Tricyclic boric acid derivatives, methods for their preparation, and uses

Abstract

Disclosed are tricyclic boric acid derivatives and methods for their preparation and uses, specifically, a compound represented by formula (I), an optical isomer thereof and a pharmaceutically acceptable salt thereof, and the use of said compound as a β-lactamase inhibitor and the use of a composition as an antimicrobial drug.

Description

Technology Field

[0001] This application claims the following priority.

[0002] CN202111217905.0, Filing Date: October 19, 2021;

[0003] CN202211255968.X, Filing Date: October 13, 2022.

[0004] The present invention belongs to the field of medicinal chemistry, and specifically, the present invention relates to a compound represented by formula (I), an optical isomer thereof and a pharmaceutically acceptable salt thereof, and the use of said compound as a β-lactamase inhibitor and the use of a composition as an antimicrobial drug. Background Technology

[0005] The widespread and excessive use of antibiotics has caused pathogenic bacteria to rapidly evolve resistance to antimicrobial drugs, giving rise to large numbers of drug-resistant strains, multidrug-resistant strains, and even superbugs. Bacterial drug resistance has become a major challenge in global public health. According to the 2014 "Global Antimicrobial Resistance Review," 700,000 people currently die annually due to antibiotic resistance. The rate of bacterial drug resistance in China is significantly higher than in European and American countries, at approximately 45%. In China, more than 80,000 people die each year from infections caused by drug-resistant bacteria. If the current situation does not improve and no new anti-drug resistant antibiotics emerge, 1 million people will die annually in China by 2050, and GDP losses will exceed $20 trillion.

[0006] Beta-lactam antibiotics are currently the most important antimicrobial drugs in clinical practice, accounting for over 50% of the total market. Beta-lactam antibiotics refer to a broad class of antibiotics possessing a beta-lactam ring in their chemical structure, including the most commonly used penicillins and cephalosporins in clinical practice, as well as carbapenems and other atypical beta-lactam antibiotics such as monocyclic beta-lactams. This type of antibiotic possesses advantages such as strong bactericidal activity, low toxicity, a broad range of indications, and good clinical efficacy. The mechanisms of action of beta-lactam antibiotics are all similar; they all disrupt mucin synthesis in the cell wall by inhibiting cell wall mucin synthases, specifically penicillin-binding proteins, thereby damaging the bacterial cell wall and causing the bacterial cells to swell and lyse.

[0007] One of the major mechanisms of bacterial resistance to β-lactam antibiotics is the production of β-lactamase. There are over 2,800 types of β-lactamase reported to date. These differ significantly in terms of source, substrate, inhibitor, and structure. In 1980, Ambler classified β-lactamases into four classes based on their molecular structure using amino acid sequence analysis: Class A is penicillinase, Class B is metallo-β-lactamase, Class C is cephalosporinase, and Class D is oxacillinase. Here, the active group of Classes A, C, and D is serine (SBL), while the active group of Class B is a metallic zinc ion (MBL).

[0008] β-lactamase inhibitors can bind to β-lactamase and inactivate the enzyme; clinically, when used in combination with β-lactam antibiotics, they can suppress drug-resistant bacteria, reduce dosage, expand the antimicrobial spectrum, and enhance antimicrobial activity. To date, there are six β-lactamase inhibitors approved by the FDA, but all of them have a relatively significant limitation in that they cannot effectively treat superbug resistance mediated by MBL. Clavulanic acid, Sulbactam, and Tazobactam inhibit only certain Class A SBLs, while Avibactam inhibits Class A, C, and D SBLs but is ineffective against pathogenic bacteria resistant to MBL. MBL can hydrolyze all β-lactam antimicrobial drugs except for monocyclic β-lactams, such as penicillin, cephalosporin, extended-spectrum cephalosporin, and carbapenem. According to the China Bacterial Resistance Monitoring Network (CHINET), among clinically isolated strains in China in 2018, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter showed resistance to carbapenem antibiotics, such as meropenem, at rates of 26.3%, 25.8%, and 73.9%, respectively. Specifically, the resistance rate of Klebsiella pneumoniae to meropenem increased from 2.9% in 2005 to 26.3%, while that of Acinetobacter baumannii increased from 41.3% in 2005 to 73.9%. Acinetobacter baumannii has a strong ability to acquire drug resistance and propagate clones, and has evolved into a significant pathogen of hospital-acquired infections. In the WHO's priority list for developing drugs effective against antibiotic-resistant bacteria, carbapenem-resistant Acinetobacter baumannii ranks very high.Carbapenem drugs serve as the last line of defense against bacterial infections; once drug resistance develops, available drugs become extremely limited, and in certain cases, drugs cannot be used. Therefore, there is an urgent need for new antimicrobial drugs to overcome clinical treatment difficulties and address the increasingly prominent challenge of drug resistance.

[0009] Bacterial resistance involves various mechanisms and can be summarized as follows: (1) Changes in the permeability of the bacterial cell wall or outer membrane, such as a decrease in the expression of phorin and an increase in the expression of efflux pumps, prevent the bacteria from entering the body and reaching the target site of action, or they barely enter; the outer membrane of Gram-negative bacteria is the first barrier that limits the delivery of β-lactam antibiotics into the cell; (2) The generation of mutations in target proteins leads to a decrease in binding affinity with antibiotics, an increase in target proteins, or the generation of new target proteins. For example, high resistance in methicillin-resistant Staphylococcus aureus is due to the generation of a new PBP2' between the original PBP2 and PBP3, while low and moderate resistance is due to an increase in the production of PBPs or a decrease in affinity with methicillin, etc.; (3) Bacteria produce β-lactamase to hydrolyze and inactivate antibiotics, or bind to antibiotics to keep them in the extracellular space, preventing them from entering the cell and binding to target proteins. The main resistance mechanism of Gram-positive bacteria is the production of β-lactamase and PBP mutations, and the main resistance mechanism of Gram-negative bacteria is the production of β-lactamase.

[0010] In a first aspect of the present invention, the present invention provides a compound represented by formula (I), an optical isomer thereof, and a pharmaceutically acceptable salt thereof, and

[0011] ,

[0012] In the above formula,

[0013] X is selected from S, S(=O) and S(=O)2;

[0014] L1 is a single bond, C 1-6 Alkyl and C 1-6 Selected from heteroalkyl, and C 1-6 alkyl or C 1-6 The heteroalkyl group is optionally substituted by 1, 2, or 3 R groups;

[0015] L2 is a single bond, C 3-6 Selected from cycloalkyl and quaternary to ninth-membered heterocycloalkyl, and said C 3-6 The cycloalkyl or quaternary to ninth-membered heterocycloalkyl is optionally substituted by 1, 2, or 3 Rs;

[0016] L3 is a single bond, C 1-6 Alkyl, C 1-6 Selected from heteroalkyl and quaternary to ninth-membered heterocycloalkyl, and C 1-6 Alkyl, C 1-6 The heteroalkyl or quaternary to ninth-membered heterocycloalkyl is optionally substituted by 1, 2, or 3 Rs;

[0017] R1 is NH2, , -NR a C(=NH)R b , -NR a C(=NH)NR b1 R b2 , -C(=NH)R b , C 1-6 Alkyl, C 3-6 Selected from cycloalkyl, tetrocycloalkyl, partially unsaturated tetrocycloalkyl, and zetroaryl, and hexacycloalkyl, and C 1-6 Alkyl, C 3-6 The cycloalkyl, tetanical to octanine heterocycloalkyl, partially unsaturated tetanical to octanine heterocycloalkyl, or quintical to hexavalent heteroaryl is optionally substituted by 1, 2, or 3 R groups;

[0018] R, R a , Rb , R b1 , R b2 Each independently contains H, F, Cl, Br, OH, NH2, CN, and C 1-6 Alkyl and C 3-6 Selected from cycloalkyl, and C 1-6 alkyl or C 3-6 The cycloalkyl group is optionally substituted by 1, 2, or 3 R' groups;

[0019] R' is each independently selected from F, Cl, Br, I, NH2, OH, and Me;

[0020] The above C 1-6 Heteroalkyl, quaternary to ninth heterocycloalkyl, partially unsaturated quaternary to eighth heterocycloalkyl or quinary to sixth heteroaryl independently comprise one, two, or three heteroatoms or heteroatom groups selected from O, NH, S, C(=O), C(=NH), C(=O)O, S(=O), S(=O)2, and N.

[0021] In some embodiments of the present invention, the compound represented by formula (I), its optical isomers, and pharmaceutically acceptable salts thereof are selected from the compounds represented by formulas (IA) and (IB), their optical isomers, and pharmaceutically acceptable salts thereof, and

[0022] , ,

[0023] In the above formula,

[0024] X, L1, L2, L3, and R1 are as defined above.

[0025] In some embodiments of the present invention, R is independently R is F, Cl, Br, OH, NH2, CH3, , and Selected from, and the above CH3, , or is arbitrarily substituted by 1, 2, or 3 R', and other variables are as defined in the present invention.

[0026] In some embodiments of the present invention, R is each independently F, Cl, Br, OH, NH2, CH3, , , , and Selected from, and other variables as defined in the present invention.

[0027] In some embodiments of the present invention, L1 is a single bond, C 1-3 Alkyl, -C 1-3 Alkyl-O-, -C 1-3 Alkyl-S-, -C 1-3 Alkyl-NH- and -C 1-3 Selected from alkyl-C(=O)-, and said C 1-3 Alkyl, -C 1-3 Alkyl-O-, -C 1-3 Alkyl-S-, -C 1-3 Alkyl-NH- or -C 1-3 Alkyl-C(=O)- is optionally substituted by 1, 2 or 3 R groups, and other variations are as defined in the present invention.

[0028] In some embodiments of the present invention, L1 is a single bond, CH2, , , , , , , and Selected from, and the above CH2, , , , , , , or is arbitrarily substituted by 1, 2, or 3 Rs, and other variables are as defined in the present invention.

[0029] In some embodiments of the present invention, L1 is a single bond, CH2, , , , , , , , , , , and Selected from, and other variables as defined in the present invention.

[0030] In some embodiments of the present invention, L2 is selected from a single bond, cyclobutyl, cyclopentyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, and 2,6-diazaspiro[3.3]heptyl, wherein the cyclobutyl, cyclopentyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, or 2,6-diazaspiro[3.3]heptyl is optionally substituted by 1, 2, or 3 Rs, and other variations are as defined in the present invention.

[0031] In some embodiments of the present invention, L2 is a single bond, , , , , , and Selected from, and other variables as defined in the present invention.

[0032] In some embodiments of the present invention, L3 is a single bond, C(=O), C 1-3 Alkyl, -C 1-3 Alkyl-C(=O)- and -C 1-3 Selected from alkyl-C(=O)NH-, and said C 1-3 Alkyl, -C 1-3 Alkyl-C(=O)- or -C 1-3 Alkyl-C(=O)NH- is optionally substituted by 1, 2, or 3 R groups, and other variations are as defined in the present invention.

[0033] In some embodiments of the present invention, L3 is a single bond, C(=O), , , , , , and Selected from, and other variables as defined in the present invention.

[0034] In some embodiments of the present invention, R1 is NH2, , , , , , , , , , C 1-3 Alkyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranil, tetrahydro-2H-pyranil, morpholinil, piperidinyl, piperazinyl, octahydrocyclopentadiene[c]pyrrolyl, 4,5-dihydro-1H-imidazolyl, imidazolyl, 4,5-dihydro-1H-imidazolyl, imidazoline-2-imino, tetrahydropyrimidine-2(1H)-imino, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 6-oxa-2-azspiro[3.4]octyl, Selected from 2,6-diazaspiro[3.4]octyl, 3,6-diazabicyclo[3.1.1]heptyl and 2,5-diazabicyclo[2.2.1]heptyl, and C 1-3Alkyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranil, tetrahydro-2H-pyranil, morpholinil, piperidinyl, piperazinyl, octahydrocyclopentadiene[c]pyrrolyl, 4,5-dihydro-1H-imidazolyl, imidazolyl, 4,5-dihydro-1H-imidazolyl, imidazoline-2-imino, tetrahydropyrimidine-2(1H)-imino, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 6-oxa-2-azspiro[3.4]octyl, 2,6-diazaspiro[3.4]octyl, 3,6-diazabicyclo[3.1.1]heptyl or 2,5-diazabicyclo[2.2.1]heptyl are optionally substituted by 1, 2 or 3 Rs, and other variables are as defined in the present invention.

[0035] In some embodiments of the present invention, R1 is NH2, , , , , , , , , , Me, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Selected from, and the above Me, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , or is arbitrarily substituted by 1, 2, or 3 Rs, and other variables are as defined in the present invention.

[0036] In some embodiments of the present invention, R1 is NH2, Me, CF3, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Selected from, and other variables as defined in the present invention.

[0037] In some embodiments of the present invention, structural unit is Me, CF3, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Selected from, and other variables as defined in the present invention.

[0038] In a second aspect of the present invention, the present invention also provides a compound represented by the following formula, an optical isomer thereof, and a pharmaceutically acceptable salt thereof.

[0039] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0040] In another aspect of the present invention, the present invention also provides a compound represented by a formula selected from the following, an optical isomer thereof, and a pharmaceutically acceptable salt thereof.

[0041] , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0042] In another aspect of the present invention, the present invention also provides the use of the aforementioned compound, its optical isomer, and its pharmaceutically acceptable salt in the manufacture of a drug for treating bacterial infectious diseases.

[0043] In some embodiments of the present invention, the combination of the aforementioned compound, its optical isomer and its pharmaceutically acceptable salt, and other β-lactam antibiotics is further included.

[0044] In some embodiments of the present invention, the β-lactam antibiotic is selected from penicillin, cephalosporin, carbapenem, monocyclic β-lactam antibiotic, or a combination thereof.

[0045] In some embodiments of the present invention, the penicillin is selected from acid-resistant penicillin, enzyme-resistant penicillin, ampicillin, amoxicillin, pivampicillin, carbenicillin, sulbenicillin, ticarcillin, furbenicillin, azlosillin, and piperacillin.

[0046] In some embodiments of the present invention, the cephalosporin is selected from cephalexin, cefradine, cefazolin, ceproxim, cefamandol, cefachlor, cefotaxim, ceftazidime, ceftriaxone, cefoperazone, ceftizoxime, cefepim, cefpirom, and ceftolozane.

[0047] In some embodiments of the present invention, the carbapenem is selected from imipenem, meropenem, panipenem, viapenem, ertapenem, and paropenem.

