.23 (m, 1H), 1.23 (s, 1H), 1.23 – 1.11 (m, 3H), 0.75 (t, 6H).

[0236]

[0237] Compound D (2 g) and 2,2-methoxypropane (3.43 g) were mixed in acetone (100 mL), concentrated sulfuric acid (875 mg, 0.5 mL) was added dropwise at room temperature, stirred at room temperature for 30 min, and then heated to 45 o C. and stirred for 30 min. The mixture was cooled to rt, solid sodium bicarbonate (2.02 g) and water (1.98 g) were added, and the mixture was stirred for 15 min. The reaction solution was concentrated, diluted with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated and passed through a column chromatography (DCM / MeOH=50 / 1-20 / 1) to obtain compound E (2.5 g, white solid).

[0238] 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 2H), 7.96 (s, 1H), 6.95 – 6.87(m, 2H), 5.38 (d, 1H), 5.03 (t, 1H), 4.90 (dd, 1H), 4.32 (td, 1H), 3.61 –3.45 (m, 2H), 1.64 (s, 3H), 1.37 (s, 3H).

[0239]

[0240] Compound E (300 mg), compound C (602 mg), and MgCl2 (86 mg) were dissolved in MeCN (10 mL, dry) under N2 and stirred at 50°C for 10 min. DIEA (293 mg) was added and stirred at 50°C overnight. The reaction solution was cooled to rt, diluted with EA, and washed sequentially with 5% citric acid solution, saturated NH4Cl solution, water, saturated NaHCO3, and brine. The product was dried over anhydrous sodium sulfate and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated and filtered through a column (DCM / MeOH = 20 / 1) to obtain compound F (468 mg, impure, white solid).

[0241]

[0242] Compound F (200 mL) was dissolved in THF (5 mL), and HCl (5 mL, 1 M in water) was added dropwise at rt. The mixture was stirred at 50°C for 6 h and cooled to rt. The reaction solution was concentrated and dissolved in EA. Saturated NaHCO3 solution was added to adjust the solution pH to 7. The organic phase was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and filtered through a column chromatography (DCM / MeOH = 20 / 1) to obtain compound G (140 mg, white solid).

[0243] 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (d, 1H), 7.87 (s, 2H), 7.80 (d, 1H), 7.58 – 7.47 (m, 1H), 7.47 (d, 1H), 7.26 (td, 1H), 6.86 (dd, 1H), 6.81 (dd,1H), 6.31 (dd, 1H), 5.81 – 5.71 (m, 1H), 5.35 (d, 1H), 5.30 – 5.23 (m, 1H), 4.65 (td, 1H), 4.28 (d, 1H), 4.25 – 4.12 (m, 2H), 3.93 (dt,1H), 3.85 (dd,2H), 2.47 – 2.39 (m, 2H), 2.36 – 2.25 (m, 2H), 2.08 (dd, 4H), 1.37 (p, 1H), 1.33 – 1.27 (m, 5H), 1.22 (dt, 5H), 0.77 (tt, 6H).

[0244]

[0245] Compound G (140 mg) was dissolved in THF (5 mL, dry), and DMF-DMA (49 mg) was added at rt. The mixture was stirred overnight at rt. The reaction solution was concentrated and filtered through a column (DCM / MeOH = 20 / 1) to obtain product H (127 mg, colorless, transparent, oily liquid).

[0246]

[0247] Compound H (576 mg) was dissolved in DCM (10 mL). EtN (251 mg), DMAP (43 mg), and compound I (281 mg) were added sequentially under N at rt. The mixture was stirred at rt for 8 h, quenched with methanol, and stirred for 30 min. The reaction solution was concentrated and purified by column chromatography (DCM / MeOH = 20 / 1) to obtain product J (492 mg, white solid).

[0248] 1 H NMR (400 MHz, DMSO-d6) δ 7.96 – 7.87 (m, 1H), 7.80 (d, 1H), 7.49(t, 1H), 7.43 (t, 1H), 7.24 (t, 1H), 6.92 – 6.69 (m, 2H), 6.11 – 6.02 (m,1H), 5.82 (t, 1H), 5.54 – 5.34 (m, 1H), 5.23 (s, 1H), 4.65 – 4.58 (m, 1H), 4.33 (d, 2H), 3.84 (t, 2H), 3.20 (d,3H), 2.87 (s, 1H), 2.71 (s, 1H), 2.65 –2.52 (m, 2H), 2.40 (dd, 2H), 2.27 (s, 1H), 2.08 (d, 3H), 1.41 – 1.00 (m,27H), 0.76 (t, 6H).

[0249]

[0250] Compound J (492 mg) was dissolved in THF (10 mL), and HCl (10 mL, 1 M in water) was added dropwise at rt. Stirring was continued for 1 h. The reaction solution was concentrated and purified by column chromatography (DCM / MeOH = 50 / 1-20 / 1) to afford product Z2-F (387 mg, white solid). Chiral separation afforded two compounds, 2-C28-1 (57 mg) and 2-C28-2 (50 mg).

[0251] Chromatographic column: Daicel CHIRALPAK® IG 250*30 mm, 10µm;

[0252] Mobile phase A: n-hexane;

[0253] Mobile phase B: isopropanol;

[0254] Detection wavelength: 254 nm;

[0255] Flow rate: 25 mL / min;

[0256] Column temperature: RT;

[0257] Run time: 20 minutes

[0258] Isocratic elution program: mobile phase A: mobile phase B = 70:30 (V / V);

[0259] 2-C28-1: 1 H NMR (400 MHz, DMSO-d6) δ 8.02 (s, 1H), 7.96 (s, 1H), 7.91 (s, 1H), 7.85 – 7.79 (m, 1H), 7.51 (ddd, 1H), 7.45 (d, 1H), 7.27 (dd, 1H), 6.91 (d, 1H), 6.79 (d, 1H), 6.09 (d, 1H), 5.83 (d, 1H), 5.44 (dd, 1H), 5.25(s, 1H), 4.64 – 4.58 (m, 1H), 4.35 (qt, 2H), 3.85 (dd, 2H), 2.59 (dp, 2H),2.49 – 2.41 (m, 2H), 2.33 (s, 4H), 2.09 (d, 5H), 1.32 – 1.25 (m, 7H), 1.28 –1.16 (m, 11H), 1.19 – 1.08 (m, 9H), 1.08 (s, 3H), 0.83 – 0.74 (m, 6H).

[0260] 2-C28-2: 1H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.92 (s, 2H), 7.82 (dd, J = 7.7, 1.6 Hz, 1H), 7.50 (td, J = 7.8, 7.3, 1.8 Hz, 1H), 7.44 (d, J =8.3 Hz, 1H), 7.27 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 4.6 Hz, 1H), 6.74 (d, J =4.6 Hz, 1H), 6.07 (d, J = 5.8 Hz, 1H), 5.87 (d, J = 9.7 Hz, 1H), 5.48 (dd, J= 5.8, 3.8 Hz, 1H), 5.25 (dd, J = 6.9, 3.6 Hz, 1H), 4.66 – 4.59 (m, 1H), 4.34(qt, J = 11.4, 5.5 Hz, 2H), 3.86 (d, J = 5.6 Hz, 2H), 2.60 (dp, J = 16.0, 7.1Hz, 2H), 2.49 – 2.41 (m, 1H), 2.36 – 2.26 (m, 2H), 2.09 (s, 4H), 1.32 – 1.21(m, 12H), 1.19 – 1.06 (m, 12H), 0.78 (td, J = 7.5, 2.0 Hz, 6H).

[0261] Example 6

[0262]

[0263] Salicylic acid (1 g), 4-hydroxycyclohexanone (909 mg), and DMAP (848 mg) were dissolved in THF (20 mL, dry). A solution of DCC (1.79 g) in THF (20 mL, dry) was added dropwise at rt under N2. The mixture was refluxed with stirring overnight. The reaction solution was concentrated, and EA was added to dissolve the crude product. The insoluble matter was removed by filtration. The filtrate was concentrated and passed through a column chromatography (PE / EA=10 / 1) to give compound A (1.28 g, colorless, transparent, oily liquid).

[0264] 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 7.88 (dt, 1H), 7.51 (ddd,1H), 7.01 – 6.89 (m, 2H), 5.37 (p, 1H), 2.59 – 2.48 (m, 2H), 2.36 (d, 1H),2.36 – 2.28 (m, 1H), 2.13 (t, 4H).

[0265]

[0266] 2-Methylalanine (5 g) and 2-ethyl-1-butanol (50 g) were mixed in toluene (150 mL). p-Toluenesulfonic acid monohydrate (9.22 g) was added at rt. The mixture was refluxed for 25 h after a water separator was installed. After the reaction was completed, the mixture was cooled to rt. The reaction solution was concentrated, slurried with ether, filtered, and the filter cake was washed with ether. The filter cake was dried to obtain compound B (8.82 g, white solid, in the form of p-toluenesulfonate).

[0267] 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 3H), 7.47 (d, 2H), 7.11 (d, 2H), 4.10 (d, 2H), 2.29 (s, 3H), 1.55-1.50 (m, 1H), 1.46 (s, 6H), 1.37-1.30 (m,4H), 0.87 (t, 6H).

[0268]

[0269] Compound A (4 g) was dissolved in DCM (50 mL, dry). Phosphorus oxychloride (2.62 g) was added dropwise at -78°C under N₂. Et₃N (1.73 g) was then added dropwise. The mixture was stirred at -20°C to -30°C for 4 h. A solution of the p-toluenesulfonate salt of compound B (6.14 g) in DCM (20 mL, dry) was then added dropwise at -78°C, followed by Et₃N (3.63 g). The mixture was stirred at rt overnight. p-Nitrophenol (2.38 g) was added at 0°C, followed by Et₃N (1.73 g), and the reaction was stirred at rt until complete. Saturated NaHCO₃ solution was added dropwise at 0°C, and the mixture was extracted with DCM. The organic phase was separated, washed with brine, dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated and passed through a column chromatography (PE / EA = 5 / 1) to afford product C (3.9 g, a colorless, transparent oil).

[0270] 1H NMR (400 MHz, DMSO-d6) δ 8.32 – 8.23 (m, 2H), 7.83 (d, 1H), 7.62(td, 1H), 7.56 (d, 1H), 7.46 (d, 2H), 7.32 (t, 1H), 6.53 (d, 1H), 5.23 (tt,1H), 3.84 (d, 2H), 2.46 – 2.24 (m, 4H), 2.15 – 1.92 (m, 4H), 1.38 (s, 6H),1.37 – 1.23 (m, 1H), 1.23 (s, 1H), 1.23 – 1.11 (m, 3H), 0.75 (t, 6H).

[0271]

[0272] Compound D (2 g) and 2,2-methoxypropane (3.43 g) were mixed in acetone (100 mL), concentrated sulfuric acid (875 mg, 0.5 mL) was added dropwise at room temperature, stirred at room temperature for 30 min, and then heated to 45 o C. and stirred for 30 min. The mixture was cooled to rt, solid sodium bicarbonate (2.02 g) and water (1.98 g) were added, and the mixture was stirred for 15 min. The reaction solution was concentrated, diluted with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated and passed through a column chromatography (DCM / MeOH=50 / 1-20 / 1) to obtain compound E (2.5 g, white solid).

[0273] 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 2H), 7.96 (s, 1H), 6.95 – 6.87(m, 2H), 5.38 (d, 1H), 5.03 (t, 1H), 4.90 (dd, 1H), 4.32 (td, 1H), 3.61 –3.45 (m, 2H), 1.64 (s, 3H), 1.37 (s, 3H).

[0274]

[0275] Compound E (300 mg), compound (602 mg) and MgCl2 (86 mg) were dissolved in MeCN (10 mL, dry) under N2 and stirred at 50°C for 10 min. DIEA (293 mg) was added and stirred at 50°C overnight. The reaction solution was cooled to rt, diluted with EA, and washed sequentially with 5% citric acid solution, saturated NH4Cl solution, water, saturated NaHCO3, and brine. The solution was dried over anhydrous sodium sulfate and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated and passed through a column (DCM / MeOH = 20 / 1) to obtain compound F (468 mg, impure, white solid).