[0048] In some embodiments of the present invention, the single-ring β-lactam system is selected from aztreonam.

[0049] Definition and explanation

[0050] Unless otherwise specified, the following terms and phrases used in this text have the following meanings. No specific term or phrase shall be considered indeterminate or unclear unless specifically defined otherwise, and shall be understood in its ordinary meaning. Where a product name appears in this text, it indicates the corresponding product or its active ingredient.

[0051] The phrase “at least one” as used in the present invention should be understood to mean at least one element selected from any one or more elements of the list of elements when referring to a list of one or more elements, but it does not necessarily include at least one of each element specifically listed in the list of elements, nor does it exclude any combination of elements in the list of elements. This definition also allows for the optional existence of elements other than the specifically determined elements within the list of elements referred to by the phrase “at least one,” whether or not they are related to such specifically determined elements.

[0052] As used herein, the term “pharmaceuticalally acceptable” means that, within the scope of reliable medical judgment, such compounds, materials, compositions and / or formulations are suitable for use in contact with human and animal tissues, without excessive toxicity, irritation, hypersensitivity reactions or other problems or complications, and have a reasonable benefit / risk ratio.

[0053] The term “pharmaceutically acceptable salt” refers to a salt of a compound of the present invention, prepared with a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base. If the compound of the present invention contains a relatively acidic functional group, a base addition salt may be obtained by contacting a sufficient amount of base with a neutral form of such compound in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. If the compound of the present invention contains a relatively basic functional group, an acid addition salt may be obtained by contacting a sufficient amount of acid with a neutral form of such compound in a solution or a suitable inert solvent. An embodiment of a pharmaceutically acceptable acid addition salt includes an inorganic salt, said inorganic acid including, for example, hydrochloric acid, hydrobromide, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodide, phosphite, etc.; and includes organic acid salts, wherein the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also includes salts of amino acids (e.g., arginine, etc.) and salts of organic acids such as glucuronic acid. Some specific compounds of the present invention may include basic and acidic functional groups and may be converted into any base or acid addition salt.

[0054] The pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods with a parent compound containing an acid group or a base. In general, the method of preparing such salts is to react such compounds in the form of a free acid or base with a chemically weighed suitable base or acid in water or an organic solvent or a mixture of both.

[0055] The compounds of the present invention may exist in specific geometric or stereoisomer forms. These compounds anticipated in the present invention include cis and trans isomers, (-)- and (+)- enantiomers, ( R )- and ( S )-enhanced mirror image isomer, diastereomer, ( D )-isomer, ( L It includes racemic mixtures and other mixtures, such as mixtures rich in )-isomers, and enantiomers or diastereomers, and all such mixtures are within the scope of the present invention. Other asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are within the scope of the claims of the present invention.

[0056] The compounds of the present invention may exist as specific. Unless otherwise specified, the terms “tautomer” or “tautomeric form” refer to isomers having different functional groups that are in dynamic equilibrium at room temperature and can rapidly interconvert. Where tautomers are possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) involve interconversion through the transfer of protons, such as keto-enol isomerization and imine-enamin isomerization. Valence tautomers involve interconversion by the recombination of some bonded electrons. A specific example of ketone-enol tautomerization is the interconversion between the two tautomers of pentan-2,4-dione and 4-hydroxypent-3-en-2-one.

[0057] The compound of the present invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, tritium ( 3H), iodine-125( 125 I) or C-14( 14 Compounds can be labeled with radioactive isotopes such as C). As another example, deuterated drugs can be formed by replacing hydrogen with deuterium; the bond composed of deuterium and carbon is stronger than the bond composed of ordinary hydrogen and carbon, and compared to non-deuterated drugs, deuterated drugs have advantages such as reducing toxic side effects, increasing drug stability, enhancing drug efficacy, and extending the biological half-life. All transformations composed of isotopes of the compounds of the present invention, whether radioactive or not, fall within the scope of the present invention. The terms “at will” or “optional” refer to the event or situation described below, which may occur but are not necessarily guaranteed to occur, and include cases where said event or situation occurs and cases where said event or situation does not occur.

[0058] Dotted line on the valence bond of the energy If ” is present, for example, “ In ”, the dotted line indicates the connection site between the corresponding group and the rest of the molecule. For a single bond, “ If ” is present, for example, “ In ”, the above dotted line represents a single connection or member, which also “ ” is a single combination “ ” or double bond “ It means ”

[0059] The terms “substituted” or “substituted by” refer to any one or more hydrogen atoms in a particular atom being substituted by a substituent, and may include deuterium and hydrogen variants as long as the valence state of the particular atom is normal and the compound after substitution is stable. The terms “arbitrarily substituted” or “arbitrarily substituted by” mean that the atom may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary in terms of chemical feasibility.

[0060] Where any variable (e.g., R) appears one or more times in the composition or structure of the compound, its definition in each case is independent. Thus, for example, where a group is substituted by 1, 2, or 3 R', the group may be arbitrarily substituted by 1, 2, or 3 R', and R' in each case has independent options. Furthermore, combinations of substituents and / or variants thereof are permitted only if such combinations produce a stable compound.

[0061] When one of the variables is selected from a single combination, it indicates that its two connected groups are directly connected, for example, If L1 represents a single bond, the structure is actually It indicates that.

[0062] If it is not specified through which atom of the listed substituents is connected to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl may be bonded as a substituent to the substituted group through any carbon atom of the pyridine ring.

[0063] If the connection direction of the listed connectors is not specified, the connection direction is arbitrary, for example, In this case, the linker L is -CH2O-, where -CH2O- connects phenyl and cyclopentyl in the same direction as the left-to-right reading order. It can form, by connecting phenyl and cyclopentyl in the opposite direction to the left-to-right reading order. It can form. The combination of the linker, substituent, and / or variant thereof is permitted only if such combination produces a stable compound.

[0064] Unless otherwise specified, the number of atoms in a ring is typically defined as the number of rings, for example, “three to six rings” refers to “rings” arranged in a circle with three to six atoms.

[0065] Unless otherwise specified, the term “C 1-6 “Alkyl” represents a saturated hydrocarbon group composed of 1 to 6 carbon atoms in a straight or branched chain. The above C 1-6 Alkyl is C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , including C6 and C5 alkyls, etc., which are monovalent (e.g., CH3), divalent (-CH2-), or polyvalent (e.g. ) could be. C 1-6 Examples of alkyl groups include CH3, , , , , , , , , , , , Includes, but not limited to, the following.

[0066] Unless otherwise specified, the term “C 1-4 "Alkyl" represents a saturated hydrocarbon group composed of 1 to 4 carbon atoms in a straight or branched chain. The above C 1-4Alkyl is C 1-2 , C 1-3 , C 3-4 and C 2-3 It includes alkyl groups, etc., which are monovalent (e.g., CH3), divalent (-CH2-), or polyvalent (e.g. ) could be. C 1-4 Examples of alkyl groups include CH3, , , , , Includes, but not limited to, the following.

[0067] Unless otherwise specified, the term “heteroalkyl” refers to a stable straight-chain or branched-chain alkyl group or a composition thereof, consisting of a specific number of carbon atoms and at least one heteroatom or heteroatom group, either by itself or in combination with other terms. In some embodiments, the heteroatom is selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternarily ammonized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O)2-, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. In some embodiments, the heteroalkyl is C 1-6 It is a heteroalkyl, and in some other embodiments, the heteroalkyl is C 1-3It is a heteroalkyl. A heteroatom or heteroatom group can be located at any internal position of the heteroalkyl, including a position where the alkyl is connected to the rest of the molecule, but the term “alkoxy” is a conventional expression referring to an alkyl group connected to the rest of the molecule through one oxygen atom. Examples of heteroalkyls include, but are not limited to, up to two heteroatoms that may be consecutive, such as -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH2(CH3)2, -CH2-CH2-O-CH3, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)(CH2CH3), -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, -CH2-S-CH2-CH3, -CH2-CH2, -S(=O)-CH3, -CH2-CH2-S(=O)2-CH3, and -CH2-NH-OCH3.

[0068] Unless otherwise specified, the term “C 1-6 “Alkoxy” represents an alkyl group comprising 1 to 6 carbon atoms connected to the rest of the molecule through one oxygen atom. The above C 1-6 Alkoxy is C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 Includes C6, C5, C4, and C3 alkoxy, etc. C 1-6 Examples of alkoxy include methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and butoxy ( n - Butoxy, isobutoxy, s - Butoxy and t -including butoxy), pentyloxy( n - Includes pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, etc., but is not limited thereto.

[0069] Unless otherwise specified, the term “C 1-3“Alkoxy” represents an alkyl group comprising 1 to 3 carbon atoms connected to the rest of the molecule through one oxygen atom. The above C 1-3 Alkoxy is C 1-3 , C 1-2 , C 2-3 Includes C1, C2, and C3 alkoxy, etc. C 1-3 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy).

[0070] Unless otherwise specified, the term “C 1-6 “Alkylamino” represents an alkyl group comprising 1 to 6 carbon atoms connected to the rest of the molecule through an amino group. The above C 1-6 Alkylamino is C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 Includes C6, C5, C4, C3, and C2 alkylaminos, etc. C 1-6 Examples of alkylaminos include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, etc.

[0071] Unless otherwise specified, the term “C 1-3 “Alkylamino” represents an alkyl group comprising 1 to 3 carbon atoms connected to the rest of the molecule through an amino group. The above C 1-3 Alkylamino is C 1-3 , C 1-2 , C 2-3 Includes C1, C2, and C3 alkylaminos, etc. C 1-3 Examples of alkylaminos include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2.

[0072] Unless otherwise specified, the term “C 1-6 “Alkylthio” refers to an alkyl group comprising 1 to 6 carbon atoms connected to the rest of the molecule through a sulfur atom. The above C 1-6 Alkylthios are C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 Includes C6, C5, C4, C3, and C2 alkylthio, etc. C 1-6 Examples of alkylthios include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0073] Unless otherwise specified, the term “C 1-3 “Alkylthio” refers to an alkyl group comprising 1 to 3 carbon atoms connected to the rest of the molecule through a sulfur atom. The above C 1-3 Alkylthios are C 1-3 , C 1-2 , C 2-3 Includes C1, C2, and C3 alkylthio, etc. C 1-3 Examples of alkylthios include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, etc.

[0074] Unless otherwise specified, the term “cycloalkyl” refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent, and the cycloalkyl comprises 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (which may be specific points or a range consisting of any two points, e.g., 3, 4, 5, 6 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms, etc.), more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 carbon atoms (e.g., 3, 4, 5, or 6). Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cycloalkyls, and polycyclic cycloalkyls include cycloalkyls of spiro rings, fused rings, and cross-linked rings.

[0075] Unless otherwise specified, the term “C 3-6 “Cycloalkyl” represents a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a single-ring and double-ring system, and the above C 3-6 Cycloalkyl is C 3-5 , C 4-5 and C 5-6 It includes cycloalkyls, etc., which can be monovalent, divalent, or polyvalent. C 3-6 Examples of cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0076] The term “heterocyclile” refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon substituent comprising 3 to 20 ring atoms, wherein one or more ring atoms are nitrogen, oxygen, or S(O) mA heteroatom selected from (where m is an integer from 0 to 2), but not including a ring portion of -OO-, -OS-, or -SS-, and the remaining ring atoms are carbon. Preferably, it comprises 3 to 12 ring atoms (which may be specific points or a range consisting of any two points, e.g., 3, 4, 5, 6 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms, etc.), wherein 1 to 4 are heteroatoms, preferably 3 to 8 ring atoms, wherein 1 to 3 are heteroatoms, and more preferably 3 to 6 ring atoms, wherein 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclils include azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuryl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, and pyrrolidinyl. Polycyclic heterocyclils include heterocyclils of a spiro ring, a fused ring, and a cross-linked ring.

[0077] Unless otherwise specified, the term “ternary to hexacyclic” refers to a saturated cyclic group, either by itself or in combination with other terms, each comprising 3 to 6 ring atoms, wherein 1, 2, 3, or 4 ring atoms are independently heteroatoms selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternarily ammonized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p, p can be 1 or 2). This includes single ring and double ring systems, where the double ring system includes spiro rings, fused rings, and cross-linked rings. Additionally, in the case of the “ternary to 6-membered heterocyclile,” the heteroatoms may occupy connection positions between the heterocyclile and the rest of the molecule. The ternary to 6-membered heterocyclile includes quaternary to 6-membered, 5-memberary to 6-membered, quaternary, 5-membered, and 6-membered heterocycliles, etc. Examples of 3 to 6-membered heterocyclils include azetidinyl, oxetanil, tietanil, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl, etc.), tetrahydrofuranil (including tetrahydrofuran-2-yl, etc.), tetrahydropyranil, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperidinyl and 2-piperidinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanil, dithianil, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, Includes, but is not limited to, hexahydropyridazinil, homopiperazinil or homopiperidinil.

[0078] The term “aryl” refers to a 6 to 20-membered carbon single ring or fused multi-ring (i.e., a ring sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably 6 to 10 members, more preferably 6 members, and examples are phenyl and naphthyl. The aryl comprises said aryl fused to a ring of a heteroaryl, heterocyclyl, or cycloalkyl, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples thereof include , , , , , and Includes

[0079] The aryl may be substituted or unsubstituted, and if substituted, the substituent is preferably one or more groups independently substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclil, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0080] The term “heteroaryl” refers to a heteroaromatic group comprising 1 to 4 heteroatoms and 5 to 20 ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. The heteroaryl is preferably a 5 to 10-membered group comprising 1 to 3 heteroatoms, and more preferably a 5 or 6-membered group comprising 1 to 3 heteroatoms; non-limiting examples include pyrazolyl, imidazolyl, furyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, etc. The heteroaryl ring may be fused to an aryl, heterocyclyl, or cycloalkyl ring, wherein the ring connected to the matrix structure is a heteroaryl ring; non-limiting examples include , , , , , and Includes

[0081] The heteroaryl may be optionally substituted or unsubstituted, and if substituted, the substituent is preferably one or more groups independently substituted by one or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclil, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0082] Unless otherwise specified, the terms “five-to-six-membered heteroaryl ring” and “five-to-six-membered heteroaryl” may be used interchangeably in the present invention, and the term “five-to-six-membered heteroaryl” refers to a single ring group having a conjugated π-electron system composed of five to six ring atoms, wherein one, two, three, or four ring atoms are independently heteroatoms selected from O, S, and N, and the remainder are carbon atoms. Herein, where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2) can be. The pentagonal to hexavalent heteroaryl may be connected to the rest of the molecule through heteroatoms or carbon atoms. The pentagonal to hexavalent heteroaryl includes pentagonal and hexavalent heteroaryls. Examples of the pentagonal to hexavalent heteroaryl include pyrrolyl ( N - including pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl ( N -including imidazolyl, 2-imidazolil, 4-imidazolil and 5-imidazolil, etc.), oxazolil (including 2-oxazolil, 4-oxazolil and 5-oxazolil, etc.), triazolil (1 H -1,2,3-triazolyl, 2 H -1,2,3-triazolyl, 1 H -1,2,4-triazolyl and 4 H -1,2,4-triazolil, etc.), tetrazollil, isoxazolil (including 3-isoxazolil, 4-isoxazolil and 5-isoxazolil, etc.), thiazolil (including 2-thiazolil, 4-thiazolil and 5-thiazolil, etc.), furil (including 2-furil and 3-furil, etc.), tienil (including 2-tienil and 3-tienil, etc.), pyridil (including 2-pyridil, 3-pyridil and 4-pyridil, etc.), pyrazinil or pyrimidil (including 2-pyrimidil and 4-pyrimidil, etc.), but not limited thereto.

[0083] Unless otherwise specified, C n-n+m or C n -C n+m It includes any one specific case of n to n+m carbons, for example, C 1-12 C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C 12 It includes, and also includes any one range from n to n+m, for example, C 1-12 is C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 and C 9-12 Includes the like; likewise, n to n+m means that the number of atoms in the ring is n to n+m, for example, 3 to 12 rings include 3 rings, 4 rings, 5 rings, 6 rings, 7 rings, 8 rings, 9 rings, 10 rings, 11 rings and 12 rings, and also include any one of the ranges from n to n+m, for example, 3 to 12 rings include 3 to 6 rings, 3 to 9 rings, 5 to 6 rings, 5 to 7 rings, 5 to 10 rings, 6 to 7 rings, 6 to 8 rings, 6 to 9 rings and 6 to 10 rings, etc.

[0084] The term “leaving group” refers to a functional group or atom substituted by another functional group or atom through a substitution reaction (e.g., an affinity substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, and iodine; sulfonates such as methanesulfonate, tosylate, p-bromobenzenesulfonate, and p-toluenesulfonate; and acyloxy, such as acetoxy and trifluoroacetoxy.

[0085] The term “protecting group” includes, but is not limited to, “amino protecting group,” “hydroxyl protecting group,” or “mercapto protecting group.” The term “amino protecting group” refers to a protecting group suitable for preventing side reactions at the nitrogen position of the amino group. Representative amino protecting groups include, but are not limited to, formyl; acyls such as alkanoyls (e.g., acetyl, trichloroacetyl, or triplefluoroacetyl); alkoxycarbonyls such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyls such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyls such as benzyl (Bn), triphenylmethyl (Tr), and 1,1-bis-(4'-methoxyphenyl)methyl; and silyls such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS). The term “hydroxyl protecting group” refers to a protecting group suitable for preventing side reactions of hydroxyl. Representative hydroxyl protecting groups include, but are not limited to, alkyls such as methyl, ethyl, and tert-butyl; acyls such as alkanoyls (e.g., acetyl); arylmethyls such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (diphenylmethyl, DPM); and silyls such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS).

[0086] The compounds of the present invention may be prepared by various synthesis methods known to those skilled in the art, and include specific embodiments exemplified below, embodiments formed by combining the same with other chemical synthesis methods, and equivalent substitution methods known to those skilled in the art, and include but are not limited to embodiments of the present invention as preferred embodiments.

[0087] Compounds are named using industry-standard naming conventions or ChemDraw® software, and commercially available compounds use the supplier's listing names. Specific details for implementing the invention

[0088] The present application is described in detail through the following examples, but this does not imply any adverse limitations thereof. Although the present application has been described in detail and specific embodiments disclosed herein, it is obvious to those skilled in the art that various modifications and improvements can be made to the specific embodiments of the present application without departing from the gist and scope of the application.

[0089] The raw materials used in this invention are all commercially available unless otherwise specified.

[0090] The experimental materials and reagents used in the following examples are all available commercially unless otherwise specified.

[0091] The present invention uses the following abbreviations. 9-BBN represents 9-borabicyclo(3,3,1)-nonane, Boc2O represents di-tert-butyl dicarbonate, B2Pin2 represents bis(pinacollato)diborone, DCM represents dichloromethane, DMAP represents 4-dimethylaminopyridine, DMF represents N,N-dimethylformamide, DIEA represents N,N-diisopropylethylamine, DMP represents Dess-Martin reagent, and HATU represents 2-(7-aza benzotriazole )-N,N,N',N'- Tetramethyluronium Hexafluorophosphate HBF4PCy3 represents tricyclohexyltetrafluoroborate, LDA represents lithium diisopropylamide, NaClO2 represents sodium hypochlorite, NFSI represents N-fluorobenzenesulfonimide, NMM represents N-methylmorpholine, PhI(OAc)2 represents (diacetoxyiodo)benzene, Pd(OAc)2 represents palladium acetate, Pd(dppf)Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II), THF represents tetrahydrofuran, and Ti(OEt)4 represents titanium ethoxide.

[0092] Example 1: Synthesis of Compound 1

[0093]

[0094]

[0095] Step 1: Preparation of Compound 1B

[0096] compound 1A (20 g, 86.96 mmol) was dissolved in DMF (200 mL), (diacetoxyiodo)benzene (28 g, 86.96 mmol), I2 (22 g, 86.96 mmol), and Pd(OAc)2 (970 mg, 4.35 mmol) were added, and the mixture was reacted at 100°C for 16 hours. The solvent was rotary dried, ethyl acetate was added, followed by the addition of NaHSO3 solution and stirring; the color changed from black to yellow. The mixture was extracted twice with ethyl acetate, dried, filtered, vacuum-and-rotary dried, and separated by column chromatography (9 / 1 pentane / ethyl acetate) to obtain the compound. 1B (22.4g, 72%) was obtained. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 13.79 (s, 1H), 7.56 (d, J = 8.4 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H), 3.80 (s, 3H).

[0097] Step 2: Preparation of Compound 1C

[0098] Under the protection of argon gas, compounds 1B (13.8 g, 38.76 mmol) was dissolved in tert-butanol (20 mL), DMAP (470 mg, 3.87 mmol) and BOC2O (50 mL, 193.8 mmol) were added, and the mixture was stirred at 80°C for 2 hours. The mixture was dried under reduced pressure and rotary-dried, and the compound was separated by column chromatography (9 / 1 pentane / ethyl acetate). 1C (31.4g, 87%) was obtained. 1 ¹H NMR (400 MHz, DMSO- d6) δ 7.56 (d, J = 8.4 Hz, 1H), 7.47 (d, J = 8.4 Hz, 1H), 3.81 (s, 3H), 1.57 (s, 9H).

[0099] Step 3: Preparation of Compound 1D

[0100] compound 1C (6g, 14.5mmol, 1eq) was dissolved in toluene (50mL), KSAc (6g, 52mmol, 3eq), 1-10 phenanthroline (0.3eq), and CuI (0.3eq) were added, and the mixture was reacted at 100°C for 2 days under N2 protection. The mixture was dried under reduced pressure and rotary-dried, and the compound was separated by column chromatography (9 / 1 pentane / ethyl acetate). 1D (3.7g, 54%) was obtained. 1 ¹H NMR (400 MHz, DMSO- d 6) δ 7.82 (d, J = 8.4 Hz, 1H), 7.23 (d, J = 8.4 Hz, 1H), 3.83 (s, 3H), 2.51 (q, J = 1.9 Hz, 3H), 1.52 (s, 9H).

[0101] Step 4: Preparation of Compound 1E

[0102] compound 1D (2.2g, 6.11mmol) was dissolved in methanol (30mL), cesium carbonate (3.0g, 9.17mmol) was added, and the reaction was carried out at room temperature for 10 minutes under the protection of argon gas. Then, the substrate methyl iodide (4.3g, 30.56mmol) was added, and the mixture was stirred at 40°C for 2 hours. The inorganic salt was filtered through diatomite, vacuum and rotary dried, and separated by column chromatography (9 / 1 pentane / ethyl acetate) to obtain the compound. 1E (5.5g, 85%) was obtained. MS (ESI) m / z = 333.1 [M+H] + .

[0103] Step 5: Preparation of Compound 1F

[0104] compound 1E 5.5 g (16.5 mmol) was dissolved in 30 mL of DCM, and under the protection of nitrogen gas, boron tribromide (50 mL, 50 mmol, 1 M dichloromethane solution) was added dropwise at -78 °C and stirred at room temperature for 60 minutes. The mixture was quenched with 50 mL of deionized water, the DCM was vacuum and rotary dried, and the aqueous phase was extracted three times with ethyl acetate. The compound was dried, filtered, and vacuum and rotary dried. 1F (2.6g, 60%) was obtained. MS (ESI) m / z = 263.0 [M+H] + .

[0105] Step 6: Preparation of Compound 1G

[0106] At room temperature, compounds 1F (2.6g, 10.0mmol) was added to trifluoroacetic acid (150mL), and at 80°C, acetone (3.5g, 60mmol, 44.1mL) and trifluoroacetic anhydride (6.5g, 31.2mmol, 44.1mL) were simultaneously injected using a syringe pump, with a flow rate of 0.0306mL / min for both; after injection was completed, the reaction solution was concentrated, diluted with ethyl acetate, washed with a saturated sodium bicarbonate aqueous solution and water, the organic phase was dried and concentrated, loaded by a dry method, and the compound was analyzed by silica gel column chromatography (9 / 1 petroleum ether / ethyl acetate). 1G (1.3g, 43%) was obtained. MS (ESI) m / z = 305.1 [M+H] + .

[0107] Step 7: Preparation of Compound 1H

[0108] At room temperature, compounds 1G(1.0 g, 3.30 mmol), acrylic acid (713 mg, 9.90 mmol), tetrakis(triphenylphosphine)palladium (381 mg, 0.33 mmol), and triethylamine (1.66 g, 16.5 mmol) were added to dry DMF (30 mL), stirred at 120 °C for about 6 hours under argon gas protection, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, loaded by a dry method, and the compound was analyzed by silica gel column chromatography (9 / 1 petroleum ether / ethyl acetate). 1H (0.5g, 52%) was obtained. MS (ESI) m / z = 295.2 [M+H] + .

[0109] Step 8: Preparation of Compound 1I

[0110] At 0℃, Br2 (0.92g, 5.75mmol) compound 1H It was added dropwise to a 40 mL solution of chloroform (1.7 g, 5.25 mmol) and reacted for 0.5 hours. LCMS indicated that the raw material disappeared. The reaction solution was concentrated to obtain the compound 1I (2.6g, 100%) was obtained and used directly in the next step.

[0111] Step 9: Preparation of Compound 1J

[0112] At 0℃, Et3N (0.64g, 6.3mmol) compound 1I It was added dropwise to a 30 mL DMF solution (2.6 g, 5.25 mmol), heated to room temperature, and reacted for 2 hours. Ethyl acetate was added, rinsed three times with 1 M HCl, the organic phase was concentrated and purified, and the compound was separated by column chromatography (0 to 5% ethyl acetate / pentane). 1J (580mg, 31%) was obtained. 1 H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 8.6 Hz, 1H), 7.13 (d, J = 8.1 Hz, 1H), 6.95 (d, J= 8.6 Hz, 1H), 6.50 (d, J = 8.1 Hz, 1H), 2.49 (s, 3H), 1.73 (s, 6H). MS (ESI) m / z = 329.0 [M+H] + .

[0113] Step 10: Preparation of Compound 1K

[0114] At room temperature, compounds 1J B2pin2 (637 mg, 2.5 mmol), KOAc (491 mg, 5.0 mmol), and Pd(PPh3)4 (193 mg, 0.17 mmol) were sequentially added to an 8 mL solution of dioxane (550 mg, 1.7 mmol), the mixture was purified with argon gas three times, placed in an oil bath at 70°C, and reacted for 2 hours. The reaction solution was filtered, concentrated, and purified, and the compounds were separated by column chromatography (0 to 10% ethyl acetate / pentane). 1K (510 mg, 81%) was obtained. 1 H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.5 Hz, 1H), 7.29 (d, J = 14.8 Hz, 1H), 6.84 (d, J = 8.6 Hz, 1H), 5.65 (d, J = 14.9 Hz, 1H), 2.48 (s, 3H), 1.72 (s, 6H), 1.28 (s, 12H). MS (ESI) m / z = 377.2 [M+H] + .

[0115] Step 11: Preparation of 1L of Compound

[0116] compound 1K (1S,2S,3R,5S)-(+)-2,3-pinandiol (461 mg, 2.7 mmol) was added to an 8 mL THF solution (510 mg, 1.4 mmol), placed in an oil bath at 60 °C, and reacted for 2 hours. The reaction solution was concentrated and purified, and the compound was separated by column chromatography (0 to 10% ethyl acetate / pentane). 1L(320mg, 55%) was obtained. 1 H NMR (400 MHz, CDCl3) δ 7.92 (dd, J = 8.5 Hz, 1H), 7.31 (d, J = 14.9 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 5.69 (d, J = 14.9 Hz, 1H), 4.33 (dd, J = 8.8, 2.0 Hz, 1H), 2.48 (s, 3H), 2.39 - 2.31 (m, 1H), 2.27 - 2.20 (m, 1H), 2.07 (t, J = 5.5 Hz, 1H), 1.95 - 1.92 (m, 1H), 1.88 - 1.83 (m, 1H), 1.73 - 1.71 (m, 6H), 1.41 (s, 3H), 1.30 (s, 3H), 1.17 (d, J = 10.9 Hz, 1H), 0.85 (s, 3H).MS (ESI) m / z = 429.2 [M+H] + .

[0117] Step 12: Preparation of Compound 1M

[0118] A diazomethane ether solution (50 mL, ~0.8 M) compound 1L (320 mg, 0.75 mmol) and Pd(OAc)2 were added to THF (4 mL) and reacted at room temperature for 4 hours. The reaction solution was filtered, concentrated, and purified, and separated by column chromatography (0 to 10% ethyl acetate / pentane) to obtain a crude product (250 mg), and the compound was prepared by HPLC. 1M (130 mg, 39%) was obtained. MS (ESI) m / z = 443.2 [M+H] + .