[0276]

[0277] Compound F (200 mL) was dissolved in THF (5 mL), and HCl (5 mL, 1 M in water) was added dropwise at rt. The mixture was stirred at 50°C for 6 h and cooled to rt. The reaction solution was concentrated and dissolved in EA. Saturated NaHCO3 solution was added to adjust the solution pH to 7. The organic phase was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and filtered through a column chromatography (DCM / MeOH = 20 / 1) to obtain compound G (140 mg, white solid).

[0278] 1 H NMR (400 MHz, DMSO-d6) δ 7.89 (d, 1H), 7.87 (s, 2H), 7.80 (d, 1H), 7.58 – 7.47 (m, 1H), 7.47 (d, 1H), 7.26 (td, 1H), 6.86 (dd, 1H), 6.81 (dd,1H), 6.31 (dd, 1H), 5.81 – 5.71 (m, 1H), 5.35 (d, 1H), 5.30 – 5.23 (m, 1H), 4.65 (td, 1H), 4.28 (d, 1H), 4.25 – 4.12 (m, 2H), 3.93 (dt,1H), 3.85 (dd,2H), 2.47 – 2.39 (m, 2H), 2.36 – 2.25 (m, 2H), 2.08 (dd, 4H), 1.37 (p, 1H), 1.33 – 1.27 (m, 5H), 1.22 (dt, 5H), 0.77 (tt, 6H).

[0279]

[0280] Compound G (140 mg) was dissolved in THF (5 mL, dry), and DMF-DMA (49 mg) was added at rt. The mixture was stirred overnight at rt. The reaction solution was concentrated and filtered through a column (DCM / MeOH = 20 / 1) to obtain product H (127 mg, colorless, transparent, oily liquid).

[0281]

[0282] Compound H (576 mg) was dissolved in DCM (10 mL). Et3N (251 mg), DMAP (43 mg), and compound I (281 mg) were added sequentially under N2 at rt. The mixture was stirred at rt for 8 h, quenched with methanol, and stirred for 30 min. The reaction solution was concentrated and filtered through a column chromatography (DCM / MeOH = 20 / 1) to obtain product J (492 mg, white solid).

[0283] 1 H NMR (400 MHz, DMSO-d6) δ 7.96 – 7.87 (m, 1H), 7.80 (d, 1H), 7.49(t, 1H), 7.43 (t, 1H), 7.24 (t, 1H), 6.92 – 6.69 (m, 2H), 6.11 – 6.02 (m,1H), 5.82 (t, 1H), 5.54 – 5.34 (m, 1H), 5.23 (s, 1H), 4.65 – 4.58 (m, 1H), 4.33 (d, 2H), 3.84 (t, 2H), 3.20 (d,3H), 2.87 (s, 1H), 2.71 (s, 1H), 2.65 –2.52 (m, 2H), 2.40 (dd, 2H), 2.27 (s, 1H), 2.08 (d, 3H), 1.41 – 1.00 (m,27H), 0.76 (t, 6H).

[0284]

[0285] Compound J (492 mg) was dissolved in THF (10 mL), and HCl (10 mL, 1M in water) was added dropwise at rt. Stirring was continued for 1 h. The reaction solution was concentrated and filtered through a column (DCM / MeOH = 50 / 1-20 / 1) to obtain the product Z2-F (387 mg, white solid).

[0286]

[0287] Compound K (286 mg) was dissolved in MeOH (10 mL), and NaBH4 (24 mg) was added at 0°C. The mixture was stirred at rt overnight. The reaction solution was concentrated and filtered through a column (DCM / MeOH = 50 / 1-25 / 1) to give the product 2-C25 (62 mg, white solid).

[0288] 1 H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.94 (s, 1H), 7.90 (dd, J =4.2, 2.2 Hz, 1H), 7.71 (dd, J = 17.8, 7.7 Hz, 1H), 7.50 – 7.38 (m, 2H), 7.24(q, J = 8.3 Hz, 1H), 6.89 (dd, J = 7.9, 4.6 Hz, 1H), 6.81 – 6.70 (m, 1H), 6.07 (ddd, J = 8.4, 5.7, 3.0 Hz, 1H), 5.79 (q, J = 8.5, 8.0 Hz, 1H), 5.50 –5.39 (m, 1H), 4.90-4.8 (m, 1H), 4.57-4.48 (d, J = 4.0 Hz, 1H), 4.32 (dq, J =16.0, 4.9, 4.0 Hz, 2H), 3.85 (t, J = 5.1 Hz, 2H), 3.57-3.49 (m, 1H), 2.58(dp, J = 13.8, 6.9 Hz, 2H), 1.94 (s, 1H), 1.83 (s, 2H), 1.59 (d, J = 14.3 Hz,3H), 1.41 – 1.30 (m, 1H), 1.30 – 1.18 (m, 12H), 1.18 – 1.06 (m, 9H), 1.07 (d,J = 1.6 Hz, 4H), 0.87 – 0.73 (m, 6H).

[0289] Example 7

[0290]

[0291] Compound A (6.0 g) and DMF-DMA (18.4 mL) were dissolved in DMF (200 mL, dry) and stirred at room temperature for 1 h. The reaction solution was concentrated and stirred with a mixture of petroleum ether, ethyl acetate, and methanol for half an hour. The mixture was filtered and dried to obtain product B (7.03 g, white solid).

[0292] 1 H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.15 (s, 1H), 6.98 (d, 1H), 6.83 (d, 1H), 6.14 (d, 1H), 5.23 (d, 1H), 4.93 (t, 1H), 4.66 (t, 1H), 4.07 (q,1H), 3.98 (q, 1H), 3.64 (ddd, 1H), 3.51 (dt, 1H), 3.25 (s, 3H), 3.18 (s, 3H).

[0293]

[0294] Compound B (7.0 g) and imidazole (5.50 g) were dissolved in DMF (70 mL, dry). TBDPSCl (11.11 g) was added in an ice-water bath and stirred at room temperature for 2 h. The mixture was poured into water and extracted with ethyl acetate. The organic phase was separated and washed sequentially with dilute hydrochloric acid, saturated sodium carbonate solution, and saturated brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and filtered through a column chromatography (DCM / MeOH = 50 / 1-10 / 1) to obtain product C (6.7 g, yellow oil).

[0295]

[0296] Compound C (6.9 g), triethylamine (7.16 g), and DMAP (0.72 g) were dissolved in DCM (70 mL, dry). Isobutyric anhydride (7.47 g) was added dropwise in an ice-water bath and stirred at room temperature for 4 h. The mixture was poured into water and extracted with ethyl acetate. The organic phase was washed sequentially with saturated sodium carbonate solution and saturated sodium chloride, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and filtered through a column chromatography (DCM / MeOH = 50 / 1 to 20 / 1) to obtain product D (3.0 g, yellow oil).

[0297] 1H NMR (400 MHz, DMSO-d6) δ 9.00 – 8.96 (s, 1H), 8.14 – 8.09 (d, 1H), 7.54 – 7.48 (m, 2H), 7.47 – 7.28 (m, 6H), 7.21 – 7.13 (t, 2H), 6.79 – 6.73(dd, 1H), 6.69 – 6.63 (d, 1H), 6.16 – 6.10 (d, 1H), 5.69 – 5.62 (dd, 1H),4.55 – 4.50 (d, 1H), 3.89 – 3.81 (dd, 1H), 3.78 – 3.69 (dd, 1H), 3.28 – 3.24(s, 3H), 3.20 – 3.16 (s, 3H), 1.22 – 1.09 (m, 14H), 0.94 – 0.90 (s, 9H).

[0298]

[0299] Compound D (3.1 g) was dissolved in MeCN (30 mL), and trifluoroacetic acid (8 mL) and water (2 mL) were added dropwise. The mixture was stirred at 50°C for 16 h. Saturated sodium bicarbonate solution was added dropwise in an ice-water bath to adjust the pH to 7. The reaction solution was concentrated, separated using a C18 column, and lyophilized to obtain compound E (752 mg, white solid).

[0300] 1 H NMR (400 MHz, DMSO-d6) δ 7.96 (d, 3H), 6.92 (d, 1H), 6.77 (d, 1H), 5.98 (d, 1H), 5.42 (dd, 1H), 5.18 (t,1H), 4.39 (d, 1H), 3.63 (s, 2H), 1.23(s, 1H), 1.16(dd, 7H), 1.08(dd, 6H).

[0301] ;

[0302] Under N2 protection, 2-methylalanine 2-ethylbutyl ester p-toluenesulfonate (2.46 g) was dissolved in dichloromethane (50 mL, dry). Phosphorus oxychloride (1.0 g) was added, cooled to -78°C, and triethylamine (1.38 g) was added dropwise. Stirring was continued for 3 hours after the addition of a dichloromethane solution (20 mL, dry) of triethylamine (0.69 g) and ethyl o-hydroxybenzoate (1.14 g). Stirring was continued for 3 hours. Triethylamine (1.50 g) and p-nitrophenol (2.03 g) were added, and the temperature was raised to room temperature and stirred overnight. The reaction solution was concentrated and separated on a C18 column to afford Compound F (1.49 g, a yellow oil).

[0303] 1 H NMR (400 MHz, DMSO-d6) δ 8.35 – 8.26 (m, 2H), 7.79 – 7.72 (dt, 1H), 7.67 – 7.58 (ddd, 1H), 7.58 – 7.51 (d, 1H), 7.51 – 7.44 (m, 2H), 7.37 – 7.28(t, 1H), 6.60 – 6.53 (d, 1H), 4.27 – 4.14 (qt, 2H), 3.89 – 3.83 (d, 2H), 1.45– 1.38 (d, 6H), 1.29 – 1.18 (td, 8H), 0.86 – 0.73 (m, 6H).

[0304]

[0305] Under nitrogen protection, compound E (200 mg) was dissolved in dry DMF (5 mL, dry), cooled to 0°C, and t-BuMgCl (0.93 mL, 1 mol / L in THF) was added dropwise. The mixture was stirred for 30 min, followed by the dropwise addition of a solution of compound F (497 mg) in DMF (5 mL, dry). The temperature was raised to 50°C, and stirred for 2 h. The reaction mixture was quenched by the dropwise addition of saturated ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The mixture was separated by a C18 column and lyophilized to afford product 2-C22 (239 mg, white solid).

[0306] 1H NMR (400 MHz, DMSO-d6) δ 8.00 (d, 2H), 7.92 (d, 1H), 7.73 (d, 1H), 7.55 – 7.39 (m, 2H), 7.26 (t, 1H), 6.90 (dd, 1H), 6.77 (dd, 1H), 6.07 (dd,1H), 5.86 (dd, 1H), 5.46 (ddd, 1H), 4.63 (s, 1H), 4.33 (dd, 2H), 4.28 – 4.19 (m, 2H), 3.90 – 3.83 (m, 2H), 2.65 – 2.55 (m, 2H), 1.39 (dq, 1H), 1.29 (s,6H), 1.24 (tdd, 7H), 1.15 (ddd, 6H), 1.10 (d, 6H), 0.79 (td, 6H).

[0307] Example 8

[0308]

[0309] Compound A (7 g) was dissolved in DCM (140 mL), and DMP (10.7 g) was added. The mixture was stirred at rt for 4 h. The reaction solution was concentrated, and EA and NaHCO3 solution were added. The mixture was stirred for 30 min and filtered. The filtrate was extracted with EA, and the organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to give compound B (7 g, yellow solid).

[0310]

[0311] Compound B (7 g) was dissolved in a mixture of DMSO (100 mL) and water (25 mL). TMSCN (7 mL) was added and stirred at room temperature for 3 h. The reaction mixture was poured into water (200 mL) and extracted with EA. The organic phase was separated, washed with brine, dried over anhydrous NaSO, filtered, and the filtrate concentrated to yield compound C (7 g, yellow solid).