[0119] Step 13: Preparation of Compound 1

[0120] NaOH (1 mL, 3N aqueous solution) compound 1MIt was added to 2 mL of dioxane (110 mg, 0.25 mmol), the reaction solution was placed in an oil bath at 40°C, and reacted for 2 hours. LCMS indicated that the raw material had disappeared. The reaction solution was cooled to 0°C, TES (1 mL), TFA (5 mL), and isobutylboronic acid (200 mg) were added sequentially, the temperature was slowly raised to room temperature, and the reaction was carried out for 1 hour. The reaction solution was concentrated, alkalized to pH=10 with a 3N aqueous NaOH solution, and after concentration, the compound was prepared by alkaline HPLC. 1 (32mg, 52%) was obtained. 1 H NMR (400 MHz, DO) δ 7.07 (d, J = 7.8 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 2.33 (s, 3H), 1.77 - 1.72 (m, 1H), 0.80 - 0.75 (m, 1H), 0.28 - 0.25 (m, 1H), 0.22 - 0.16 (m, 1H).MS (ESI) m / z = 232.8 [M+H-18] + .

[0121] Example 2: Synthesis of Compound 2

[0122]

[0123] Step 1: Preparation of Compound 2B

[0124] At room temperature, compounds 2A (50.0 g, 262 mmol) was dissolved in dichloromethane (300 mL), followed by the addition of DMAP (3.20 g, 26.2 mmol), and then Boc2O (66.2 mL, 288 mmol) was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature for 2 hours. Saturated NaHCO3 solution and dichloromethane were added to the reaction solution to separate the liquids. The organic phase was washed twice with saturated NaHCO3 solution, followed by one wash with water, two washes with 2 M citric acid, and two washes with saturated saline solution. The organic phase was dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the compound.2B (73.5g, 97%) was obtained, and the next step of the reaction was carried out directly. 1 H NMR (400 MHz, CDCl3) δ 7.55 (dt, J = 12.1, 6.1 Hz, 1H), 7.00 (dd, J = 8.7, 2.9 Hz, 1H), 6.89 (ddd, J = 8.8, 7.8, 2.9 Hz, 1H), 1.57 (s, 9H).

[0125] Step 2: Preparation of Compound 2C

[0126] At room temperature, compounds 2B (73.5g, 252mmol) was dissolved in ultra-dry tetrahydrofuran (400mL), and after purging with nitrogen gas three times, the mixture was cooled to -65℃ using dry ice and acetone. LDA solution (132mL, 264mmol, 2M tetrahydrofuran solution) was slowly added dropwise, ensuring that the temperature did not exceed -60℃ during the addition process. After the addition was complete, the mixture was stirred at the above temperature for 4 hours, slowly raised to 0℃, and saturated ammonium chloride solution (200mL) was added. The aqueous phase was extracted three times with ethyl acetate, the combined organic phase was washed twice with saturated saline solution, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the compound. 2C (65.0g, 88%) was obtained, and the next step of the reaction was carried out directly. 1 H NMR (400 MHz, DMSO-d6) δ 7.56 (dd, J = 8.8, 6.4 Hz, 1H), 6.45 (t, J = 9.2 Hz, 1H), 1.51 (d, J = 6.2 Hz, 9H).

[0127] Step 3: Preparation of Compound 2D

[0128] At room temperature, compounds 2C(65.0 g, 223 mmol) was dissolved in dichloromethane (200 mL), trifluoroacetic acid (100 mL) was added, stirred at room temperature for 2 hours, concentrated to remove the solvent, then dichloromethane (50 mL) was added to form a slurry and filtered, and the filtered residue was washed twice with a small amount of dichloromethane to obtain a compound 2D (40.0g, 76%) was obtained. 1 H NMR (400 MHz, DMSO-d6) δ 7.79 (dd, J = 8.9, 5.7 Hz, 1H), 6.77 (dd, J = 10.4, 8.9 Hz, 1H).

[0129] Step 4: Preparation of Compound 2E

[0130] At room temperature, compounds 2D Trifluoroacetic acid (200 mL) was added to (40.0 g, 170 mmol), the raw material was insoluble, and after purging with nitrogen gas three times, trifluoroacetic anhydride (71.0 mL, 511 mmol) was added using a syringe and stirred at room temperature for 10 minutes, then acetone (62.6 mL, 851 mmol) was slowly added using a syringe, and the temperature was slowly raised to 100°C (external temperature, internal temperature to 85°C), the raw material gradually dissolved, and the solution turned yellow. The mixture was stirred at the above temperature for 48 hours. Cool to room temperature, concentrate to remove solvent, then add ethyl acetate (300 mL) and saturated NaHCO3 solution (100 mL), separate, extract the aqueous phase three times with ethyl acetate, sequentially wash the combined organic phase with saturated NaHCO3 solution and saturated saline, dry with anhydrous sodium sulfate, filter, and concentrate to obtain the product 2E (37.5g, 80%) was obtained. 1 H NMR (400 MHz, CDCl3) δ 7.74 (dd, J = 9.0, 5.3 Hz, 1H), 6.80 (t, J = 9.2 Hz, 1H), 1.79 (s, 6H). MS (ESI) m / z = 275.0 [M+H] +.

[0131] Step 5: Preparation of Compound 2F

[0132] compound 2E Pinacol vinylboronate (500 mg, 1.818 mmol), pinacol vinylboronate (560 mg, 3.636 mmol), palladium acetate (40.8 mg, 0.182 mmol), SPhos (149 mg, 0.364 mmol), and triethylamine (550.8 mg, 5.45 mmol) were added to dioxane (6.0 mL), reacted at 80°C under argon gas protection for 16 hours, and completed (LC-MS detection). The reaction solution was directly concentrated, loaded by a dry method, and the compounds were analyzed by silica gel column chromatography. 2F (400 mg, 63%) was obtained. MS (ESI) m / z = 349.2 [M+H] + .

[0133] Step 6: Preparation of Compound 2G

[0134] compound 2F (400 mg, 1.149 mmol) and pinol (782 mg, 4.60 mmol) were added to tetrahydrofuran (20.0 mL), reacted at 65°C for 4 hours, and completed (LC-MS detection). The reaction solution was directly concentrated, and the compounds were analyzed by silica gel column chromatography. 2G (400mg, 88%) was obtained. 1H NMR (400 MHz, CDCl3) δ 7.77 (dd, J = 8.8, 5.8 Hz, 1H), 7.47 (d, J = 18.6 Hz, 1H), 6.85 (t, J = 9.2 Hz, 1H), 6.19 (d, J = 18.6 Hz, 1H), 4.39 (dd, J = 8.7, 1.7 Hz, 1H), 2.46 - 2.35 (m, 1H), 2.31 - 2.21 (m, 1H), 2.16 - 2.08 (m, 1H), 2.00 - 1.91 (m, 2H), 1.78 (d, J = 2.9 Hz, 6H), 1.59 (d, J = 8.0 Hz, 1H), 1.45 (d, J = 6.5 Hz, 3H), 1.32 (s, 3H), 0.88 (s, 3H).MS (ESI) m / z = 401.2 [M+H] + .

[0135] Step 7: Preparation of Compound 2H

[0136] At room temperature, compounds 2G After dissolving (200 mg, 0.500 mmol) in dichloromethane (5.00 mL), IrPPy3 (33 mg, 0.050 mmol) was added, the mixture was purged with nitrogen gas three times, irradiated with blue light (460 to 465 nm, 10 W) at room temperature for 4 hours, the reaction solution was directly mixed, and the compound was analyzed by column chromatography (0% to 10% EA / PE). 2H (120mg, 60%) was obtained. 1H NMR (400 MHz, DMSO-d6) δ 7.92-7.83 (m, 1H), 7.23 (d, J = 12.0 Hz, 1H), 7.11-7.01 (m, 1H), 5.73 (d, J = 12.0 Hz, 1H), 4.39-4.33 (m, 1H), 2.35-2.25 (m, 1H), 2.23-2.15 (m, 1H), 1.98-1.92 (m, 1H), 1.90-1.84 (m, 1H), 1.78-1.66 (m, 8H), 1.32 (s, 3H), 1.26 (s, 3H), 0.81 (s, 3H). MS (ESI) m / z = 401.2 [M+H] + .

[0137] Step 8: Preparation of Compound 2I

[0138] At room temperature, compounds 2H After dissolving (13.1 g, 32.8 mmol) in ultra-dry THF (79 mL), Pd(OAc)2 (368 mg, 1.64 mmol) was added, the mixture was purged with argon gas three times, cooled to approximately 0°C, and diazomethane ether solution (200 mL, ~0.6 M) was slowly added using a syringe. When the reaction solution changed from yellow to black and foam was generated, the temperature was slowly raised to room temperature and stirred for 2 hours. The reaction solution was concentrated at room temperature and purified by column chromatography (0 to 10% EA / PE) to obtain a crude product compound (10.9 g), and the compound was prepared by acidic HPLC. 2I (4.3g, 31%) was obtained. MS (ESI) m / z = 415.0 [M+H] + .

[0139] Step 11: Preparation of Compound 2J

[0140] At room temperature, compounds 2I(150 mg, 0.377 mmol) was dissolved in dimethyl sulfoxide (2 mL), cesium carbonate (246 mg, 0.754 mmol) was added, and the mixture was purged with argon gas three times. Then, 2-propanethiol (86.1 mg, 1.13 mmol) was added to the reaction system and stirred overnight at 60°C. After cooling to room temperature, ethyl acetate (10 mL) was added to dilute the mixture, and it was extracted three times with water (3 mL). The combined organic phase was then washed with saline solution (3 mL) and concentrated to obtain a crude product, which was purified by column chromatography (0 to 8% EA / PE) to obtain a compound 2J (64 mg, 36%) was obtained. MS (ESI) m / z = 471 .1 [M+H] + .

[0141] Step 12: Preparation of Compound 2

[0142] At room temperature, compounds 2J (150 mg, 0.377 mmol) was dissolved in 1,4-dioxane (1 mL), 3 M aqueous sodium hydroxide solution (1 mL, 0.816 mmol) was added, and the mixture was stirred at room temperature for 3 hours; the TLC plate indicated that the raw materials were completely reacted. Next, triethoxysilane (0.126 mL, 112 mg, 0.681 mmol), trifluoroacetic acid (0.628 mL), and isobutylboric acid (27.7 mg, 0.272 mmol) were sequentially added to the reaction system, stirred at room temperature for 0.5 hours, filtered, and concentrated. The pH of the reaction system was adjusted to 5 with an aqueous sodium bicarbonate solution, and the crude product was concentrated to obtain the compound, which was prepared by HPLC and purified. 2 (12.8 mg, 34%) was obtained. 1 H NMR (400 MHz, DO) δ 6.83 (d, J = 7.7 Hz, 1H), 6.54 (d, J = 7.7 Hz, 1H), 3.05 (dt, J = 13.3, 6.5 Hz, 1H), 1.54 (t,J = 6.7 Hz, 1H), 0.92 (d, J = 6.7 Hz, 6H), 0.58 (t, J = 7.3 Hz, 1H), 0.06 (s, 1H), -0.01 (dd, J = 15.9, 9.0 Hz, 1H). MS (ESI) m / z = 279.1 [M+H] + .

[0143] Example 3: Synthesis of Compound 3

[0144]

[0145] Step 1: Preparation of Compound 3A

[0146] At room temperature, compounds 2J (95.0 mg, 0.229 mmol) was dissolved in dichloromethane (2.00 mL), then metachloroperoxybenzoic acid (119 mg, 0.688 mmol) was added and stirred overnight at room temperature. After diluting with ethyl acetate (10.0 mL), an appropriate amount of saturated aqueous sodium thiosulfate solution was added and quenched, washed three times with saturated sodium bicarbonate solution (3.0 mL) and once with water (3.0 mL), then washed the combined organic phase with saline solution (3.0 mL) and concentrated to obtain a crude product, which was purified by column chromatography (8 to 10% EA / PE) to obtain a compound 3A (35 mg, 30%) was obtained. MS (ESI) m / z = 503.1 [M+H] + .

[0147] Step 2: Preparation of Compound 3

[0148] Compound of Example 2 2 It was prepared according to the synthesis method of the compound. 3A The product by (30 mg, 0.0597 mmol) 3 (6.8 mg, 37%) was obtained. 1 H NMR (400 MHz, DO) δ 7.37 (dd, J = 8.1, 3.1 Hz, 1H), 7.21 (dd,J = 8.1, 3.5 Hz, 1H), 3.79 - 3.58 (m, 1H), 2.26 - 2.02 (m, 1H), 1.18 (dd, J = 6.6, 3.0 Hz, 6H), 1.17 - 1.08 (m, 1H), 0.50 (d, J = 8.4 Hz, 1H), 0.44 (dd, J = 10.5, 7.3 Hz, 1H).MS (ESI) m / z = 311.1 [M+H] + .

[0149] Example 4: Synthesis of Compound 4

[0150]

[0151] Step 1: Preparation of Compound 4B

[0152] Compound of Example 2 2J It was prepared according to the synthesis method of the compound. 2I (100 mg, 0.241 mmol) and compound 4A The product by (236 mg, 1.61 mmol) 4B (120 mg, 99%) was obtained. MS (ESI) m / z = 499.1 [M+H] + .

[0153] Step 2: Preparation of Compound 4

[0154] Compound of Example 2 2 It was prepared according to the synthesis method of the compound. 4B The product by (150 mg, 0.301 mmol) 4 (36.8 mg, 40%) was obtained. 1H NMR (400 MHz, DO+NaOH) δ 6.84 (d, J = 7.8 Hz, 1H), 6.55 (d, J = 7.8 Hz, 1H), 3.71 - 3.64 (m, 2H), 3.56 (ddd, J = 16.4, 9.3, 4.8 Hz, 2H), 3.44 (dd, J = 9.3, 3.8 Hz, 1H), 1.98 (dd, J = 13.2, 7.6 Hz, 1H), 1.69 - 1.49 (m, 2H), 0.58 (t, J = 7.3 Hz, 1H), 0.12 - 0.04 (m, 2H).MS (ESI) m / z = 307.1 [M+H] + .

[0155] Example 5: Synthesis of Compound 5

[0156]

[0157] Step 1: Preparation of Compound 5B

[0158] Compound of Example 2 2J It was prepared according to the synthesis method of the compound. 2I (200 mg, 0.483 mmol) and compound 5A The product by (212 mg, 1.45 mmol) 5B (210 mg, 87%) was obtained. MS (ESI) m / z = 499.1 [M+H] + .

[0159] Step 2: Preparation of Compound 5

[0160] Compound of Example 2 2 It was prepared according to the synthesis method of the compound. 5B The product by (190 mg, 0.381 mmol) 5 (91.5 mg, 78%) was obtained. 1H NMR (400 MHz, DO+NaOH) δ 7.08 (d, J = 7.8 Hz, 1H), 6.79 (d, J = 7.8 Hz, 1H), 3.97 - 3.86 (m, 2H), 3.80 (qd, J = 8.3, 4.9 Hz, 2H), 3.69 (dd, J = 9.3, 3.7 Hz, 1H), 2.22 (dd, J = 13.4, 7.4 Hz, 1H), 1.82 (dd, J = 26.8, 4.3 Hz, 2H), 0.82 (dd, J = 12.1, 4.8 Hz, 1H), 0.37 - 0.28 (m, 1H), 0.28 - 0.18 (m, 1H).MS (ESI) m / z = 307.1 [M+H] + .

[0161] Example 6: Synthesis of Compound 6

[0162]

[0163] Step 1: Preparation of Compound 6B

[0164] Compound of Example 2 2J It was prepared according to the synthesis method of the compound. 2I (150 mg, 0.36 mmol) and compound 6A The product by (288 mg, 1.81 mmol) 6B (144 mg, 78%) was obtained. MS (ESI) m / z = 512.1 [M+H] + .

[0165] Step 2: Preparation of Compound 6

[0166] Compound of Example 2 2 It was prepared according to the synthesis method of the compound. 6B The product by (144 mg, 0.282 mmol) 6 (8.4 mg, 9%) was obtained. 1H NMR (400 MHz, DO) δ 7.15 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 7.7 Hz, 1H), 4.01 (s, 1H), 3.77 (s, 1H), 3.44 (s, 1H), 3.21 (s, 2H), 2.87 (d, J = 14.4 Hz, 3H), 2.48 (s, 1H), 1.95 (s, 2H), 1.01 (s, 1H), 0.41 - 0.27 (m, 2H).MS (ESI) m / z = 320.1 [M+H] + .

[0167] Example 7: Synthesis of Compound 7

[0168]

[0169] Step 1: Preparation of Compound 7B

[0170] Compound of Example 2 2J It was prepared according to the synthesis method of the compound. 2I (200 mg, 0.483 mmol) and compound 7 A The product by (514 mg, 2.90 mmol) 7B (180 mg, 65%) was obtained. MS (ESI) m / z = 471 .1 [M+H] + .

[0171] Step 2: Preparation of Compound 7

[0172] Compound of Example 2 2 It was prepared according to the synthesis method of the compound. 7B The product by (180 mg, 0.315 mmol) 7 (40mg, 46%) was obtained. 1 H NMR (400 MHz, DO) δ 6.84 (d, J = 7.8 Hz, 1H), 6.55 (d, J = 7.8 Hz, 1H), 2.64 (t, J = 5.9 Hz, 2H), 2.53 (t, J= 6.3 Hz, 2H), 2.44 - 2.41 (m, 2H), 1.54 (td, J = 8.5, 3.5 Hz, 1H), 0.58 (t, J = 7.2 Hz, 1H).MS (ESI) m / z = 280.1 [M+H] + .

[0173] Example 8: Synthesis of Compound 8

[0174]

[0175] Step 1: Preparation of Compound 8

[0176] At room temperature, compounds 7 (40.0 mg, 0.143 mmol) was dissolved in dimethyl sulfoxide (4.0 mL), N,N-diisopropylethylamine (27.8 mg, 0.215 mmol) was added, and after purging with argon gas three times, a compound was added to the reaction system 8A (48.8 mg, 1.57 mmol) was added and stirred overnight at 60°C. After cooling to room temperature, diluted with ethyl acetate (10.0 mL) and extracted three times with water (3.0 mL), the combined organic phase was washed with saline solution (3.0 mL) and concentrated to obtain a crude product, and a methanol hydrochloride solution (4 M, 4 mL) was added and stirred overnight at room temperature. The compound was prepared by alkaline HPLC (0.1% NH4OH) and purified. 8 (4.2 mg, 9%) was obtained. 1 H NMR (400 MHz, CD3OD) δ 7.31 (d, J = 7.9 Hz, 1H), 7.08 (d, J = 7.8 Hz, 1H), 3.47 (dd, J = 14.6, 8.4 Hz, 2H), 3.05 (t, J = 6.1 Hz, 2H), 2.19 (t, J = 7.5 Hz, 1H), 1.33 (s, 1H), 1.28 (s, 1H), 0.59 - 0.50 (m, 1H). MS(ESI) m / z = 322 .0 [M+H] + .

[0177] Example 9: Synthesis of Compound 9

[0178]

[0179] Step 1: Preparation of Compound 9A

[0180] At room temperature, compounds 7B (24.0 mg, 0.051 mmol) was dissolved in ethyl acetate hydrogen chloride solution (4 M, 5.0 mL), stirred at room temperature for 18 hours, and the complete reaction of the raw materials was indicated by a TLC plate. The crude product compound was concentrated 9A (26.0 mg) was obtained and used directly in the next step. MS (ESI) m / z = 472.4 [M+H] + .

[0181] Step 2: Preparation of Compound 9C

[0182] At room temperature, compounds 9A Dissolve (20 mg, 0.042 mmol) in tetrahydrofuran (4.0 mL), add sodium bicarbonate (7.0 mg, 0.085 mmol), replace with argon gas, and then add the compound to the reaction system 9B (21 mg, 0.085 mmol) was added, and the mixture was stirred overnight at 70°C. After cooling to room temperature, ethyl acetate (10.0 mL) was added for dilution, and the mixture was extracted three times with water (3.0 mL). Subsequently, the combined organic phase was washed with saline solution (3.0 mL) and concentrated to obtain the crude product. The compound was separated and purified by column chromatography (MeOH / DCM=1 / 9). 9C (18 mg, 79%) was obtained. MS (ESI) m / z = 540 .0 [M+H] + .

[0183] Step 3: Preparation of Compound 9

[0184] Compound of Example 2 2 It was prepared according to the synthesis method of the compound.7B Compound by (18 mg, 0.033 mmol) 9 (1.8 mg, 15%) was obtained. 1 H NMR (400 MHz, DO) δ 7.18 (d, J = 7.8 Hz, 1H), 6.87 (d, J = 7.8 Hz, 1H), 3.59 (s, 4H), 3.40 (t, J = 5.7 Hz, 2H), 3.05 (t, J = 5.6 Hz, 2H), 1.86 (t, J = 6.6 Hz, 1H), 0.90 (t, J = 7.9 Hz, 1H), 0.47 - 0.25 (m, 2H).MS (ESI) m / z = 348.0 [M+H] + .

[0185] Example 10: Synthesis of Compound 10

[0186]

[0187] Step 1: Preparation of Compound 10B

[0188] At room temperature, 10A Ammonia water (20 mL) was added to a sealed can containing (4.0 g, 46.5 mmol), bubbling and purging with argon gas for 1 minute, rotating and mixing, stirring at 110°C for 14 hours, TLC (PE:EA=5:1) indicating disappearance of the raw material, and the mixture was concentrated to obtain a racemic compound. 10B (4.8g, 100%) was obtained. The crude product was directly carried out in the next step of the reaction without purification.

[0189] Step 2: Preparation of Compound 10C

[0190] At room temperature, racemic 10B4.8g (46.5mmol) was dissolved in tetrahydrofuran (50mL), then Boc2O (12.8mL, 55.8mmol) and NaOH solution (31mL, 93mmol, 3M) were added, and the mixture was stirred at room temperature for 2 hours. TLC (PE / EA=5:1) indicated that the raw material had disappeared. Ethyl acetate and saturated saline were added to the reaction solution, the liquids were separated, and the aqueous phase was extracted twice with ethyl acetate. The combined organic phase was then washed three times with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the racemic compound. 10C (6.0g, 64%) was obtained. The crude product was directly carried out in the next step of the reaction without purification. 1 H NMR (400 MHz, CDCl3) δ 4.76 (s, 1H), 4.29 (s, 1H), 4.15 - 4.01 (m, 2H), 3.96 (s, 1H), 3.70 (d, J = 8.2 Hz, 1H), 3.62 (dd, J = 9.3, 2.4 Hz, 1H), 2.66 (s, 1H), 1.45 (s, 9H).

[0191] Step 3: Preparation of Compound 10D

[0192] At room temperature, compounds 10C After dissolving (1.0 g, 4.92 mmol) in dichloromethane (10 mL), triethylamine (0.89 mL, 6.40 mmol) was added, and the mixture was cooled to 0°C in an ice bath. Then, MsCl (0.46 mL, 5.90 mmol) was slowly added dropwise. After the addition was complete, the temperature was raised to room temperature and stirred for 2 hours. Saturated saline solution was added to the reaction solution, the solution was separated, the organic phase was washed twice with saturated saline solution, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the compound. 10D (1.3g, 94%) was obtained. The crude product was directly carried out in the next step of the reaction without purification.

[0193] Step 4: Preparation of Compound 10E

[0194] At room temperature, compounds10D (1.3g, 4.62mmol) was dissolved in ultra-dry DMF (30mL) and purged with argon gas three times. Then, potassium thioacetate (792mg, 6.93mmol) was added in a batch. The reaction solution was yellow, the temperature was slowly raised to 65°C, and the mixture was stirred for 18 hours until the raw materials were basically consumed, the reaction solution turned black, and a large amount of solid was produced. The mixture was cooled to room temperature, water (200mL) and ethyl acetate (50mL) were added and separated, the aqueous phase was extracted three times with ethyl acetate, the combined organic phase was washed four times with saturated saline solution, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The compound was purified by column chromatography (0 to 50% EA / PE). 10E (570mg, 47%) was obtained. 1 H NMR (400 MHz, CDCl3) δ 4.75 (s, 1H), 4.50 (s, 1H), 4.20 (dt, J = 13.3, 7.4 Hz, 2H), 4.02 (dd, J = 9.3, 5.8 Hz, 1H), 3.67 (dd, J = 8.8, 6.4 Hz, 1H), 3.64 - 3.55 (m, 1H), 2.36 (s, 3H), 1.51 - 1.39 (m, 9H).MS (ESI) m / z = 206.1 [M-56] + .

[0195] Step 5: Preparation of Compound 10F

[0196] Compound of Example 2 2J It was prepared according to the synthesis method of the compound. 2I (150 mg, 0.362 mmol) and compound 10E Racemic compound of crude product by (284 mg, 1.09 mmol) 10F ( 10F_1 and 10F_2 A mixture (130 mg) was obtained. Compounds were prepared and separated by alkaline HPLC. 10F_P1 (Isomers 10F_1 or 10F_2, 30mg, 13.5%) and compounds 10F_P2 (Isomers 10F_2 or 10F_1 , 32 mg, 14.4%) was obtained. Compound 10F_P1: MS (ESI) m / z = 636.2 [M+Na] + ; compound 10F_P2: MS (ESI) m / z = 636.2 [M+Na] + .

[0197] Step 6: Preparation of Compound 10

[0198] Compound of Example 2 2 It was manufactured according to the synthesis method.

[0199] compound 10F_P1 Compound by (30 mg, 0.0489 mmol) 10-P1 (Isomers 10_1 or 10_2 , 6.9mg, 44%) was obtained. 1 H NMR (400 MHz, DO) δ 7.13 (d, J = 7.9 Hz, 1H), 6.95 (d, J = 7.9 Hz, 1H), 4.17 (t, J = 9.1 Hz, 1H), 4.04 - 3.96 (m, 1H), 3.87 (d, J = 3.9 Hz, 2H), 3.82 - 3.72 (m, 1H), 3.60 (t, J = 9.0 Hz, 1H), 1.93 (dd, J = 8.1, 3.7 Hz, 1H), 1.01 (t, J = 7.6 Hz, 1H), 0.40 - 0.29 (m, 1H), 0.29 - 0.16 (m, 1H).MS (ESI) m / z = 322.0 [M+H] + .

[0200] compound 10F_P2 Compound by (30 mg, 0.0489 mmol) 10-P2 (Isomers 10_1 or 10_2 , 13.6 mg, 87%) was obtained. 1H NMR (400 MHz, DO) δ 7.16 (d, J = 7.8 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 4.23 (d, J = 9.2 Hz, 1H), 4.05 (dd, J = 14.6, 8.7 Hz, 1H), 4.00 - 3.91 (m, 2H), 3.81 (s, 1H), 3.67 (t, J = 9.1 Hz, 1H), 1.87 (dd, J = 15.5, 8.0 Hz, 1H), 0.95 (d, J = 6.8 Hz, 1H), 0.30 (d, J = 4.3 Hz, 2H).MS (ESI) m / z = 322.0 [M+H] + .

[0201] Example 11: Synthesis of Compound 11

[0202]

[0203] Step 1: Preparation of Compound 11A

[0204] At room temperature, compounds 10C After dissolving (2.0 g, 9.85 mmol) in tetrahydrofuran (20 mL), p-nitrobenzoic acid (1.8 g, 10.8 mmol) and triphenylphosphine (3.1 g, 11.8 mmol) were added, and the mixture was cooled to 0°C in an ice bath. Then, diethylazodicarboxylate (2.06 g, 11.8 mmol) was slowly added dropwise. After the dropwise addition was complete, the temperature was raised to room temperature and stirred for 16 hours. Ethyl acetate and water were added to the reaction solution, the liquids were separated, the organic phase was washed twice with saturated saline solution, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The compound was purified by column chromatography (0 to 20% EA / PE). 11A (1.00g, 29%) was obtained. MS (ESI) m / z = 338.0 [M-14] + .

[0205] Step 2: Preparation of Compound 11B

[0206] At room temperature, compounds 11AAfter dissolving (1.00 g, 2.84 mmol) in methanol (10 mL), lithium hydroxide monohydrate (357 mg, 8.51 mmol) dissolved in water (2 mL) was added, and the mixture was stirred at room temperature for 2 hours. TLC (EA / PE=3:7) indicated that the raw materials were completely reacted. Ethyl acetate and water were added to the reaction solution, the liquid was separated, the organic phase was washed twice with a saturated sodium bicarbonate aqueous solution, then washed with saturated saline solution, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain the compound. 11B (512 mg, 89%) was obtained. The crude product was directly carried out in the next step of the reaction without purification.

[0207] Step 3: Preparation of Compound 11C

[0208] Compound of Example 10 10D It was prepared according to the synthesis method of the compound. 11B Compound by (512 mg, 2.52 mmol) 11C (590 mg, 83.2%) was obtained. MS (ESI) m / z = 181.0 [M-100] + .