[0312]

[0313] Compound D (20.3 g) and 2-ethyl-1-butanol (12.3 g) were dissolved in DCM (200 mL), and HATU (45.6 g) and (25.3 g) were added. The mixture was stirred at rt for 2 d. The reaction solution was concentrated, diluted with EA, and washed with brine. The organic phase was dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and separated by column chromatography (PE / EA=10 / 1) to obtain a colorless oil (24 g). HCl in EA solution (200 mL) was added and stirred at rt overnight. The reaction solution was concentrated and pumped dry to obtain compound E (15 g, white solid).

[0314]

[0315] Compound E (3.6 g) was dissolved in DCM (50 mL), cooled to -78°C, compound F (3.4 g) was added, and a solution of Et3N (2.0 g) in DCM (10 mL) was added dropwise. The mixture was heated to rt and stirred for 7 h. The reaction solution was concentrated, methyl tert-butyl ether (50 mL) was added, stirred for 5 min, filtered, and the filtrate was concentrated to give compound G (6.3 g, yellow oil).

[0316]

[0317] Compound C (7 g) was dissolved in DCM (140 mL). Et3N (6 mL) was added at 0°C, followed by compound F (5.3 g). The mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in EA (150 mL), and washed with brine. The organic phase was separated, dried over anhydrous Na2SO4, filtered, and the filtrate concentrated to afford compound G (12 g, brown solid).

[0318]

[0319] Compound H (12 g) was dissolved in THF (120 mL), and water (25 mL) and concentrated hydrochloric acid (25 mL) were added. The temperature was raised to 65°C and stirred for 3 h. The reaction solution was poured into ice water (150 mL) and extracted with EA. The organic phase was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated to obtain a crude product (6.8 g). Compounds 2-C19-1 (190 mg, white solid) and 2-C19-2 (119 mg, white solid) were separated on a C18 column.

[0320] 2-C19-1: 1H NMR (400 MHz, DMSO-d6) δ 8.01-7.88 (m, 3H), 7.30-7.26 (m,2H), 7.17- 7.12 (m, 3H), 6.91-6.90 (m, 1H), 6.83-6.82 (m, 1H), 6.45-6.43 (m,1H), 6.32-6.29 (m, 1H), 5.57-5.50 (m, 2H), 4.64 (s, 1H), 4.40-4.38 (m, 1H),4.10-4.08 (m, 1H), 3.92 (d, 2H), 1.46-1.24 (m, 11H), 0.86-0.75 (m, 6H).

[0321] 2-C19-1: 1 H NMR (400 MHz, DMSO-d6) δ 8.01-7.88 (m, 3H), 7.40-7.35 (m,2H), 7.24-7.18 (m, 3H), 6.91 (d, 2H), 6.49-6.40 (m, 2H), 5.77 (s, 1H), 5.65-5.63 (m, 1H), 4.88 (t, 1H), 4.41-4.36 (m, 1H), 4.20-4.18 (m,1H), 3.95-3.92(m, 2H), 1.46-1.23 (m, 11H), 0.81 (t,6H).

[0322] Example 9

[0323] ;

[0324] Compound A (5 g) and compound B (50 g) were mixed in toluene (150 mL), and p-toluenesulfonic acid monohydrate (9.22 g) was added at rt. After installing a water separator, the mixture was refluxed for 25 h. After the reaction was completed, it was cooled to rt, the reaction solution was concentrated, slurried with ether, filtered, and the filter cake was washed with ether. The filter cake was dried to obtain compound C (8.82 g, white solid, in the form of p-toluenesulfonate).

[0325] 1H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 3H), 7.47 (d, 2H), 7.11 (d, 2H), 4.10 (d, 2H), 2.29 (s, 3H), 1.55-1.50 (m, 1H), 1.46 (s, 6H), 1.37-1.30 (m,4H), 0.87 (t, 6H).

[0326]

[0327] Under nitrogen protection, compound C (2.46 g) was dissolved in dichloromethane (50 mL, dry). Phosphorus oxychloride (1.0 g) was added, and the mixture was cooled to -78°C. Triethylamine (1.38 g) was added dropwise, and the mixture was stirred for 3 hours. A dichloromethane solution (20 mL, dry) of triethylamine (0.69 g) and ethyl o-hydroxybenzoate (1.14 g) was added dropwise. Stirring continued for 3 hours. Triethylamine (1.50 g) and p-nitrophenol (2.03 g) were then added. The temperature was raised to room temperature and stirred overnight. The reaction mixture was concentrated and separated on a C18 column to afford compound F (1.49 g, a yellow oil).

[0328] 1 H NMR (400 MHz, DMSO-d6) δ 8.35 – 8.26 (m, 2H), 7.79 – 7.72 (dt, 1H), 7.67 – 7.58 (ddd, 1H), 7.58 – 7.51 (d, 1H), 7.51 – 7.44 (m, 2H), 7.37 – 7.28(t, 1H), 6.60 – 6.53 (d, 1H), 4.27 – 4.14 (qt, 2H), 3.89 – 3.83 (d, 2H), 1.45– 1.38 (d, 6H), 1.29 – 1.18 (td, 8H), 0.86 – 0.73 (m, 6H).

[0329]

[0330] Compound D (2 g) and 2,2-methoxypropane (3.43 g) were mixed in acetone (100 mL), concentrated sulfuric acid (875 mg, 0.5 mL) was added dropwise at room temperature, stirred at room temperature for 30 min, and then heated to 45 oC. and stirred for 30 min. The mixture was cooled to rt, solid sodium bicarbonate (2.02 g) and water (1.98 g) were added, and the mixture was stirred for 15 min. The reaction solution was concentrated, diluted with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated and passed through a column chromatography (DCM / MeOH=50 / 1-20 / 1) to obtain compound E (2.5 g, white solid).

[0331] 1 H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 2H), 7.96 (s, 1H), 6.95 – 6.87(m, 2H), 5.38 (d, 1H), 5.03 (t, 1H), 4.90 (dd, 1H), 4.32 (td, 1H), 3.61 –3.45 (m, 2H), 1.64 (s, 3H), 1.37 (s, 3H).

[0332]

[0333] Compound E (200 mg) was dissolved in DMF (2 mL, dry) and t-BuMgCl (1.20 mL, 1 mol / L in THF) was added dropwise under N2 at 0°C. The mixture was stirred at 0°C for 30 min, and a solution of compound F (648 mg) in DMF (2 mL, dry) was added dropwise. The temperature was raised to 50°C and stirred for 2 h. After cooling to room temperature, the reaction solution was quenched with saturated ammonium chloride solution, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to obtain the crude product, which was then separated on a C18 column to afford G (269 mg, yellow solid).

[0334] 1H NMR (400 MHz, DMSO-d6) δ 8.06 – 7.85 (s, 3H), 7.76 – 7.69 (d, 1H), 7.54 – 7.47 (m, 1H), 7.47 – 7.40 (d, 1H), 7.31 – 7.23 (t, 1H), 6.93 – 6.88(t, 1H), 6.87 – 6.82 (t, 1H), 5.89 – 5.79 (dd, 1H), 5.43 – 5.31 (dd, 1H), 5.01 – 4.90 (m, 1H), 4.57 – 4.53 (s, 1H), 4.26 – 4.12 (m, 4H), 3.89 – 3.83(s, 2H), 1.66 – 1.61 (s, 3H), 1.39 – 1.32 (d, 3H), 1.32 – 1.29 (d, 6H), 1.28– 1.19 (d, 7H), 0.86 – 0.83 (s, 1H), 0.83 – 0.75 (t, 6H).

[0335]

[0336] Compound G (380 mg) was dissolved in THF (4 mL), and TFA (4 mL) was added. The temperature was raised to 50°C and stirred overnight. The pH was adjusted to 7-8 with 1 M sodium hydroxide solution. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, separated by a C18 column, and lyophilized to obtain compound 2-C4 (211 mg, white solid).

[0337] 1H NMR (400 MHz, DMSO-d6) δ 8.01 – 7.80 (d, 3H), 7.77 – 7.71 (d, 1H), 7.57 – 7.45 (m, 2H), 7.30 – 7.22 (tt, 1H), 6.91 – 6.86 (dd, 1H), 6.86 – 6.80(dd, 1H), 6.33 – 6.27 (dd, 1H), 5.80 – 5.74 (d, 1H), 5.40 – 5.34 (d, 1H), 4.71 – 4.64 (m, 1H), 4.36 – 4.23 (qd, 4H), 4.22 – 4.14 (dq, 1H), 4.01 – 3.92(dq, 1H), 3.92 – 3.83 (m, 2H), 1.45 – 1.35 (dq, 1H), 1.35 – 1.30 (d, 6H), 1.30 – 1.20 (dtt, 7H), 0.83 – 0.75 (tt, 6H).

[0338] Example 10

[0339] ;

[0340] Compound A (2.0 g) and compound B (3.50 g) were mixed in toluene (20 mL), and p-toluenesulfonic acid monohydrate (3.6 g) was added. Under nitrogen protection, the mixture was refluxed at 130°C with a water separator to remove water and stirred for 16 hours. The crude product was concentrated, separated by a C18 column, and lyophilized to obtain C (5.72 g, white solid).

[0341] 1 H NMR (400 MHz, DMSO-d6) δ 8.40 (s, 3H), 7.52 – 7.44 (m, 2H), 7.12(d, J = 7.9 Hz, 2H), 4.18 – 4.05 (m, 2H), 2.29 (s, 3H), 1.89 – 1.72 (m, J =7.3 Hz, 2H), 1.52 (h, J = 6.0 Hz, 1H), 1.44 (s, 3H), 1.32 (td, J = 7.7, 6.3Hz, 4H), 0.87 (td, J = 7.5, 3.3 Hz, 9H).

[0342] ;

[0343] Under nitrogen protection, compound C (5.20 g) and phenyl dichlorophosphate (3.10 g) were dissolved in DCM (50 mL) and cooled to -10°C. Triethylamine (5.64 g) was added dropwise, and the mixture was heated to room temperature and stirred for 16 hours. Triethylamine (1.50 g) and p-nitrophenol (2.03 g) were then added dropwise, and stirring continued for 3 hours. The reaction solution was concentrated, separated by a C18 column, and lyophilized to obtain compound F (4.32 g, a white solid).

[0344] 1 H NMR (400 MHz, Chloroform-d) δ 8.27 – 8.14 (m, 2H), 7.46 – 7.30 (m,4H), 7.34 – 7.18 (m, 2H), 7.23 – 7.12 (m, 1H), 4.50 – 4.42 (dd, J = 9.6, 4.3Hz, 1H), 4.14 – 3.96 (m, 2H), 2.11 – 1.92 (m, 1H), 1.92 – 1.77 (dq, J = 14.3,7.3 Hz, 1H), 1.71 – 1.60 (d, J = 4.4 Hz, 3H), 1.60 – 1.43 (m, J = 6.9, 6.5Hz, 1H), 1.43 – 1.24 (m, 4H), 0.93 – 0.82 (t, J = 7.4 Hz, 6H), 0.82 – 0.71 (dt, J = 17.2, 7.4 Hz, 3H).

[0345] ;

[0346] Compound D (2 g) and 2,2-methoxypropane (3.43 g) were mixed in acetone (100 mL), concentrated sulfuric acid (875 mg, 0.5 mL) was added dropwise at room temperature, stirred at room temperature for 30 min, and then heated to 45 o C. and stirred for 30 min. The mixture was cooled to rt, solid sodium bicarbonate (2.02 g) and water (1.98 g) were added, and the mixture was stirred for 15 min. The reaction solution was concentrated, diluted with water, and extracted with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated and passed through a column chromatography (DCM / MeOH=50 / 1-20 / 1) to obtain compound E (2.5 g, white solid).

[0347] 1H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 2H), 7.96 (s, 1H), 6.95 – 6.87(m, 2H), 5.38 (d, 1H), 5.03 (t, 1H), 4.90 (dd, 1H), 4.32 (td, 1H), 3.61 –3.45 (m, 2H), 1.64 (s, 3H), 1.37 (s, 3H).

[0348] ;

[0349] Under N2 protection, compound E (2.0 g) was dissolved in THF (20 mL, dry), cooled to 0°C, and t-BuMgCl (8.5 mL, 1 mol / L in THF) was added dropwise. The mixture was stirred at 0°C for 30 min, and a solution of compound F (4.10 g) in THF (10 mL, dry) was added dropwise. The temperature was raised to 50°C and stirred overnight. After cooling to room temperature, the reaction solution was quenched with saturated ammonium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain the crude product. The crude product was separated by a C18 column and lyophilized to obtain compound G (2.52 g, yellow solid).

[0350] 1 H NMR (400 MHz, DMSO-d6) δ 8.11 – 7.80 (s, 3H), 7.33 – 7.24 (m, 2H), 7.20 – 7.05 (tt, 3H), 6.94 – 6.89 (m, 1H), 6.88 – 6.79 (dd, 1H), 5.70 – 5.57(dd, 1H), 5.42 – 5.13 (dd, 1H), 5.00 – 4.81 (ddd, 1H), 4.60 – 4.47 (dq, 1H), 4.18 – 4.09 (q, 2H), 3.97 – 3.82 (m, 2H), 1.77 – 1.54 (m, 5H), 1.47 – 1.38(dd, 1H), 1.38 – 1.17 (m, 10H), 0.87 – 0.77 (t, 6H), 0.77 – 0.68 (td, 3H).

[0351] ;

[0352] Compound G (2.50 g) was dissolved in methanol (25 mL), cooled to 0°C, and 6 M hydrochloric acid (13 mL) was added dropwise. The mixture was stirred at room temperature overnight. 1 M sodium hydroxide solution was added dropwise to adjust the pH to 7–8. The mixture was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, separated using a C18 column, and lyophilized to afford compound 2-C2 (1.97 g, white solid).

[0353] 1H NMR (400 MHz, DMSO-d6) δ 8.00 – 7.81 (d, 3H), 7.37 – 7.26 (dt,2H), 7.21 – 7.11 (m, 3H), 6.92 – 6.86 (dd, 1H), 6.85 – 6.78 (dd, 1H), 6.35 – 6.26 (dd, 1H), 5.66 – 5.53 (dd, 1H), 5.41 – 5.35 (dd, 1H), 4.70 – 4.60 (ddd,1H), 4.32 – 4.20 (dt, 2H), 4.19 – 4.07 (tt, 1H), 4.01 – 3.83 (ddp, 3H), 1.78– 1.56 (dtt, 2H), 1.49 – 1.37 (dt, 1H), 1.36 – 1.33 (s, 1H), 1.33 – 1.22 (m,6H), 0.85 – 0.77 (tt, 6H), 0.77 – 0.67 (q, 3H).

[0354] Example 11

[0355] ;

[0356] Compound A (5 g) was dissolved in MeOH (100 mL, dry). o C, H2SO4 (0.6 mL) was added under N2. The mixture was stirred at rt overnight, and solid Na2CO3 (2.34 g) was added to adjust the solution to pH>7. The solution was filtered through a layer of celite, and the filter cake was washed with MeOH. The filtrate was concentrated and pumped to dryness. The product was directly used in the next step without further purification to obtain compound B (6.31 g, colorless oily liquid).

[0357] 1H NMR (400 MHz, Methanol-d4) δ 4.74 (s, 1H), 4.06 -3.97 (m, 3H), 3.74-3.68 (m, 3H), 3.66-3.52 (m, 1H), 3.43-3.41 (m, 1H), 3.35-3.31 (m, 3H).

[0358] ;

[0359] Compound B (6.31 g, impure) was dissolved in DMF (100 mL, dry). o C, NaH (6.66 g) was added under N2, and stirred at rt for 10 min. o BnBr (22.80 g) was added at 400 °C. The reaction mixture was stirred overnight at rt and poured into o The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and passed through a column (PE / EA = 20 / 1-10 / 1) to obtain compound C (9.74 g, colorless oily liquid).

[0360] 1 H NMR (400 MHz, DMSO-d6) δ 7.37 – 7.22 (m, 15H), 4.92 (s, 1H), 4.67 –4.42 (m, 6H), 4.11 (td, 1H), 3.97 (dd, 1H), 3.91 (d, 1H), 3.55 (dd, 1H), 3.43(dd, 1H), 3.21 (s, 3H).

[0361] ;

[0362] Compound C (2 g) was dissolved in AcOH (30 mL, V / V=80 %). o C, add concentrated sulfuric acid (0.2 mL), 80 o The reaction mixture was stirred at 40°C for 6 h. The reaction solution was slightly concentrated, and water and DCM were added. Then, solid Na2CO3 was added until the solution pH was >7. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and passed through a column chromatography (PE / EA = 5 / 1) to obtain compound D (1.05 g, colorless, transparent, oily liquid).

[0363] 1H NMR (400 MHz, DMSO-d6) δ 7.41 – 7.22 (m, 15H), 6.56 (d, 1H), 5.22(d, 1H), 4.68 – 4.40 (m, 6H), 4.08 – 3.95 (m, 2H), 3.80 (d, 1H), 3.61 – 3.40(m, 2H).

[0364] ;

[0365] Compound D (1.05 g) was dissolved in DMSO (10 mL). AcO (1.27 g, 1.18 mL) was added dropwise at room temperature under N₂, and stirred overnight at room temperature. The reaction mixture was poured into ice water and extracted with EA. The organic phase was washed with brine, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated and filtered through a column chromatography (PE / EA = 20 / 1) to afford compound E (787 mg, a colorless, transparent oily liquid).

[0366] 1 H NMR (400 MHz, DMSO-d6) δ 7.32 (dq, 13H), 7.24 – 7.17 (m, 2H), 4.76– 4.54 (m, 6H), 4.47 (s, 2H), 4.29 (d, 1H), 3.66 (d, 2H).

[0367] ;

[0368] Compound F (504 mg) was mixed in THF (5 mL, dry), and TMSCl (514 mg) was added dropwise at rt under N2, and stirred at rt for 2 h. o C. n-BuLi (5.38 mL, 1.6 M in hexane) was added dropwise, stirred for 1 h, and a solution of compound E (900 mg) in THF (5 mL, dry) was added dropwise. o C and continued stirring for 1 h, and the reaction solution was slowly heated to 0 o C, saturated NaHCO3 was added dropwise to quench the reaction, the reaction solution was warmed to rt, extracted with EA, and the organic phase was separated. The organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and passed through a column (PE / EA=1 / 1-1 / 2) to obtain compound G (375 mg, brown solid).

[0369] 1H NMR (400 MHz, DMSO-d6) δ 8.04 (s, 2H), 7.97 (s, 1H), 7.37 – 7.19 (m, 12H), 7.19 – 7.03 (m, 2H), 7.06 – 6.95 (m, 2H), 6.92 (d, 1H), 5.36 (d,1H), 4.63 – 4.48 (m, 2H), 4.52 – 4.33 (m, 4H), 3.99 (s, 1H), 3.91 (dd, 1H), 3.67 (dd, 1H), 3.45 (dd, 1H), 1.36 – 1.12 (m, 1H).

[0370] ;

[0371] Compound G (375 mg) was dissolved in DCM (10 mL, dry) at -78 o C, TfOH (204 mg) was added dropwise under N2, stirred for 10 min, then TMSOTf (317 mg) was added dropwise, stirred for 30 min, then TMSCN (369 mg) was added slowly, and the temperature was kept at -78 o C for 2 h, Et3N (241 mg, 0.33 mL) was added dropwise, the reaction solution was slowly warmed to rt, solid NaHCO3 (514 mg) was added, and then water (2 mL) was slowly added. The mixture was stirred for 10 min, and DCM was added for extraction. The organic phase was separated, washed with brine, dried over anhydrous sodium sulfate, and filtered to remove anhydrous sodium sulfate. The filtrate was concentrated and passed through a column chromatography (PE / EA=1 / 1) to obtain compound H (288 mg, light yellow solid).

[0372] 1 H NMR (400 MHz, DMSO-d6) δ 7.90 (s, 2H), 7.87 (s, 1H), 7.35 – 7.21(m, 14H), 6.86 (d, 1H), 6.74 (d, 1H), 4.89 (d, 1H), 4.84 (d, 1H), 4.75 (d,1H), 4.60 – 4.42 (m, 4H), 4.38 (q, 1H), 4.10 (t, 1H), 3.68 (dd, 1H), 3.58(dd, 1H), 1.36 – 1.19 (m, 1H).

[0373] ;

[0374] Compound H (14.34 g) was dissolved in DCM (200 mL, dry) o C, BCl3 (97.02 mL, 1M in hexane) was added dropwise under N2, -40 o C for 2 h, then cooled to -78 o C, MeOH (22.09 g) was added dropwise, and then a solution of Et3N (25.83 g) in MeOH (44.18 g) was added dropwise. The reaction was allowed to rise to rt. The reaction solution was concentrated, and the crude product was triturated with a mixed solution of DCM / MeOH (100 mL, V / V=1 / 1). The product was filtered, and the filter cake was washed with a small amount of methanol. The filter cake was dried to obtain compound I (6.78 g, white solid).

[0375] ;

[0376] At rt under N2 protection, compound I (480 mg) and imidazole (225 mg) were dissolved in DMF (4 mL, dry). TBDMSCl (498.9 mg) was added and stirring continued for 2 h. The reaction solution was poured into water and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by column chromatography (MeOH / DCM = 0-20%) to obtain compound J (377 mg, yellow solid).

[0377] 1 H NMR (400 MHz, DMSO-d6) δ 7.96 – 7.76 (s, 3H), 6.90 – 6.85 (d, 1H), 6.85 – 6.79 (d, 1H), 6.25 – 6.19 (d, 1H), 5.21 – 5.15 (d, 1H), 4.63 – 4.56(m, 1H), 4.11 – 4.03 (dt, 1H), 4.00 – 3.91 (q, 1H), 3.87 – 3.79 (dd, 1H), 3.73 – 3.64 (dd, 1H), 0.86 – 0.79 (s, 9H), -0.02 – -0.05 (s, 3H), -0.08 – -0.11 (s, 3H).

[0378] ;

[0379] Under N2 protection, compound J (376 mg) and DMAP (396 mg) were dissolved in THF (8 mL, dry), cooled to 0°C, and isobutyric anhydride (323 mg) was added dropwise. Stir for 5 min. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and separated by column chromatography (MeOH / DCM = 0-20%) to afford compound K (432 mg, yellow solid).

[0380] 1H NMR (400 MHz, DMSO-d6) δ 8.05 – 7.85 (s, 3H), 6.94 – 6.88 (d, 1H), 6.70 – 6.65 (d, 1H), 5.97 – 5.91 (d, 1H), 5.44 – 5.37 (dd, 1H), 4.49 – 4.42(q, 1H), 3.84 – 3.75 (m, 2H), 2.67 – 2.54 (dp, 2H), 1.19 – 1.08 (m, 12H), 0.80 – 0.77 (s, 9H), -0.02 – -0.05 (s, 3H), -0.08 – -0.11 (s, 3H).

[0381] ;

[0382] Under nitrogen, compound K (420 mg) was dissolved in dry THF (42 mL, dry), cooled to 0°C, and pyridinium hydrofluoride (4.58 mg) was added dropwise. The mixture was stirred for 2 h. The reaction mixture was poured into saturated sodium bicarbonate solution and extracted with ethyl acetate. The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography (MeOH / DCM = 0-20%) to obtain compound L (278 mg, yellow solid).

[0383] 1H NMR (400 MHz, DMSO-d6) δ 8.12 – 7.87 (s, 3H), 6.95 – 6.89 (d, 1H), 6.81 – 6.75 (d, 1H), 6.02 – 5.96 (d, 1H), 5.45 – 5.39 (dd, 1H), 5.20 – 5.13(t, 1H), 4.42 – 4.37 (d, 1H), 3.68 – 3.57 (d, 2H), 2.65 – 2.54 (dt, 2H), 1.20 – 1.12 (dd, 6H), 1.12 – 1.05 (dd, 6H).