[0209] Step 4: Preparation of Compound 11D

[0210] Compound of Example 10 10E It was prepared according to the synthesis method of the compound. 11C Compound by (590 mg, 2.10 mmol) 11D (250 mg, 46%) was obtained. MS (ESI) m / z = 284.0 [M+Na] + .

[0211] Step 5: Preparation of Compound 11E

[0212] Compound of Example 2 2J It was prepared according to the synthesis method of the compound. 2I (132 mg, 0.319 mmol) and compound 11D Racemic compound by (250 mg, 0.958 mmol) 11E (Isomers 10E_1 and 10E_2A mixture (120 mg) was obtained. Compounds were prepared and separated by alkaline HPLC. 11E_P1 (Isomers 11E_1 or 11E_2 , 50mg, 26%) and compounds 11E_P2 (Isomers 11E_2 or 11E_1 , 40 mg, 21%) was obtained. Compound 11E_P1: MS (ESI) m / z = 636.3 [M+Na] + ; compound 11E_P2: MS (ESI) m / z = 636.3 [M+Na] + .

[0213] Step 6: Preparation of Compound 11

[0214] Compound of Example 2 2 It was manufactured according to the synthesis method.

[0215] compound 11E_P1 The product by (50 mg, 0.0815 mmol) 11-P1 (Isomers 11_1 or 11_2 , 23.2mg, 89%) was obtained. 1 H NMR (400 MHz, DO) δ 7.23 (d, J = 7.8 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 4.28 (dd, J = 9.8, 6.9 Hz, 1H), 4.08 (dd, J = 10.6, 5.5 Hz, 1H), 3.87 (dd, J = 10.6, 2.7 Hz, 1H), 3.80 (dt, J = 5.6, 2.9 Hz, 1H), 3.75 (dd, J = 11.1, 4.6 Hz, 1H), 3.68 (dd, J = 9.8, 5.7 Hz, 1H), 2.12 (d, J = 3.7 Hz, 1H), 1.18 (t, J = 7.5 Hz, 1H), 0.48 (dd, J= 16.9, 7.6 Hz, 1H), 0.41 - 0.32 (m, 1H).MS (ESI) m / z = 322.0 [M+H] + .

[0216] compound 11E_P2 The product by (40 mg, 0.0652 mmol) 11-P2 (Isomers 11_1 or 11_2 , 18.4mg, 88%) was obtained. 1 H NMR (400 MHz, DO) δ 7.23 (d, J = 7.7 Hz, 1H), 7.04 (d, J = 7.9 Hz, 1H), 4.27 (dd, J = 9.8, 6.8 Hz, 1H), 4.08 (dd, J = 10.6, 5.6 Hz, 1H), 3.87 (dd, J = 10.6, 2.8 Hz, 1H), 3.82 - 3.78 (m, 1H), 3.75 (dd, J = 11.0, 4.5 Hz, 1H), 3.68 (dd, J = 9.8, 5.6 Hz, 1H), 2.10 (t, J = 9.9 Hz, 1H), 1.16 (t, J = 8.2 Hz, 1H), 0.46 (dd, J = 16.2, 8.1 Hz, 1H), 0.40 - 0.31 (m, 1H).MS (ESI) m / z = 322.0 [M+H] + .

[0217] Example 12: Synthesis of Compound 12

[0218]

[0219] Step 1: Preparation of Compound 12B

[0220] Compound of Example 10 10C It was prepared according to the synthesis method of the compound. 12A Compound by (1.0g, 9.7mmol) 12B (1.9g, 96%) was obtained.1 ¹H NMR (400 MHz, DMSO- d 6) δ 7.06 (d, J = 6.7 Hz, 1H), 5.15 (d, J = 4.0 Hz, 1H), 4.02 (tt, J = 4.2, 2.1 Hz, 1H), 3.86 (dd, J = 8.8, 5.6 Hz, 1H), 3.81 - 3.76 (m, 1H), 3.72 (s, 1H), 3.45 (dt, J = 8.8, 2.3 Hz, 2H), 1.39 (s, 9H).

[0221] Step 2: Preparation of Compound 12C

[0222] Compound of Example 10 10D It was prepared according to the synthesis method of the compound. 12B Compound by (500 mg, 2.46 mmol) 12C (688 mg, 100%) was obtained. MS (ESI) m / z = 181.2 [M-100] + .

[0223] Step 3: Preparation of Compound 12D

[0224] Compound of Example 10 10E It was prepared according to the synthesis method of the compound. 12C Compound by (688 mg, 2.46 mmol) 12D (430 mg, 67%) was obtained. MS (ESI) m / z = 206.2 [M+H-56] + .

[0225] Step 4: Preparation of Compound 12E

[0226] compound 12DSodium hydroxide (400 mg, 10.0 mmol) and sodium (430 mg, 1.65 mmol) were dissolved in methanol (10 mL), the mixture was switched with argon gas, and reacted at 0°C for 0.5 hours. 0.5 M dilute hydrochloric acid was added to adjust the pH to 6, the mixture was extracted twice with ethyl acetate, dried with anhydrous sodium sulfate, the reaction solution was concentrated, and the compound was separated by column chromatography (PE / EA=80:20). 12E (320 mg, 59%) was obtained. MS (ESI) m / z = 164.2 [M+H-56] + .

[0227] Step 5: Preparation of Compound 12F

[0228] Compound of Example 2 2J It was prepared according to the synthesis method of the compound. 2I (100 mg, 0.24 mmol) and compound 12E Compound by (110 mg, 0.5 mmol) 12F (100 mg, 58%) was obtained. MS (ESI) m / z = 514.4 [M+H-100] + .

[0229] Step 6: Preparation of Compound 12G

[0230] compound 12F Dioxane hydrogen chloride (2 mL) was added to a 1 mL solution of tetrahydrofuran (100 mg, 0.163 mmol) and stirred at 0°C for 2 hours. After the reaction was completed, the solution was concentrated to obtain a compound 12G (90 mg, 100%) was obtained. The crude product was directly carried out in the next step of the reaction without purification. MS (ESI) m / z = 514.4 [M+H] + .

[0231] Step 7: Preparation of Compound 12H

[0232] compound 12G (90 mg, 0.163 mmol), compound 8ADissolve (186 mg, 0.6 mmol) and DIPEA (78 mg, 0.6 mmol) in acetonitrile (4.0 mL), stir overnight at room temperature, and separate using a reverse-phase column to obtain the compound 12H (110 mg, 89%) was obtained. MS (ESI) m / z = 756.6 [M+H] + .

[0233] Step 8: Preparation of Compound 12I

[0234] compound 12H 30 mg (0.047 mmol) and sodium hydroxide (80 mg, 2.0 mmol) were dissolved in tetrahydrofuran / water (0.5 mL / 0.5 mL) and stirred at 30°C for 3 hours. After the reaction was complete, the mixture was cooled to 0°C and the pH was adjusted to 3 to 4 with trifluoroacetic acid. Then, at 0°C, trifluoroacetic acid (1.0 mL), triethylsilane (0.3 mL), and isobutylboric acid (51 mg, 0.5 mmol) were added sequentially, followed by continuous stirring at 0°C for 2 hours. After the reaction was complete, the pH was adjusted to 9 with sodium hydroxide at 0°C. The compound was prepared by alkaline HPLC. 12I (50 mg, 38%) was obtained. MS (ESI) m / z = 402.1 [M+H-100] + .

[0235] Step 9: Preparation of Compound 12

[0236] compound 12I (8 mg, 0.018 mmol) was dissolved in tetrahydrofuran (0.1 mL), dioxane hydrogen chloride (0.3 mL) was added, and the mixture was stirred at 0°C for 2 hours. After the reaction was complete, the compound was prepared by alkaline HPLC. 12 (1.1 mg, 17%) was obtained. 1 H NMR (400 MHz, DO) δ 6.93 (d, J = 7.8 Hz, 1H), 6.64 (d, J= 7.8 Hz, 1H), 4.10-4.07 (m, 1H), 3.98-3.94 (m, 1H), 3.85-3.81 (m, 2H), 3.67-3.64 (m, 1H), 3.54-3.50 (m, 1H), 1.65-1.62 (m, 1H), 0.69-0.66 (m, 1H), 0.20-0.03 (m, 2H).MS (ESI) m / z = 364.0 [M+H] + .

[0237] Example 13: Synthesis of Compound 13

[0238]

[0239] Step 1: Preparation of Compound 13B

[0240] compound 13A (10.0 g, 142.8 mmol) is dissolved in tert-butanol (50 mL), sodium tert-butoxide (14.4 g, 150 mmol) and nitromethane (9.2 g, 150 mmol) are added in batches at 0°C, stirred for 2 hours at 0°C, diluted by adding ethyl acetate (500 mL), filtered the turbid solution, washed the mother liquor with a 1 M aqueous HCl solution, washed the organic phase once with a saturated NaCl solution, dried with anhydrous sodium sulfate, and concentrated to obtain the compound 13B (18.7 g, 100%) was obtained. The crude product was directly carried out in the next step of the reaction without purification. MS (ESI) m / z = 114.1[M+H-18] + .

[0241] Step 2: Preparation of Compound 13C

[0242] compound 13B (18.1g, 142.8mmol), Pd / C (1.0g) were dissolved in methanol (300mL), replaced with hydrogen gas, and stirred overnight at room temperature. Filtered through diatomite and directly concentrated to obtain the compound 13C (14.4g, 100%) was obtained. MS (ESI) m / z = 102.4 [M+H] + .

[0243] Step 3: Preparation of Compound 13D

[0244] Compound of Example 10 10C It was prepared according to the synthesis method of the compound. 13C Compound by (14.4g, 142.8mmol) 13D (13.2g, 46%) was obtained. MS (ESI) m / z = 202.6 [M+H] + .

[0245] Step 4: Preparation of Compound 13E

[0246] Compound of Example 10 10D It was prepared according to the synthesis method of the compound. 13D Compound by (10.0g, 49.5mmol) 13E (11.0g, 70%) was obtained. MS (ESI) m / z = 180.2 [M+H-100] + .

[0247] Step 5: Preparation of Compound 13F

[0248] Compound of Example 10 10E It was prepared according to the synthesis method of the compound. 13E Compound by (11.0g, 39.6mmol) 13F (6.8g, 66%) was obtained. MS (ESI) m / z = 160.2 [M+H-100] + .

[0249] Step 6: Preparation of Compound 13G

[0250] Compound of Example 12 12E It was prepared according to the synthesis method of the compound. 13F Compound by (1.0g, 3.86mmol) 13G (200 mg, 24%) was obtained. MS (ESI) m / z = 218.2 [M+H] + .

[0251] Step 7: Preparation of Compound 13H

[0252] Compound of Example 2 2J It was prepared according to the synthesis method of the compound.2I (60 mg, 0.145 mmol) and compound 13G Compound by (110 mg, 0.5 mmol) 13H (30 mg, 32%) was obtained. MS (ESI) m / z = 512.0 [M+H-100] + .

[0253] Step 8: Preparation of Compound 13I

[0254] Compound of Example 12 12I It was prepared according to the synthesis method of the compound. 13H Compound by (30 mg, 0.047 mmol) 13I (8 mg, 38%) was obtained. MS (ESI) m / z = 320.2 [M+H-100] + .

[0255] Step 10: Preparation of Compound 13

[0256] Compound of Example 12 12 It was prepared according to the synthesis method of the compound. 13I Compound by (10 mg, 0.0238 mmol) 13 (0.7mg, 9%) was obtained. 1 H NMR (400 MHz, DO) δ 7.57 (d, J = 8.0 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 2.75 - 2.50 (m, 2H), 2.35 - 2.25 (m, 1H), 1.25 - 1.75 (m, 1H), 0.70 - 0.60 (m, 2H), 0.60 - 0.40 (m, 2H), 0.30 - 0.20 (m, 4H). MS (ESI) m / z = 320.0 [M+H] + .

[0257] Example 14: Synthesis of Compound 14

[0258]

[0259] Step 1: Preparation of Compound 14B

[0260] Compound of Example 13 13B It was prepared according to the synthesis method of the compound.14A Compound by (10.0g, 100mmol) 14B (16.1g, 100%) was obtained. MS (ESI) m / z = 161.60 [M+H] + .

[0261] Step 2: Preparation of Compound 14C

[0262] Compound of Example 13 13C It was prepared according to the synthesis method of the compound. 14B Compound by (16.1g, 100mmol) 14C (13.1g, 100%) was obtained. MS (ESI) m / z = 131.60 [M+H] + .

[0263] Step 3: Preparation of Compound 14D

[0264] Compound of Example 10 10C It was prepared according to the synthesis method of the compound. 14C Compound by (13.1g, 100mmol) 14D (15.2g, 66%) was obtained. MS (ESI) m / z = 231.6 [M+H] + .

[0265] Step 4: Preparation of Compound 14E

[0266] Compound of Example 10 10D It was prepared according to the synthesis method of the compound. 14D Compound by (10.0g, 43.3mmol) 14E (13.5g, 100%) was obtained. MS (ESI) m / z = 210.0 [M+H-100] + .

[0267] Step 5: Preparation of Compound 14F

[0268] Compound of Example 10 10E It was prepared according to the synthesis method of the compound. 14E Compound by (13.5g, 43.7mmol) 14F (8.7g, 69%) was obtained. MS (ESI) m / z = 190.2 [M+H-100]+ .

[0269] Step 6: Preparation of Compound 14G

[0270] Compound of Example 12 12E It was prepared according to the synthesis method of the compound. 14F Compound by (1.0g, 3.45mmol) 14G (500 mg, 59%) was obtained. MS (ESI) m / z = 248.0 [M+H] + .

[0271] Step 7: Preparation of Compound 14H

[0272] Compound of Example 2 2J It was prepared according to the synthesis method of the compound. 2I (60 mg, 0.145 mmol) and compound 14G Compound by (124 mg, 0.5 mmol) 14H_P1 (Isomers 14H_1 or 14H_2 , 32mg, 34%) and compounds 14H_P2 (Isomers 14H_2 or 14H_1 , 30mg, 32%) was obtained. 14H_P1: MS (ESI) m / z = 542.0 [M+H-100] + ; 14H_P2: MS (ESI) m / z = 542.0 [M+H-100] + .