[0384] ;

[0385] Compound M (5 g) and compound N (50 g) were mixed in toluene (150 mL), and p-toluenesulfonic acid monohydrate (9.22 g) was added at rt. The mixture was refluxed for 25 h with a water separator. After the reaction was completed, the mixture was cooled to rt, concentrated, slurried with ether, and filtered. The filter cake was washed with ether and dried to obtain compound O (8.82 g, white solid, in the form of p-toluenesulfonate).

[0386] 1 H NMR (400 MHz, DMSO-d6) δ 8.39 (s, 3H), 7.47 (d, 2H), 7.11 (d, 2H), 4.10 (d, 2H), 2.29 (s, 3H), 1.55-1.50 (m, 1H), 1.46 (s, 6H), 1.37-1.30 (m,4H), 0.87 (t, 6H).

[0387] ;

[0388] Under nitrogen protection, compound O (2.46 g) was dissolved in dichloromethane (50 mL, dry). Phosphorus oxychloride (1.0 g) was added, and the mixture was cooled to -78°C. Triethylamine (1.38 g) was added dropwise, and the mixture was stirred for 3 hours. A dichloromethane solution (20 mL, dry) of triethylamine (0.69 g) and ethyl o-hydroxybenzoate (1.14 g) was added dropwise. Stirring was continued for 3 hours. Triethylamine (1.50 g) and p-nitrophenol (2.03 g) were added, and the temperature was raised to room temperature and stirred overnight. The reaction mixture was concentrated and separated on a C18 column to afford compound P (1.49 g, a yellow oil).

[0389] 1H NMR (400 MHz, DMSO-d6) δ 8.35 – 8.26 (m, 2H), 7.79 – 7.72 (dt, 1H), 7.67 – 7.58 (ddd, 1H), 7.58 – 7.51 (d, 1H), 7.51 – 7.44 (m, 2H), 7.37 – 7.28(t, 1H), 6.60 – 6.53 (d, 1H), 4.27 – 4.14 (qt, 2H), 3.89 – 3.83 (d, 2H), 1.45– 1.38 (d, 6H), 1.29 – 1.18 (td, 8H), 0.86 – 0.73 (m, 6H).

[0390] ;

[0391] Under nitrogen, compound L (270 mg) was dissolved in DMF (5 mL, dry) and cooled to 0°C. t-BuMgCl (2.5 mL, 1M in THF) was added dropwise, and the mixture was stirred at 0°C for 30 min. A solution of compound P (671.5 mg) in DMF (5 mL) was then added dropwise, and the temperature was raised to 50°C and stirred overnight. After cooling to room temperature, the reaction mixture was poured into saturated ammonium chloride solution and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated by column chromatography (MeOH / DCM = 0-20%) to afford compound 2-C32 (220 mg, pale yellow solid).

[0392] 1H NMR (400 MHz, DMSO-d6) δ 8.07 – 7.87 (m, 3H), 7.76 – 7.70 (d, J =8.0 Hz, 1H), 7.54 – 7.39 (m, 2H), 7.29 – 7.21 (t, J = 7.5 Hz, 1H), 6.94 –6.86 (dd, J = 7.2, 4.6 Hz, 1H), 6.82 – 6.72 (dd, J = 16.8, 4.6 Hz, 1H), 6.12– 6.03 (dd, J = 10.2, 5.8 Hz, 1H), 5.87 – 5.79 (m, 1H), 5.51 – 5.40 (ddd, J =13.8, 5.8, 3.9 Hz, 1H), 4.65 – 4.60 (s, 1H), 4.39 – 4.28 (dq, J = 11.1, 5.5Hz, 2H), 4.28 – 4.19 (m, 2H), 3.90 – 3.83 (m, 2H), 2.66 – 2.54 (m, 2H), 1.43– 1.36 (m, 1H), 1.32 – 1.28 (s, 6H), 1.27 – 1.21 (m, 7H), 1.19 – 1.11 (ddd, J= 13.1, 7.0, 2.7 Hz, 6H), 1.11 – 1.07 (d, J = 7.0 Hz, 6H), 0.82 – 0.75 (m,6H).

[0393] Example 12

[0394] ;

[0395] Compound A (4.5 g) was mixed with compound B (90 mL), 70 o C, TMSCl (26.5 g) was added under N2, 70 o C overnight, the reaction solution was concentrated and pumped dry, Et2O was added to make a slurry, the insoluble matter was removed by filtration, and the filtrate was concentrated and pumped dry to obtain compound C (8.21 g, light brown glassy solid).

[0396] 1H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 3H), 4.07 (d, 2H), 1.52 (m, 1H), 1.33 (m, 7H), 1.28 (m, 1H), 0.86 (m, 6H), 0.66 – 0.57 (m, 1H), 0.53 (m, 3H).

[0397] ;

[0398] Compound C (4.89 g) was dissolved in DCM (100 mL, dry) at -78 o C, phosphorus oxychloride (3.78 g) was added dropwise under N2, and then Et3N (3.78 g) was added dropwise, and stirred at rt for 6 h. o A solution of pentafluorophenol (3 g) in DCM (50 mL, dry) was added dropwise at 4°C, and then Et3N (1.81 g) was added dropwise. The mixture was stirred at rt overnight. The reaction solution was concentrated and passed through a column chromatography (PE / EA = 20 / 1) to obtain compound D (5.27 g, colorless oily liquid).

[0399] 1 H NMR (400 MHz, Chloroform-d) δ 7.35 (t, 2H), 7.30 – 7.15 (m, 3H), 4.33 (m, 1H), 4.16 – 4.01 (m, 2H), 1.62 (m, 3H), 1.53 (m, 1H), 1.36 (m, 4H), 1.27 – 1.19 (m, 1H), 0.89 (m, 6H), 0.57 – 0.38 (m, 4H).

[0400] ;

[0401] Compound E (6 g) was mixed in acetone (100 mL), compound F (10.3 g) was added at rt, and then H2SO4 (2.63 g) was added dropwise, and stirred at rt for 30 min. o C for 30 min, the reaction solution was cooled to rt, and solid NaHCO3 (16.07 g) and H2O (6 mL) were added in sequence and stirred for 15 min. The reaction solution was concentrated, water was added, and extracted with EA. The organic phase was separated and dried over anhydrous Na2SO4. The anhydrous Na2SO4 was removed by filtration, and the filtrate was concentrated and passed through a column (DCM / MeOH=20 / 1) to obtain compound G (7.21 g, white solid).

[0402] 1H NMR (400 MHz, DMSO-d6) δ 7.98 (s, 2H), 7.96 (s, 1H), 6.95 – 6.87(m, 2H), 5.38 (d, 1H), 5.03 (t, 1H), 4.90 (dd, 1H), 4.32 (td, 1H), 3.61 –3.45 (m, 2H), 1.64 (s, 3H), 1.37 (s, 3H).

[0403] ;

[0404] Compound G (500 mg), compound D (1.13 g) and MgCl2 (144 mg) were mixed in MeCN (30 mL, dry). o C, stirred under N2 for 10 min, then DIEA (488 mg), 90 o The mixture was stirred at 400 °C for 6 h, then compound D (162 mg) and MgCl₂ (144 mg) were added. The mixture was stirred for 10 min, followed by the addition of DIEA (488 mg). The mixture was stirred for another 2 h, cooled to room temperature, diluted with EA, and washed sequentially with 5% citric acid solution, saturated ammonium chloride solution, saturated NaHCO₃ solution, and saturated NaCl. The organic phase was dried over anhydrous Na₂SO₄ and filtered. The filtrate was concentrated and filtered through a column chromatography (DCM / MeOH = 80 / 1) to afford product H (953 mg, white solid).

[0405] 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (d, 3H), 7.29 (m, 2H), 7.19 – 7.06(m, 3H), 6.91 (d, 1H), 6.84 (m, 1H), 5.64 (m, 1H), 5.36 (t, 1 / 2H), 5.18 (t,1 / 2H), 5.00 – 4.91 (m, 1 / 2H), 4.86 (m, 1 / 2H), 4.53 (m, 1H), 4.13 (m, 2H), 3.98 – 3.83 (m, 2H), 1.63 (d, 3H), 1.48 – 1.12 (m, 12H), 0.81 (t, 6H), 0.40 –0.23 (m, 4H).

[0406] ;

[0407] Compound H (799 mg) was dissolved in HCOOH (20 mL, v / v = 80% in water) and stirred at rt for 3 h. The reaction solution was concentrated and filtered through a column (DCM / MeOH = 50 / 1-30 / 1) to obtain the product 2-C1 (634 mg, white solid).

[0408] 1 H NMR (400 MHz, DMSO-d6) δ 7.91 (d, 3H), 7.38 – 7.26 (m, 2H), 7.22 –7.10 (m, 3H), 6.89 (m, 1H), 6.82 (d, 1H), 6.31 (m, 1H), 5.64 – 5.53 (m, 1H),5.38 (d, 1H), 4.66 (m, 1H), 4.25 (m, 2H), 4.20 – 4.07 (m, 1H), 3.95 (m, 2H),3.92 – 3.84 (m, 1H), 1.44 (m, 1H), 1.37 – 1.11 (m, 8H), 0.80 (m, 6H), 0.47 –0.21 (m, 4H).

[0409] ;

[0410] Compound 2-C1 (733 mg) and fumaric acid (133 mg) were mixed in acetone (10 mL) and stirred at 60 °C until the reaction solution became clear. The reaction solution was cooled to rt and the insoluble matter was removed by filtration to obtain compound J (323 mg, white solid).

[0411] 1H NMR (400 MHz, DMSO-d6) δ 13.14 (s, 2H), 7.91 (d, 3H), 7.32 (tdd,2H), 7.22 – 7.10 (m, 3H), 6.92 – 6.85 (m, 1H), 6.81 (d, 1H), 6.63 (s, 2H), 6.36 – 6.26 (m, 1H), 5.65 – 5.54 (m, 1H), 5.38 (d, 1H), 4.66 (p, 1H), 4.30 –4.20 (m, 2H), 4.18 – 4.07 (m, 1H), 3.94 (ddd, 2H), 3.93 – 3.83 (m, 1H), 1.43(p,1H), 1.24 (dtt, 7H), 1.16 (d, J = 6.7 Hz, 1H), 0.80 (td, 6H), 0.38 (s,1H), 0.32 (dd, 2H), 0.31 – 0.27 (m, 1H).

[0412] Example 13

[0413]

[0414]

[0415] Compound A (4.5 g) was mixed with compound B (90 mL), 70 o C, TMSCl (26.5 g) was added under N2, 70 o C overnight, the reaction solution was concentrated and pumped dry, Et2O was added to make a slurry, the insoluble matter was removed by filtration, and the filtrate was concentrated and pumped dry to obtain compound C (8.21 g, light brown glassy solid).

[0416] 1 H NMR (400 MHz, DMSO-d6) δ 8.81 (s, 3H), 4.07 (d, 2H), 1.52 (m, 1H), 1.33 (m, 7H), 1.28 (m, 1H), 0.86 (m, 6H), 0.66 – 0.57 (m, 1H), 0.53 (m, 3H).

[0417] ;

[0418] Compound C (4.89 g) was dissolved in DCM (100 mL, dry) at -78 oC, add phenyl dichlorophosphate (3.78 g) dropwise under N2, then add Et3N (3.78 g) dropwise, stir at rt for 6 h, 0 o A solution of pentafluorophenol (3 g) in DCM (50 mL, dry) was added dropwise at 4°C, followed by Et3N (1.81 g). The mixture was stirred at rt overnight. The reaction solution was concentrated and purified by column chromatography (PE / EA = 20 / 1) to obtain compound D (5.27 g, colorless oily liquid).

[0419] 1 H NMR (400 MHz, Chloroform-d) δ 7.35 (t, 2H), 7.30 – 7.15 (m, 3H), 4.33 (m, 1H), 4.16 – 4.01 (m, 2H), 1.62 (m, 3H), 1.53 (m, 1H), 1.36 (m, 4H), 1.27 – 1.19 (m, 1H), 0.89 (m, 6H), 0.57 – 0.38 (m, 4H).

[0420] ;

[0421] Compound E (1 g) was dissolved in Pyridine (50 mL, dry), 0 o C, TIPDSCl (1.62 g) was added dropwise under N2, and stirred at rt overnight. o The reaction mixture was quenched by adding water dropwise at 4°C, and the reaction solution was concentrated and passed through a column (DCM / MeOH = 20 / 1) to obtain product G (1.05 g, light yellow solid).

[0422] 1 H NMR (400 MHz, DMSO-d6) δ 8.95 (s, 1H), 8.56 (s, 1H), 8.10 (s, 1H), 7.16 (d, J = 4.5 Hz, 1H), 6.86 (d, J = 4.5 Hz, 1H), 6.54 (s, 1H), 4.54 (d, J = 3.4 Hz, 1H), 4.19 – 4.11 (m, 2H), 3.92 (d, J = 12.9 Hz, 1H), 1.24 (s, 1H), 1.11 – 0.79 (m, 28H).

[0423] ;

[0424] Compound G (2 g) was dissolved in DCM (100 mL, dry). AgNO₃ (2.55 g), collidine (1.82 g), and MMTrCl (3.47 g) were added sequentially at room temperature under N₂. The mixture was stirred overnight at room temperature and quenched with MeOH dropwise. The mixture was filtered through a layer of Celite. The filtrate was concentrated and purified by column chromatography (PE / EA = 30 / 1-15 / 1) to afford product H (2.99 g, white solid).

[0425] ;

[0426] Compound H (2.86 g) was dissolved in THF (100 mL, dry). TBAF (5.30 mL, 1 M in THF) was added dropwise at 0°C under N2. The mixture was stirred at rt for 6 h. The reaction solution was quenched with water and extracted with EA. The organic phase was separated, washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and passed through a column chromatography (PE / EA = 10 / 1-1 / 1) to obtain product J (2.15 g, white solid).

[0427] 1 H NMR (400 MHz, DMSO-d6) δ 8.80 (s, 1H), 7.41 – 7.16 (m, 18H), 7.12 – 6.83 (m, 11H), 6.80 – 6.72 (m, 2H), 5.32 (d, 1H), 4.67 – 4.56 (m, 2H), 3.97(t, 1H), 3.73 (d, 6H), 3.24 (h, 2H), 2.88 (dd, 1H).

[0428] ;

[0429] Compound J (4 g), AgNO3 (2.44 g) and Collidine (2.90 g) were dissolved in DCM (200 mL, dry). MMTrCl (4.43 g) was added batchwise at rt under N2. The mixture was stirred overnight at rt. The reaction solution was filtered, and the filtrate was concentrated and passed through a column chromatography (PE / EA = 10 / 1-5 / 1) to obtain product K (2.47 g, white solid).

[0430] 1H NMR (400 MHz, DMSO-d6) δ 8.75 (s, 1H), 7.49 – 6.99 (m, 39H), 6.89 (s, 2H), 6.78 (d, 2H), 6.67 (d, 3H), 5.50 (d, 1H), 4.49 (d,1H), 3.73 (s, 3H), 3.65 (d, 6H), 2.90 (dd, 1H), 2.74 (q, 2H).

[0431] ;

[0432] Compound K (1.99 g) and pyridine (1.42 g) were dissolved in DCM (50 mL, dry). DAST (1.45 g) was added dropwise at 0°C under N2 and stirring was continued for 5 min. The temperature was then raised to rt and stirring was continued for 4 h. The mixture was cooled to 0°C and quenched by adding saturated NaHCO3 solution dropwise. The mixture was extracted with DCM, and the organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and passed through a column (PE / EA=10 / 1-5 / 1) to obtain product L (1.03 g, light brown solid, impure).

[0433] ;

[0434] At rt, compound L (1.03 g) was dissolved in HCOOH (20 mL, V / V = 80% in water) and stirred for 1 h. The reaction solution was concentrated and separated on a reverse phase column (C18 column) to obtain product M (65 mg, white solid).

[0435] 1 H NMR (400 MHz, DMSO-d6) δ 7.94 (m, 3H), 7.06 (d, 1H), 6.90 (t, 1H), 6.74 (d, 1H), 5.18 – 4.99 (m, 2H), 4.92 (dd, 1H), 4.44 (dtd, 1H), 3.70 (s,2H).

[0436] 19 F NMR (377 MHz, DMSO-d6) δ -198.15.

[0437] ;

[0438] Compound M (1.24 g) was dissolved in NMP (40 mL, dry). t-BuMgCl (6.34 mL, 1 Min THF) was added dropwise at 0°C under N2. Stirring was continued for 30 min. A solution of compound D (3.11 g) in THF (40 mL, dry) was added dropwise. The mixture was stirred at rt overnight. The reaction solution was quenched by adding MeOH dropwise, diluted with water, and extracted with DCM. The organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated and passed through a column (DCM / MeOH = 40 / 1-20 / 1) to obtain the product 2-D1 (1.0 g, light yellow solid).

[0439] 1 H NMR (400 MHz, DMSO-d6) δ 8.08-7.80 (m, 3H), 7.41 – 7.31 (m, 2H), 7.22 (dt, 2H), 7.19 – 7.12 (m, 2H), 6.90 (d, 1H), 6.79 (q, 1H), 5.72 (dd,1H), 5.30 – 5.06 (m, 1H), 4.99 (dd, 1H), 4.83 – 4.60 (m, 1H), 4.32 (ddd, 2H),4.02 – 3.86 (m, 2H), 1.46 (dq, 1H), 1.37 – 1.18 (m, 8H), 0.82 (dd, 6H), 0.42 (dd, 1H), 0.34 (td, 3H).

[0440] 19 F NMR (377 MHz, DMSO-d6) δ -197.92.

[0441] 31 P NMR (162 MHz, DMSO-d6) δ 2.59, 2.26.

[0442] ;

[0443] Compound 2-D1 (550 mg) was dissolved in ACN (20 mL). HBr (259 mg, 40% in water) was added dropwise at 0°C under N2 protection. The mixture was heated to room temperature and stirred for 2 h. After completion of the reaction, the reaction solution was concentrated and methyl tert-butyl ether was added. The mixture was stirred at 60°C for 2 h. After cooling to room temperature, the mixture was filtered with suction. The filter cake was washed two to three times with acetonitrile and dried to obtain compound 2-F (490 mg, light yellow solid).

[0444] 1H NMR (400MHz, DMSO-d6): δ 9.61 (s, 1H), 8.98 (s, 1H), 8.26 (s, 1H), 7.39-7.34 (m, 3H), 7.26-7.16 (m, 3H), 6.97-9.94 (m, 1H), 5.76 (d, 1H), 5.19(d, 1H), 4.91 (d, 1H), 4.73 (d, 1H), 4.40-4.26 (m, 2H), 4.00-3.89 (m, 2H), 1.49-1.43 (m, 1H), 1.35-1.19(m, 8H), 1.11(s, 2H), 0.87-0.81(m, 6H), 0.46-0.29(m, 4H).

[0445] Materials and instruments

[0446] cell lines

[0447]

[0448] Main reagents

[0449]

[0450] Reagent test kit

[0451]

[0452] instrument

[0453]

[0454] In the process of establishing the 2-C1 series of compounds, we have conducted explorations in many aspects. There have been cases of complete failure as well as cases of partial success. We have selected 8 representative cases and announced them as follows.

[0455] Example 14

[0456] Experimental steps:

[0457] Huh-7 cells (1.5*10 4 / well), cultured for 24 hours. The supernatant was removed and washed once with serum-free medium. 10 -3100 μL of HCoV virus solution was added to each well and adsorbed in a 37°C, 5% CO2 incubator for 2 hours. The culture medium was aspirated, and 100 μL of the test drug solution was added to the experimental drug groups, with duplicate wells for each concentration. An equal volume of maintenance culture medium was added to the normal and virus control groups. After incubation at 37°C, 5% CO2 for 48 hours, CPE was recorded under a light microscope. 15 μL of 5 mg / mL MTT solution was added to each well and incubated for another 4 hours. The supernatant was aspirated, and 100 μL of DMSO was added to each well. The cells were lysed by low-speed shaking. The OD value was measured at 490 nm and the cell viability was calculated relative to that of the normal control group (mean OD value of the drug group / mean OD value of the normal control group × 100%).

[0458] Experimental results:

[0459]

[0460] Experimental conclusion:

[0461] (1) 2-C19-1 and 2-C19-2 are much better than the control drug remdesivir in terms of both efficacy and toxicity, especially 2-C19-1.

[0462]

[0463] Experimental conclusion:

[0464] (1) In the test concentration range of 25-0.008 μM, the cell survival rate data of remdesivir and compounds 2-C19-1 and 2-C19-2 did not exceed 50%, and the efficacy of the three was so poor that the IC 50 data.

[0465] (2) At first glance, the efficacy of the three drugs seems to be similar.

[0466] Experimental results:

[0467]

[0468] * The company announced the compounds that have achieved partial good results in the research and development process, thereby indicating that the aforementioned best results were obtained after multi-faceted exploration.

[0469] Example 15

[0470] Experimental steps:

[0471] Anti-coronavirus 229E activity test

[0472] Bel7402 cells (2.5×10 4 / well) and cultured for 24 h. The supernatant was removed by aspiration, and 10 -2 HCoV virus solution (100 μL / well) was added and adsorbed in a 37°C, 5% CO2 incubator for 5 hours. The culture medium was aspirated, and 100 μL / well of the test drug solution was added to the experimental drug groups, with two replicates per well. An equal volume of maintenance culture medium was added to the normal and virus control groups. After incubation at 37°C, 5% CO2 for 72 hours, CPE was recorded under an optical microscope. Cell viability was determined by the MTT assay, and cell viability was calculated as (mean OD value of the drug group – OD value of the blank) / (mean OD value of the normal control group – OD value of the blank) × 100%.

[0473] Experimental results: (first experiment)

[0474]

[0475] Experimental conclusion: In addition to compound 2-C1, compound 2-C4 is also more effective than Paxlovid and VV116.

[0476] Experimental results: (Second experiment)

[0477]

[0478] Experimental conclusion: In addition to compound 2-C1, compounds 2-C4 and 2-C22 also showed better efficacy than VV116. It was also found that their efficacy was dependent on the test method used.

[0479] Example 16

[0480] Experimental steps:

[0481] Anti-coronavirus 229E activity test

[0482] Bel7402 cells (2.5*10 4 / well) and cultured for 24 h. The supernatant was removed by aspiration, and 10 -2 HCoV virus solution (100 μL / well) was added and adsorbed in a 37°C, 5% CO2 incubator for 5 hours. The culture medium was aspirated, and 100 μL / well of the test drug solution was added to the experimental drug groups, with two replicates per well. An equal volume of maintenance culture medium was added to the normal and virus control groups. After incubation at 37°C, 5% CO2 for 72 hours, CPE was recorded under an optical microscope. Cell viability was determined by the MTT assay, and cell viability was calculated as (mean OD value of the drug group – OD value of the blank) / (mean OD value of the normal control group – OD value of the blank) × 100%.

[0483] Experimental results:

[0484]

[0485] *2-C1-1 and 2-C1-2 are products synthesized from different batches of 2-C1.

[0486] Experimental conclusion: The efficacy of 2-C1-1 is slightly better than that of VV116, and the efficacy of other compounds is not as good as that of VV116.

[0487] Example 17

[0488] Experimental steps:

[0489] Bel7402 cells (2.5*10 4 / well) and cultured for 24 h. The supernatant was removed by aspiration, and 10 -2 HCoV virus solution (100 μL / well) was added and adsorbed in a 37°C, 5% CO2 incubator for 5 h. The culture medium was aspirated, and 100 μL / well of the test drug solution was added to the experimental groups, with two replicates for each concentration. An equal volume of maintenance culture medium was added to the normal and virus control groups. After incubation for 72 h at 37°C, 5% CO2, CPE was recorded under an optical microscope, and cell viability was determined by the MTT assay.

[0490] Experimental results:

[0491]

[0492] Experimental conclusion: The two components 2-C7-1 and 2-C7-2 obtained after the splitting of 2-C7 were so poor in efficacy that the IC values could not be measured. 50 data.