[0273] Step 8: Preparation of Compound 14I

[0274] Compound of Example 12 12I It was prepared according to the synthesis method of the compound. 14H_P1 Compound by (32 mg, 0.05 mmol) 14I_1 (Isomers 14I_1 or 14I_2 , 9 mg, 40%) is obtained; compound 14H_P2 Compound by (30 mg, 0.05 mmol) 14I_P2 (Isomers 14I_2 or 14I_1 , 8mg, 38%) was obtained. 14I_P1:MS (ESI) m / z = 350.2 [M+H-100] + ; 14I_P2: MS (ESI) m / z = 350.2 [M+H-100] + .

[0275] Step 10: Preparation of Compound 14

[0276] Compound of Example 12 12 It was manufactured according to the synthesis method.

[0277] compound 14I_P1 Compound by (9 mg, 0.02 mmol) 14_P1 (Isomers 14_1 or 14_2 , 5.5mg, 78%) was obtained. 1 H NMR (400 MHz, DO)δ 6.78 (d, J = 7.7 Hz, 1H), 6.50 (d, J = 7.7 Hz,1H), 3.75 - 3.51 (m, 3H), 3.47 - 3.39 (m, 2H), 3.31 - 3.21 (m, 2H), 2.81 - 2.75 (m, 1H), 2.37 - 2.32 (m, 1H), 2.26 - 2.16 (m, 1H), 1.88 - 1.78 (m, 1H), 1.52 - 1.46 (m, 1H), 0.58 - 0.50 (m, 1H), 0.03 - 0.01 (m, 1H). MS (ESI) m / z = 350.2 [M+H] + .

[0278] compound 14I_P2 Compound by (8 mg, 0.018 mmol) 14_P2 (Isomers 14_2 or 14_1 , 1.1mg, 17%) was obtained. 1 H NMR (400 MHz, DO) δ 6.82 (d, J = 7.8 Hz, 1H), 6.54 (d, J= 7.5 Hz, 1H), 3.78 - 3.60 (m, 2H), 3.48 - 3.44 (m, 1H), 3.32 - 3.29 (m, 1H), 2.84 - 2.80 (m, 1H), 2.42 - 2.21 (m, 3H), 1.88 - 1.80 (m, 1H), 1.55 - 1.50 (m, 2H), 0.58 - 0.56 (m, 1H), 0.10 - 0.07 (m, 2H).MS (ESI) m / z = 350.2 [M+H] + .

[0279] Example 15: Synthesis of Compound 15

[0280]

[0281] Step 1: Preparation of Compound 15A

[0282] compound 2E (5g, 18.2mmol) was dissolved in N,N-dimethylformamide (100mL), and under a nitrogen gas atmosphere, p-methoxybenzyl mercaptan (4.2g, 27.3mmol) and cesium carbonate (17.7g, 54.6mmol) were added and stirred at room temperature for 16 hours. After the reaction was complete, the mixture was filtered, the cake was washed with ethyl acetate, the filtrate was collected, concentrated under reduced pressure, 50mL of methanol was added and stirred for 10 minutes, filtered, the cake was washed with methanol, and dried under reduced pressure to obtain a white solid. 15A (5.7g, yield: 76.1%) was obtained.

[0283] 1 ¹H NMR (400 MHz, DMSO-d6) δ 7.85 (d, J = 8.7 Hz, 1H), 7.39 - 7.34 (m, 2H), 7.15 (d, J = 8.8 Hz, 1H), 6.95 - 6.88 (m, 2H), 4.20 (s, 2H), 3.74 (s, 3H), 1.69 (s, 6H).

[0284] Step 2: Preparation of Compound 15B

[0285] compound 15A(3g, 7.3mmol) was dissolved in dichloromethane (30mL), trifluoromethanesulfonic acid (2mL) was added at 0°C, and stirring was continued for 1 hour. After the reaction was complete, sodium bicarbonate solution was added to adjust the pH to neutral, the mixture was extracted with dichloromethane (50mL × 3), the organic phase was combined, washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 3g of crude product. 15B ...was obtained and used directly in the next step without the need for purification. MS(ESI)m / z:(M+H)+= 288.80.

[0286] Step 3: Preparation of Compound 15C

[0287] At room temperature, compounds 15B (3g, 7.3mmol) was dissolved in N,N-dimethylformamide (30mL), potassium carbonate (1.5g, 10.95mmol) and 2-(4-morpholine)ethyl bromide (2.0g, 7.3mmol) were added, and the mixture was stirred for 2 hours. After the reaction was complete, the mixture was washed with water (100mL), extracted with ethyl acetate (50mL × 3), the organic phase was combined, washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to separate and purify the crude product by column chromatography (petroleum ether / ethyl acetate = 5:3) to obtain the compound. 15C (2.6g, two-step yield: 88.4%) was obtained. MS(ESI)m / z:(M+H)+= 401.8.

[0288] Step 4: Preparation of Compound 15D

[0289] compound 15C(1.6 g, 3.9 mmol), acrylic acid (861.8 mg, 11.9 mmol), palladium acetate (175.1 mg, 0.78 mmol), tri(o-tolyl)phosphine (948.4 mg, 3.1 mmol), and diisopropylethylenediamine (2.5 g, 19.5 mmol) were dissolved in N,N-dimethylformamide (20 mL), the solution was purged with nitrogen gas three times, the temperature was raised to 100°C, and the mixture was stirred for 16 hours. After the reaction was complete, the solution was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was combined, washed with saturated saline solution, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (dichloromethane / methanol = 10:1) to obtain the compound. 15D (1.1g, yield: 70.5%) was obtained. MS (ESI) m / z (M+ H) + = 394.0.

[0290] Step 5: Preparation of Compound 15E

[0291] compound 15D (676 mg, 1.72 mmol) was dissolved in chloroform (6 mL), acetic acid (2 mL) was added under an ice bath, liquid bromine (330 mg, 2.06 mmol) was slowly added dropwise, and the mixture was stirred at 0°C for 2 hours. After the reaction was complete, N,N-dimethylformamide (6 mL) was added to the residual solid obtained by vacuum concentration, triethylamine (347.4 mg, 3.44 mmol) was added at room temperature, and the mixture was stirred continuously for 1 hour. After the reaction was complete, ethyl acetate (20 mL) was added to dilute the mixture, it was washed with water (50 mL × 3), washed with saturated saline solution, dried with anhydrous sodium sulfate, filtered, and vacuum concentrated to purify the crude product by column chromatography (petroleum ether / ethyl acetate = 5:3) to obtain the compound. 15E (488 mg, yield: 66.4%) was obtained. MS(ESI)m / z:(M+H)+= 428.0.

[0292] Step 6: Preparation of Compound 15F

[0293] compound 15E (1.3g, 3.04mmol) was dissolved in isopropyl acetate (10mL), bis[(1S,2S,3R,5S)(+)-pinandiolate]diborone (1.63g, 4.56mmol), allylpalladium(II) chloride dimer (111.0mg, 0.304mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (289.8mg, 0.608mmol), and potassium isooctanoate (1.2g, 6.69mmol) were added, the mixture was replaced with argon gas 4 times, the temperature was raised to 35℃, and the mixture was stirred for 16 hours. After the reaction is complete, the mixture is washed with water (100 mL), extracted with ethyl acetate (50 mL × 3), the organic phase is combined, washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to separate and purify the crude product by column chromatography (petroleum ether / ethyl acetate = 5:3) to obtain the compound. 15F (372 mg, yield: 23.5%) was obtained. MS(ESI)m / z:(M+H)+= 528.2.

[0294] Step 7: Preparation of Compounds 15G-a and 15G-b

[0295] At -20℃, under a nitrogen gas atmosphere, compounds 15F CH2N2 (0.2M, 9.19mL) ether solution was added to a THF (3mL) solution in which (97mg, 183.89μmol) and Pd(OAc)2 (4.13mg, 18.39μmol) were dissolved, and after returning to room temperature, stirring was continued for 16 hours. After the reaction was complete, the crude product was concentrated under reduced pressure and separated and purified (0 to 40% petroleum ether / ethyl acetate) by column chromatography to obtain a yellow oily compound. 15G A mixture (60 mg, yield: 60.25%) is obtained, and the compound is separated and purified by SFC. 15G-a and 15G-b obtained.

[0296] SFC separation conditions: Chiral column: Chiralpak IC-3 150×4.6mm ID, 3μm; Mobile phase: 50% of IPA (0.05% DEA) in CO2; Flow rate: 2.5mL / min; Column temperature: 35℃; ABPR: 1500psi.

[0297] 15G-a : Retention time: t=4.021 min, HPLC: 91.78%; Retention time: t=4.52 min, 25 mg white solid.

[0298] 15G-b : Retention time: t=4.860 min, HPLC: 94.11%; Retention time: t=4.58 min, 25 mg white solid.

[0299] MS (ESI) m / z (M+1)+=542.4.

[0300] Step 13: Preparation of Compounds 15-a and 15-b

[0301] compound 15G-a NaOH solution (3M, 46.17 μL) was added to a 1 mL solution of dioxane (25 mg, 46.17 μmol) dissolved in it, and the mixture was stirred at room temperature for 24 hours. Subsequently, the reaction solution was lowered to 0°C, and triethylsilane (0.1 mL), trifluoroacetic acid (0.2 mL), and isobutylboric acid (9.41 mg, 92.34 μmol) were added sequentially and stirred for 1 hour. After the reaction was complete, the crude product obtained by concentrating under reduced pressure was separated and purified by HPLC. 15-a (5mg, yield: 31.01%) was obtained.

[0302] 1 ¹H NMR (400 MHz, METHANOL-d4)δ = 7.39 (d, J = 8.1 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 3.89 (br s, 4H), 3.28 - 3.19 (m, 8H), 2.27 (dt, J = 4.2, 7.9 Hz, 1H), 1.42 - 1.32 (m, 1H), 0.66 - 0.58 (m, 1H), 0.41 - 0.33 (m, 1H). MS (ESI) m / z (M+1)+=350.1.

[0303] HPLC Separation and Purification Conditions: Chromatography Column: Welch Xtimate C18 100×40mm×3μm; Mobile Phase: [Water (TFA)-Acetonitrile]; B%: 8% to 38%, 8 min;

[0304] HPLC 99.92%; retention time: t=1.82 min.

[0305] 15-b The manufacturing of 15G-b Using as a raw material 15-a 5 mg was obtained using the same method.

[0306] 1 ¹H NMR (400 MHz, METHANOL-d4) δ = 7.39 (d, J = 7.9 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 3.89 (br s, 4H), 3.27 - 3.17 (m, 8H), 2.28 (dt, J = 4.1, 8.1 Hz, 1H), 1.42 - 1.33 (m, 1H), 0.66 - 0.58 (m, 1H), 0.41 - 0.34 (m, 1H). MS (ESI) m / z (M+1)+=350.1.

[0307] HPLC 99.89%; retention time: t=1.69 min.

[0308] Example 16: Synthesis of Compound 16

[0309]

[0310]

[0311] Step 1: Preparation of Compound 16B

[0312] At -20℃, compounds 16A Liquid bromine (2.05 g, 12.79 mmol) was slowly added to a toluene (10 mL) solution in which (1.00 g, 11.62 mmol) and triphenylphosphine (3.35 g, 12.79 mmol) were dissolved, and the mixture was stirred continuously for 2 hours. After the reaction was complete, the solution was returned to room temperature, filtered, and washed with toluene (2 mL) to obtain the compound. 16B A toluene solution (11 mL, 1.06 N) was obtained and used directly in the next step without the need for purification.

[0313] Step 2: Preparation of Compound 16C

[0314] At room temperature, under a nitrogen gas atmosphere, compounds 15B In N,N-dimethylformamide (3 mL) in which potassium carbonate (100 mg, 0.346 mmol) and potassium carbonate (96.0 mg, 0.69 mmol) were dissolved 16B A toluene solution (0.4 mL) was slowly added dropwise, and the mixture was stirred at room temperature for 1 hour. After the reaction was complete, water (10 mL) was added and the mixture was quenched. It was then extracted with ethyl acetate (5 mL × 3), the organic phase was collected, washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the compound. 16C (50 mg, yield: 41%) was obtained. MS(ESI)m / z:(M+H)+= 357.0.

[0315] Step 3: Preparation of Compound 16D

[0316] 16CA solution of toluene (3.0 mL) containing (200 mg, 0.56 mmol), pinacol vinylboronate (260 mg, 1.68 mmol), tris[dibenzylideneacetone]dipalladium (0) (50.0 mg, 0.056 mmol), tri-tert-butylphosphine tetrafluoroborate (32.0 mg, 0.11 mmol), and N,N-diisopropylethylamine (215 mg, 1.68 mmol) was stirred at 115°C for 1 hour under a nitrogen gas atmosphere. After the reaction is complete, water (15 mL) is added for quenching, extracted with ethyl acetate (5 mL × 3), the organic phase is combined, washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure to separate and purify the crude product by column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain the compound 16D (140 mg, yield: 58%) was obtained. MS(ESI)m / z:(M+H)+= 431.2.

[0317] Step 4: Preparation of Compound 16E

[0318] At room temperature, compounds 16D (1S,2S,3R,5S)-(+)-2,3-pinandiol (2.00 g, 12.2 mmol) was added to a 12 mL solution of tetrahydrofuran (1.05 g, 2.43 mmol) dissolved in (1.05 g, 2.43 mmol) and stirred for 2 hours. After the reaction was complete, the solution was concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the compound. 16E (1.00g, yield: 85.4%) was obtained. MS (ESI) m / z (M- H) + = 483.2.

[0319] Step 5: Preparation of Compound 16F

[0320] compound 16E(80.0 mg, 0.166 mmol) was dissolved in acetonitrile (8 mL), tris(2-phenylpyridine)iridium (8.00 mg) was added at room temperature, and after irradiating with LED blue light (wavelength = 450 nM, 10 W) for 1.5 hours under a nitrogen gas atmosphere, the reaction solution was concentrated under reduced pressure, and the crude product obtained was separated and purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to obtain the compound 16F (36 mg, yield: 45%) was obtained. MS (ESI) m / z (M + H) + = 483.2

[0321] Step 7: Preparation of Compound 16G-a or 16G-b

[0322] compound 16F (400 mg, 829.12 μmol) white solid compound obtained through preparative chiral splitting 16G-a (120 mg, yield: 30.00%) was obtained, and retention time: t=3.700 min.