[0493] Example 18

[0494] Experimental steps:

[0495] Bel7402 cells (2.5*10 4 / well) and cultured for 24 h. The supernatant was removed by aspiration, and 10 -2100 μL of HCoV virus solution (prepared in serum-free medium) was added to each well. The normal control group received an equal volume of serum-free medium and inoculated for 2 hours at 37°C, 5% CO2. The drug control group received 100 μL / well of the test drug solution (prepared in complete medium). Two replicates were prepared for each concentration. Equal volumes of complete medium were added to the normal and virus control groups. After incubation at 37°C, 5% CO2 for 72 hours, CPE was recorded under a light microscope. The remaining liquid was aspirated, and the cells were washed once with sugar-free, serum-free medium. 100 μL of MTT working solution (0.5 mg / mL, prepared in serum-free medium) was added to each well and incubated for an additional 2.5 hours. The supernatant was aspirated, 100 μL of DMSO was added to each well, and the cells were vortexed at low speed for dissolution. The OD value was measured at 490 nm, and the cell viability was calculated as [(average OD value of the drug group - blank control) / (average OD value of the normal control group - blank control) × 100%], as well as the antiviral activity [average OD value of the drug group - average OD value of the virus group) / (average OD value of the normal group - average OD value of the virus group) × 100%].

[0496] Experimental results:

[0497]

[0498] Experimental conclusion: It suggests that the efficacy of combination drugs may be better than that of single drugs.

[0499] Example 19

[0500] Experimental process

[0501] Experimental cells:

[0502] Vero E6 cells were maintained by the Virology Laboratory of the State Key Laboratory of Respiratory Diseases.

[0503] SARS-COV-2 is maintained by the Health Quarantine Institute of Guangzhou Customs Technical Center / National Key Laboratory of Biosafety Testing (P3).

[0504] Antiviral experiments

[0505] Drug cytotoxicity assay (MTT assay)

[0506] Vero E6 cells were washed once with PBS in a 96-well plate, the supernatant was discarded, and 100 μL of 2-fold serial dilutions of drugs were added to each well. oC, 5% CO2 for 3 days. Subsequently, 20 μL of 5 mg / mL MTT solution was added to each well and incubated for another 4 hours. The supernatant was discarded, 100 μL of DMSO was added to each well, and the cells were shaken at low speed for 5 minutes. The OD value was measured at 490 nm. The inhibition rate was calculated. Inhibition rate = (average OD value of the normal group - average OD value of the drug group) / (average OD value of the normal group) × 100%. The half-maximal cytotoxic concentration (CC) of the drug was calculated using the nonlinear regression method of GraphPad Prism 8.0. 50 ) and the highest non-toxic concentration (CC0).

[0507] Antiviral efficacy test (CPE method)

[0508] 100 μL of 2×10 5 Vero E6 cells / mL, 37 o C, 5% CO2 for 24 hours; 100 μL / well of 20 TCID50 SARS-COV-2 virus solution was added to the drug experimental group and the virus control group, and the culture was continued at 37 o C. Incubate in a 5% CO2 incubator for 1 hour. Discard the culture medium and add 100 μL / well of a two-fold serial dilution of the test drug, with 4 replicates per concentration. At the same time, set up a cell control, a virus control (negative control), and a positive drug control, remdesivir. o C. After 3 days of incubation in a 5% CO2 incubator, CPE was recorded under a light microscope. The percentage of cells with CPE was recorded according to the following 6-level scale: -: none; ±: <10%; +: 25%; ++: 50%; +++: 75%; ++++: >75%. The half-maximal inhibitory concentration (IC) of drugs against virus-induced cell death in the CPE reduction assay was calculated using the nonlinear regression method in GraphPadPrism 8.0. 50 ) Calculate the Selective Index SI (Selective index: CC 50 / IC 50 ).

[0509] Inhibitory effect of drugs on CPE-induced by SARS-COV-2 infection in Vero E6 cells

[0510] First experiment

[0511]

[0512] Second experiment

[0513]

[0514] The average ratio of the two drug effects is (1.16-3.93) / 2=-1.39

[0515] It can be seen that the efficacy of 2-C19 is slightly worse than that of remdesivir, but its toxicity is much lower than that of remdesivir. At the same time, it can be seen that for the new coronavirus, the efficacy of the compound is also a random function.

[0516] In this patent, only a preliminary discussion of novel coronavirus therapeutic compounds was conducted, and deeper research and development work is the research and development goal of the next patent.

[0517] Example 20 Experimental process

[0518] Huh-7 cells were seeded in 96-well plates (1.5*10 4 / well) and cultured for 24 h. The supernatant was removed and the cells were washed once with serum-free medium. 10 -3 HCoV-229E virus solution (100 μL / well) was added and adsorbed in a 37°C, 5% CO2 incubator for 2 hours. The culture medium was aspirated, and 100 μL / well of the test drug solution was added to the experimental drug groups, with duplicate wells for each concentration. An equal volume of maintenance culture medium was added to the normal and virus control groups. After 48 hours of incubation at 37°C, 5% CO2, CPE was recorded under a light microscope. 15 μL of 5 mg / mL MTT solution was added to each well and incubated for an additional 4 hours. The supernatant was aspirated, and 100 μL of DMSO was added to each well. The solution was shaken at low speed, and the OD value was measured at 490 nm. Cell viability was calculated relative to that of normal cells (mean OD value of the drug group / mean OD value of the normal control group × 100%).

[0519] The following summarizes the research conducted at the School of Pharmacy of Fudan University in Shanghai from September 2022 to January 2024 on the anti-COVID-19 compound developed by our company and the comparative drug {VV116 and Pfizer's "P drug" (Paxlovid)}. -3 Valid experimental data from in vitro efficacy tests of HCoV virus fluid on Hch-7 cells revealed that the relationship between the IC50 (dependent variable), a key indicator of in vitro efficacy testing, and the amount of drug added (independent variable) does not follow the classical relationship between dependent and independent variables, but rather follows a stochastic function. In vitro efficacy data obtained from different batches of tests conducted at different times under identical experimental conditions showed significant fluctuations in the relative IC50 values of the test compound and the control drug. This fluctuation is so large that it cannot be explained by the ±20-30% error characteristic of biological experimental data.

[0520] Mathematically, describing the relationship between dependent and independent variables in natural phenomena involves not only classical functions but also random functions. The significant fluctuations in the IC50 values obtained for the different batches of in vitro efficacy data above demonstrate that for certain viruses, the relationship between the IC50 (dependent variable) and the dosage of the drug (independent variable) follows a random function. Therefore, comprehensive analysis of valid experimental data from different time periods is essential to obtain realistic in vitro efficacy comparisons.

[0521] This patent defines valid test data as in vitro efficacy data measured with a blank cell viability of less than 50%, with a particular preference for in vitro efficacy data with a blank cell viability between 20% and 40%. Compared to the former, in vitro efficacy data measured with a blank cell viability of >50% is less reliable.

[0522] The more nucleotides a single-stranded RNA virus's RNA gene molecule contains, the greater the chance of randomly selecting the wrong nucleotide during replication. Because the virus itself lacks a mechanism to detect and correct incorrect nucleotide selection during replication, random mutations in the daughter RNA genes are inevitable. This leads to large, random fluctuations in IC50 values, a natural phenomenon.

[0523] Table 1. Randomly determined IC50 values of Z10-B and VV116 in vitro

[0524]

[0525] *Extrapolated experimental data

[0526] From the random experimental data of IC50 measurements in the table, we can see that when the IC50 value of Z10-B is "smaller" than the IC50 value of VV116, the ratio of "smallness" is a double-digit value of 27-36, and when the IC50 value of VV116 is "smaller" than the IC50 value of Z10-B, the ratio of "smallness" is a single-digit value of "1.3-5.5". Therefore, the comprehensive statistical analysis result must be that the IC50 value of Z10-B is smaller than the IC50 value of VV116. The ratio of the IC50 value of Z10-B to the IC50 value of VV116 is:

[0527] [(36.1+27.1+28.9)-(4.3+5.4+1.3+2.8)] / 7=11.9

[0528] Table 2. Randomly measured IC50 values of Z10-B and Pfizer "P" drug in vitro

[0529]

[0530] (13.7+12.1) / 2=12.9; the IC50 value of Z10-B is 12.9 times "smaller" than the IC50 of Pfizer P drug.

[0531] Table 3.

[0532] Cell survival rate of Z10-B series compounds, VV116, and Pfizer "P" drug at a concentration of 5uM during the eighth in vitro efficacy

[0533]

[0534] From the experimental data in Table 3, we can see that:

[0535] (1) At a concentration of 5uM, the cell survival rate of any compound in the Z10-B series is higher than that of VV116 and Pfizer P drug.

[0536] (2) Once the compounds in the Z10-B series are acidified, their cell survival rates can be improved; for example, once the main component and the secondary component are acidified, the cell survival rates can be increased from 48.7% and 34.1% to 75.2% and 51.5% at a drug concentration of 5uM.

[0537] (3) Once the acidic main component and secondary component in the Z10-B series are combined, the cell survival rate can be increased from 71.4% to 90.9% at a drug concentration of 5uM.

[0538] (4) The molecular structure of the Z10-B series compounds is shown below:

[0539]

[0540] The foregoing descriptions of specific exemplary embodiments of the present invention are for purposes of illustration and description. These descriptions are not intended to limit the invention to the precise forms disclosed, and it is apparent that many variations and modifications are possible in light of the foregoing teachings. The exemplary embodiments have been selected and described for the purpose of explaining the specific principles of the invention and their practical application, thereby enabling those skilled in the art to realize and utilize a variety of exemplary embodiments of the invention and various options and modifications. The scope of the invention is intended to be defined by the claims and their equivalents.

Claims

1. β-nucleoside compound, characterized in that Its structure is shown in Formula 1: ； R1, R2, R3...R14 and R are selected as follows: H, D, substituents (C1-C8)alkyl, monosubstituted or polysubstituted (C1-C8)alkyl; (C2-C8)alkenyl, monosubstituted or polysubstituted (C2-C8)alkenyl; (C2-C8)alkynyl, monosubstituted or polysubstituted (C2-C8)alkynyl; (C3-C8)cycloalkyl, monosubstituted or polysubstituted (C3-C8)cycloalkyl; (C3-C8)cycloalkenyl, monosubstituted or polysubstituted (C3-C8)cycloalkenyl; (C6-C 20 ) aryl, monosubstituted or polysubstituted (C6-C 20 ) aryl; 3-8 membered heterocyclic group, monosubstituted or polysubstituted 3-8 membered heterocyclic group, any carbon atom of which can be replaced by -Se-, -NR-, -O- or -S-; (C6-C 20 ) heteroaryl, monosubstituted or polysubstituted (C6-C 20 ) heteroaryl, any carbon atom of which may be replaced by -Se-, -NR-, -O- or -S-; (C6-C 20 ) aryl (C1-C8) alkyl, mono- or polysubstituted (C6-C 20 ) aryl (C1-C8) alkyl; (C6-C 20 ) aryl-monosubstituted or polysubstituted (C1-C8) alkyl; monosubstituted or polysubstituted (C6-C 20 )aryl-monosubstituted or polysubstituted (C1-C8)alkyl; (C1-C8)alkyl-(C6-C 20 )aryl, monosubstituted or polysubstituted (C1-C8)alkyl-(C6-C 20 ) aryl; (C1-C8) alkyl-monosubstituted or polysubstituted-(C6-C 20 ) aryl; monosubstituted or polysubstituted (C1-C8) alkyl-monosubstituted or polysubstituted (C6-C 20 )aryl; HC=O, (C1-C7)alkyl-C=O, monosubstituted or polysubstituted (C1-C7)alkyl-C=O; (C6-C 20 ) aryl-C=O, monosubstituted or polysubstituted (C6-C 20 )Aryl-C=O; (C6-C 20 ) aryloxy, mono- or polysubstituted (C6-C 20 )aryloxy; Substituents or substitutions include halogen, -OH, -OR, -NO2, -N(R)O, -NR2 (each R can be selected from the same element or different elements in the R set), -NH2, -NHR, -CN, -C=N=N, -CHO, -N3, -COOH, -COOR, -SH, -SR, -COSH, -COSR; thiocyanate, oxycyanate, methylcyanate, urea, and guanidinium; Polysubstitution includes selecting multiple substituents of the same type or selecting multiple substituents of different types; Monosubstituted means that only one substituent is selected.

2. The β-nucleoside compound according to claim 1, characterized in that: R1 and R2 have the following options: Class A selection of R1 and R2: R1 and R2 each select OH or OR; Category B selection for R1 and R2: select type I, type II, type III, type IV and R or OH; ； In the B-type expression, R a 、R b 、R c 、R d and R e Each of them may be H, halogen; (C1-C8) alkyl, mono- or poly-substituted (C1-C8) alkyl; (C3-C8) cycloalkyl, mono- or poly-substituted (C3-C8) cycloalkyl; (C1-C8) alkoxy, mono- or poly-substituted (C1-C8) alkoxy; (C3-C8) cycloalkoxy, mono- or poly-substituted (C3-C8) cycloalkoxy; (C6-C 20 ) aryl, monosubstituted or polysubstituted (C6-C 20 ) aryl; R in Type I b and R c , select ethylene, (C3-C8) cycloalkyl, monosubstituted or polysubstituted ethylene, monosubstituted or polysubstituted (C3-C8) cycloalkyl.

3. The β-nucleoside compound according to claim 2, characterized in that: After appropriately selecting R1 and R2, the specific structures of the compound of Formula 1 are the compound shown in Formula 2, the compound shown in Formula 3, the compound shown in Formula 4, and the compound shown in Formula 5; 。 4. The β-nucleoside compound according to claim 3, characterized in that: R3, R4, R5, R6, R7 and R8 are each selected from H, a substituent as defined, and (C1-C8)alkyl, mono-substituted or poly-substituted (C1-C8)alkyl; (C1-C8)alkoxy, mono-substituted or poly-substituted (C1-C8)alkoxy; (C3-C8)cycloalkyl, mono-substituted or poly-substituted (C3-C8)cycloalkyl; (C3-C8)cycloalkoxy, mono-substituted or poly-substituted (C3-C8)cycloalkoxy; (C2-C8)alkenyl, mono-substituted or poly-substituted (C1-C8)alkenyl; (C2-C8)alkynyl, mono-substituted or poly-substituted (C1-C8)alkynyl.

5. The β-nucleoside compound according to claim 3, characterized in that: After appropriately selecting R3, R4, R5, R6, R7 and R8, the specific structure of the compound of Formula 2 is the compound shown in Formula 2-A and the compound shown in Formula 2-B, the specific structure of the compound of Formula 3 is the compound shown in Formula 3-A and the compound shown in Formula 3-B, the specific structure of the compound of Formula 4 is the compound shown in Formula 4-A and the compound shown in Formula 4-B, and the specific structure of the compound of Formula 5 is the compound shown in Formula 5-A and the compound shown in Formula 5-B; .

6. The β-nucleoside compound according to claim 3, characterized in that: R5 and R7 can also be selected from the following: (C1-C7) alkyl-C(O)O-, mono- or poly-substituted (C1-C7) alkyl-C(O)O-, (C1-C7) alkoxy-C(O)O-, mono- or poly-substituted (C1-C7) alkoxy-C(O)O-, (C1-C7) alkyl-C(O)-NH-, mono- or poly-substituted (C1-C7) alkyl-C(O)-NH-, (C1-C7) alkoxy-C(O)-NH-, mono- or poly-substituted (C1-C7) alkoxy-C(O)-NH-, (C1-C7) alkyl-C(O)-NR-, Mono- or poly-substituted (C1-C7)alkyl-C(O)-NR-, (C1-C7)alkoxy-C(O)-NR-, mono- or poly-substituted (C1-C7)alkoxy-C(O)-NR-, (C6-C 20 ) aryl-C(O)-O-, monosubstituted or polysubstituted (C6-C 20 ) aryl-C(O)-O-, (C6-C 20 ) aryl-C(O)-NH-, monosubstituted or polysubstituted (C6-C 20 ) aryl-C(O)-NH-, (C6-C 20 ) aryl-C(O)-NR-, monosubstituted or polysubstituted (C6-C 20 )aryl-C(O)-NR-, (C1-C7)alkyl-C(O)S-, mono- or poly-substituted (C1-C7)alkyl-C(O)-S-, (C1-C7)alkoxy-C(O)S-, mono- or poly-substituted (C1-C7)alkoxy-C(O)-S-.

7. The β-nucleoside compound according to claim 3, characterized in that: R8 can also be selected from: -C(O)-NH2, -C(O)-NHR, -C(O)-NRR.

8. The β-nucleoside compound according to claim 5, characterized in that: The R9 and R10 can be H, -NH2, -NHR, -NRR, respectively. The two Rs can be selected from the same or different groups in the R set, such as -OH, -SeH, -SH, -COOH, -COOR, -COSH, -COSR, -NH2·HX; HX is hydrobromic acid, fumaric acid, or other pharmaceutically acceptable inorganic or organic acids. R11 and R12 can be H, D and halogen respectively; R13 and R14 can be H, (C1-C8) alkyl, mono-substituted or poly-substituted (C1-C8) alkyl; (C1-C8) alkoxy, mono-substituted or poly-substituted (C1-C8) alkoxy; (C2-C8) alkenyl, mono-substituted or poly-substituted (C2-C8) alkenyl; (C2-C8) alkynyl, mono-substituted or poly-substituted (C2-C8) alkynyl; (C3-C8) cycloalkyl, mono-substituted or poly-substituted (C3-C8) cycloalkyl; (C6-C20) aryl, mono-substituted or poly-substituted (C6-C20) aryl; 3-8 membered heterocyclyl, mono-substituted or poly-substituted 3-8 membered heterocyclyl, any carbon atom of which can be replaced by -Se-, -NR-, -O- or -S-.

9. The β-nucleoside compound according to claim 5, characterized in that: By appropriately selecting R9, R10, R11, R12, R13 and R14, compounds of formula 2-C and formula 2-D can be obtained from compounds of formula 2-A and formula 2-B, respectively; From the compounds of formula 3-A and formula 3-B, compounds of formula 3-C and formula 3-D are obtained; From the compounds represented by formula 4-A and formula 4-B, compounds represented by formula 4-C and formula 4-D are obtained; Formula 5-C and Formula 5-D are obtained from the compounds represented by Formula 5-A and Formula 5-B; Among them, formula 2-C is a collection of 32 structural formulas selected from its structural cluster, namely formula 2-Ci, where i = 1, 2, 3…32; Formula 2-D is a general term for selecting 5 structural formulas from its structural cluster, formula 2-Di, where i = 1, 2, 3…5; .

10. The β-nucleoside compound according to claim 9, characterized in that: The structure of the salt formed by -NH2 on the base and the acid is -NH2·HX. From formula 2-C1, the compound represented by 2-E1 can be obtained, and from formula 2-D1, the compound represented by 2-F1 can be obtained; from the compounds represented by formula 2-Ci (i=1,2,3,……32) and 2-Dj (j=1,2,3,4,5), the compounds represented by formula 2-Ei (i=1,2,3,……32) and 2-Fj (j=1,2,3,4,5) can be obtained; from the compounds represented by formula 3-C and formula 3-D, the compounds represented by formula 3-E and formula 3-F can be obtained; from the compounds represented by formula 4-C and formula 4-D, the compounds represented by formula 4-E and formula 4-F can be obtained; from the compounds represented by formula 5-C and formula 5-D, the compounds represented by formula 5-E and formula 5-F can be obtained. The molecular structures are as follows: 。 11. The β-nucleoside compound according to claim 10, characterized in that: HX can be selected from HBr, fumaric acid and other pharmaceutically acceptable organic or inorganic acids.

12. The β-nucleoside compound according to claim 1, characterized in that: The ribose structure in formula 1 can be the following: Option a: , wherein R3, R4, R5, R6, R7 and R8 are each a substituent as defined, (C1-C8)alkyl, monosubstituted or polysubstituted (C1-C8)alkyl; (C1-C8)alkoxy, monosubstituted or polysubstituted (C1-C8)alkoxy; (C3-C8)cycloalkyl, monosubstituted or polysubstituted (C3-C8)cycloalkyl; (C3-C8)cycloalkoxy, monosubstituted or polysubstituted (C3-C8)cycloalkoxy; (C2-C8)alkenyl, monosubstituted or polysubstituted (C2-C8)alkenyl; (C2-C8)alkynyl, monosubstituted or polysubstituted (C2-C8)alkynyl; (C6-C 20 ) aryl, monosubstituted or polysubstituted (C6-C 20 ) aryl; R9, R 10 Each is H, deuterium D or halogen, halogen is F or Cl; Option b: , wherein X is -O- or -S- or -Se-; R3, R6, R7 and R8 are each a "substituent" as defined in the definition, (C1-C8) alkyl, mono- or poly-substituted (C1-C8) alkyl; (C1-C8) alkoxy, mono- or poly-substituted (C1-C8) alkoxy; (C3-C8) cycloalkyl, mono- or poly-substituted (C3-C8) cycloalkyl; (C3-C8) cycloalkoxy, mono- or poly-substituted (C3-C8) cycloalkoxy; (C2-C8) alkenyl, mono- or poly-substituted (C2-C8) alkenyl; (C2-C8) alkynyl, mono- or poly-substituted (C2-C8) alkynyl; (C6-C 20 ) aryl, monosubstituted or polysubstituted (C6-C 20 ) aryl; R9, R 10 Each is H, deuterium D or halogen, halogen is F or Cl; Select c: ; wherein R4 (except the -OH group in the substituent), R6, R7 and R8 are each a substituent as defined, (C1-C8) alkyl, monosubstituted or polysubstituted (C1-C8) alkyl; (C1-C8) alkoxy, monosubstituted or polysubstituted (C1-C8) alkoxy; (C3-C8) cycloalkyl, monosubstituted or polysubstituted (C3-C8) cycloalkyl; (C3-C8) cycloalkoxy, monosubstituted or polysubstituted (C3-C8) cycloalkoxy; (C2-C8) alkenyl, monosubstituted or polysubstituted (C2-C8) alkenyl; (C2-C8) alkynyl, monosubstituted or polysubstituted (C2-C8) alkynyl; (C6-C 20 ) aryl, monosubstituted or polysubstituted (C6-C 20 ) aryl; R9, R 10 Each is H, deuterium D or halogen, halogen is F or C1; R4 substituents exclude -OH; Option d: ; wherein R3, R4, R5, R6 and R8 are each a substituent as defined, (C1-C8)alkyl, monosubstituted or polysubstituted (C1-C8)alkyl; (C1-C8)alkoxy, monosubstituted or polysubstituted (C1-C8)alkoxy; (C3-C8)cycloalkyl, monosubstituted or polysubstituted (C3-C8)cycloalkyl; (C3-C8)cycloalkoxy, monosubstituted or polysubstituted (C3-C8)cycloalkoxy; (C2-C8)alkenyl, monosubstituted or polysubstituted (C2-C8)alkenyl; (C2-C8)alkynyl, monosubstituted or polysubstituted (C2-C8)alkynyl; (C6-C 20 ) aryl, monosubstituted or polysubstituted (C6-C 20 ) aryl; R9, R 10 Each is H, deuterium D or halogen, halogen is F or C1; R4 and R6 substituents exclude -OH; There are four types of ribose: a, b, c, and d. Any of the molecular structures mentioned above can be derived into four related molecular structures including its original structure; among them, the molecular structure of type a is the original molecular structure.

13. The β-nucleoside compound according to claim 11, characterized in that: Formula 2-C1 derives compounds represented by formula 2-C1 / a, formula 2-C1 / b, formula 2-C1 / c, and formula 2-C1 / d; 。 14. The β-nucleoside compound according to claim 1 in inhibiting the human coronavirus and the COVID-19 virus in the Coronaviridae family, the coronavirus α and β genera.

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