[0323] SFC Separation Conditions: Chiral Column: Chiralcel OD-3 150 mm × 4.6 mm ID, 3 μm; Mobile Phase: A: CO2, B: Isopropanol (0.05% DEA); Gradient: Mobile Phase B rises from 5% to 40% within 5 minutes, then drops from 40% to 5% within 30 seconds and is maintained for 1.5 minutes; Flow Rate: 2.5 mL / min; Column Temperature: 35 ℃; ABPR: 1500 psi; Retention Time: t=3,700 min.

[0324] 16G-b (130 mg, Yield: 32.50%), white solid, retention time: t=4.046 min.

[0325] SFC Separation Conditions: Chiral Column: Chiralcel OD-3 150 mm × 4.6 mm ID, 3 μm; Mobile Phase: A: CO2; B: Isopropanol (0.05% DEA); Gradient: Mobile Phase B rises from 5% to 40% within 5 minutes, then drops from 40% to 5% within 30 seconds and maintains for 1.5 minutes; Flow Rate: 2.5 mL / min; Column Temperature: 35 ℃; ABPR: 1500 psi; Retention Time: t=4.046 min.

[0326] Step 8: Preparation of Compounds 16H-aa, ab, ba, and bb

[0327] At -20℃, compounds 16G-a Pd(OAc)2 (55.84 mg, 248.74 μmol) was added to a 10 mL solution of tetrahydrofuran (120 mg, 248.74 μmol) dissolved therein, followed by the slow addition of a 6.22 mL solution of CH2N2 (0.2 M), and the reaction was carried out at room temperature for 16 hours. After the reaction was complete, the crude product obtained by vacuum concentration was first purified by column chromatography (ethyl acetate / petroleum ether = 15%), and the resulting crude product was further subjected to chiral cleavage to obtain a white solid compound. 16H-aa (45 mg, yield: 36.44%), and a white solid compound 16H-ab (40mg, yield: 32.39%) was obtained.

[0328] 1 ¹H NMR (400MHz, CHLOROFORM-d)δ = 7.21 (d, J = 8.5 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 4.00 (br d, J = 7.3 Hz, 1H), 2.94 - 2.85 (m, 1H), 2.32 - 2.24 (m, 1H), 2.17 (br dd, J = 8.6, 14.4 Hz, 1H), 1.85 - 1.78 (m, 2H), 1.76 (br s, 2H), 1.75 (s, 3H), 1.71 (s, 3H), 1.44 (d, J = 6.6 Hz, 3H), 1.18 (d, J = 3.9 Hz, 7H), 1.15 - 1.10 (m, 1H), 1.08 - 1.00 (m, 1H), 1.05 (br dd, J = 4.8, 13.0 Hz, 1H), 0.73 (s, 3H), 0.65 - 0.59 (m, 2H), 0.55 - 0.47 (m, 2H), 0.43 - 0.32 (m, 2H). MS (ESI) m / z (M+ H)+=497.4.

[0329] 16H-ab (40mg, 수율: 32.39%), 백색 고체.

[0330] 1 ¹H NMR (400MHz, CHLOROFORM-d)δ = 7.23 (d, J = 8.5 Hz, 1H), 6.82 (d, J = 8.5 Hz, 1H), 4.02 (d, J = 6.8 Hz, 1H), 2.85 - 2.78 (m, 1H), 2.34 - 2.26 (m, 1H), 2.15 - 2.07 (m, 1H), 2.02 - 1.95 (m, 1H), 1.85 (t, J = 5.6 Hz, 1H), 1.73 (d, J = 3.5 Hz, 6H), 1.41 (d, J = 6.5 Hz, 3H), 1.33 (br s, 1H), 1.29 - 1.23 (m, 2H), 1.19 (s, 3H), 1.15 - 1.10 (m, 1H), 1.08 (s, 3H), 1.04 - 0.99 (m, 1H), 0.72 (s, 3H), 0.63 (br d, J = 8.8 Hz, 3H), 0.58 - 0.52 (m, 1H), 0.43 - 0.38 (m, 1H), 0.36 - 0.31 (m, 1H). MS (ESI) m / z (M+ H)+=497.4.

[0331] SFC Splitting Conditions: Chiral Column: Chiralpak IC-3 100mm×4.6mm ID, 3μm; Mobile Phase: A: CO2; B: Methanol (0.05% DEA); Gradient: Mobile Phase B rises from 5% to 40% within 4 minutes and is maintained for 2.5 minutes, followed by the mobile phase being maintained at 5% for 1.5 minutes; Flow Rate: 2.8mL / min; Column Temperature: 35℃; ABPR: 1500psi; Retention Time: t=2.873min.

[0332] HPLC conditions: Mobile phase: 2.75 mL / 4 L TFA / water (Mobile Phase A), 2.5 mL / 4 L TFA / acetonitrile (Mobile Phase B); using Mobile Phase B, rise from 30% to 90% within 6 minutes and maintain for 2 minutes, flow rate 1.2 mL / min; Chromatography column: Ultimate C18 3.0 × 50 mm, 3 μm; Wavelength: UV 220 nm, 215 nm, 254 nm; Column temperature: 40 ℃; Retention time: t = 6.36 min.

[0333] At -20℃, compounds 16G-b CH2N2 (10.45 mg, 248.74 μmol) was added to a 20 mL solution of tetrahydrofuran containing (120.00 mg, 248.74 μmol) and Pd(OAc)2 (55.84 mg, 248.74 μmol), and the reaction was carried out at room temperature for 16 hours. After the reaction was complete, the crude product obtained by vacuum concentration was separated and purified by column chromatography (ethyl acetate / petroleum ether = 15%), and the crude product obtained was further chirally partitioned to obtain a white solid compound. 16H-ba (45 mg, yield: 36.44%, retention time: t=3.711 min.), and compound 16H-BB (40 mg, yield: 32.39%, retention time: t=4.242 min.) was obtained.

[0334] SFC Conditions: Chiral Column: (S,S)Whelk-01 100×4.6mm ID, 5.0μm; Mobile Phase: A: CO2, B: Ethanol (0.05% DEA); Gradient: Mobile Phase B rises from 5% to 40% within 4.5 minutes and maintains for 1.5 minutes; Flow Rate: 2.5 mL / min; Column Temperature: 40℃; ABPR: 100 bar;

[0335] HPLC Analysis Conditions: Mobile Phase: 2.75 mL / 4 L TFA / Water (Mobile Phase A) and 2.5 mL / 4 L TFA / Acetonitrile (Mobile Phase B); using Mobile Phase B, rise from 30% to 90% within 6 minutes and maintain for 2 minutes, with a flow rate of 1.2 mL / min; Chromatography Column: Ultimate C18 3.0 × 50 mm, 3 μm; Wavelength: UV 220 nm, 215 nm, 254 nm; Column Temperature: 40 ℃.

[0336] Step 9: Preparation of Compounds 16-a, b, c, and d

[0337] At room temperature, compounds 16H-aaAfter adding an aqueous sodium hydroxide solution (3M, 80μL) to a mixed solvent of acetonitrile (1mL) and water (0.5mL) in which (40mg, 80μmol) was dissolved, the temperature was raised to 60°C and stirred for 2 hours. The reaction was cooled to room temperature, and isobutylboric acid (41mg, 0.4mmol) and hydrochloric acid (100μL) were added to the reaction solution, and stirring was continued at room temperature for 0.5 hours. After the reaction was completed, the crude product obtained by vacuum concentration was separated and purified by HPLC (chromatography column: Boston Green ODS 150×30mm×5μm; mobile phase: [water(HCl)-ACN]; B%: 40% to 60%, 10 min) to obtain the compound 16-a (10 mg, yield: 41%) was obtained.

[0338] 1 ¹H NMR (400 MHz, Methanol-d4) δ 7.12 (d, J = 7.9 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 2.39 (dq, J = 9.5, 6.7 Hz, 1H), 2.11 (td, J = 8.0, 4.2 Hz, 1H), 1.19 (ddd, J = 11.1, 7.9, 3.6 Hz, 1H), 1.07 (d, J = 6.7 Hz, 3H), 0.65 (dddd, J = 13.0, 9.6, 8.1, 4.9 Hz, 1H), 0.42 (ddd, J = 10.4, 8.1, 6.1 Hz, 1H), 0.35 - 0.25 (m, 2H), 0.18 (dt, J = 6.2, 3.9 Hz, 1H), 0.05 -0.06 (m, 2H). MS (ESI) m / z (M+ H) + =304.7.

[0339] 16b was obtained by using 16H-ab as a starting material and using the same synthesis and manufacturing method as 16-a to obtain 17.88 mg.

[0340] 1 ¹H NMR (400 MHz, Methanol-d4)δ 7.13 (d, J = 7.9 Hz, 1H), 6.97 (d, J = 7.9 Hz, 1H), 2.40 (dq, J = 9.5, 6.7 Hz, 1H), 2.11 (td, J = 8.0, 4.1 Hz, 1H), 1.19 (ddd, J = 10.4, 7.9, 3.6 Hz, 1H), 1.08 (d, J = 6.7 Hz, 3H), 0.71 - 0.61 (m, 1H), 0.42 (ddd, J = 10.4, 8.1, 6.2 Hz, 1H), 0.34 - 0.24 (m, 2H), 0.19 (dt, J = 6.2, 3.9 Hz, 1H), -0.00 (ddt, J = 6.4, 4.9, 2.2 Hz, 2H). MS (ESI) m / z (M+ H) + =304.7.

[0341] 16-c was obtained by using 16H-ba as a starting material and using the same synthesis and manufacturing method as 16-a to obtain 15.4 mg.

[0342] 1 ¹H NMR (400 MHz, Methanol-d4) δ 7.12 (d, J = 7.9 Hz, 1H), 6.96 (d, J = 7.9 Hz, 1H), 2.39 (dq, J = 9.5, 6.7 Hz, 1H), 2.11 (td, J = 8.0, 4.1 Hz, 1H), 1.22 - 1.17 (m, 1H), 1.07 (d, J = 6.7 Hz, 3H), 0.69 - 0.61 (m, 1H), 0.45 - 0.39 (m, 1H), 0.34 - 0.26 (m, 2H), 0.18 (dt, J = 6.2, 3.9 Hz, 1H), 0.04 - -0.04 (m, 2H). MS (ESI) m / z (M+ H)+=304.7.

[0343] 16-d was obtained by using 16H-bb as a starting material and using the same synthesis and manufacturing method as 16-a to obtain 21.66 mg.

[0344] 1 ¹H NMR (400 MHz, Methanol-d4)δ 7.13 (d, J = 7.9 Hz, 1H), 6.97 (d, J = 7.9 Hz, 1H), 2.40 (dq, J = 9.5, 6.7 Hz, 1H), 2.11 (td, J = 8.0, 4.1 Hz, 1H), 1.20 (ddd, J = 10.5, 8.0, 3.6 Hz, 1H), 1.08 (d, J = 6.7 Hz, 3H), 0.70 - 0.62 (m, 1H), 0.42 (ddd, J = 10.4, 8.1, 6.1 Hz, 1H), 0.34 - 0.26 (m, 2H), 0.19 (dt, J = 6.2, 3.9 Hz, 1H), -0.00 (tdd, J = 4.9, 2.8, 1.6 Hz, 2H). MS (ESI) m / z (M+ H)+=304.7.

[0345] Example 17: Synthesis of Compound 17

[0346]

[0347] Step 1: Preparation of Compound 17B

[0348] At -10℃, compounds 17A Methanesulfonyl chloride (210 mg, 1.84 mmol) was slowly added dropwise to a dichloromethane (4 mL) solution containing dissolved (200 mg, 1.54 mmol) and triethylamine (233 mg, 2.31 mmol), and stirred for 1 hour. After the reaction was complete, the solution was returned to room temperature, washed with water (10 mL), extracted with dichloromethane (20 mL × 3), the organic phase was collected, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the compound. 17B (319 mg, yield: 99%) was obtained.

[0349] Step 2: Preparation of Compound 17C

[0350] At room temperature, compounds 15B (70 mg, 0.24 mmol) and potassium carbonate (50.0 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (1.5 mL), and under a nitrogen gas atmosphere 17BA DMF solution (60.0 mg, 0.28 mmol) was added dropwise, and after the addition was complete, the temperature was raised to 100°C and stirred for 1 hour. After the reaction was complete, the mixture was washed with water, extracted with ethyl acetate (5 mL × 3), the organic phase was collected, washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to separate and purify the crude product using column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain the compound. 17C (45 mg, yield: 46%) was obtained. MS(ESI)m / z:(M+H)+= 401.0.

[0351] Step 3: Preparation of Compound 17D

[0352] At room temperature, 17C (40.0 mg, 0.1 mmol), pinacol vinylboronate (46.0 mg, 0.3 mmol), tris[dibenzylideneacetone]dipalladium (0) (9.15 mg, 0.1 mmol), tri-tert-butylphosphine tetrafluoroborate (6.0 mg, 0.02 mmol), and N,N-diisopropylethylamine (40 mg, 0.3 mmol) were dissolved in toluene (1.5 mL), the mixture was purged with nitrogen gas three times, heated to 115°C, and stirred for 2 hours. After the reaction is complete, return to room temperature, wash with water, extract with ethyl acetate (3 mL × 3), combine the organic phase, wash with saturated saline, dry with anhydrous sodium sulfate, filter, and concentrate directly under reduced pressure to obtain the crude product, which is then separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to form the compound 17D (26 mg, yield: 55%) was obtained. MS(ESI)m / z:(M+H)+= 475.2.

[0353] Step 4: Preparation of Compound 17E

[0354] At room temperature, compounds 17D(1S,2S,3R,5S)-(+)-2,3-pinandiol (591.0 mg, 3.48 mmol) was added to a 6 mL solution of tetrahydrofuran (550.0 mg, 1.16 mmol) dissolved in it, and the mixture was stirred for 2 hours. After the reaction was complete, the crude product obtained by concentrating under reduced pressure was separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the compound. 17E (520.0 mg, yield: 85.2%) was obtained. MS (ESI) m / z (M- H) + = 527.2.

[0355] Step 5: Preparation of Compound 17F

[0356] compound 17E (100.0 mg, 0.19 mmol) was dissolved in dichloromethane (9 mL), tris(2-phenylpyridine)iridium (5.00 mg) was added at room temperature, and after irradiating with LED blue light for 1.5 hours under a nitrogen gas atmosphere, the crude product obtained by vacuum concentration was separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain a compound 17F (55 mg, yield: 55%) was obtained. MS (ESI) m / z (M + H) + = 527.2.

[0357] Step 6: Preparation of Compound 17G

[0358] In an ice bath, under a nitrogen gas atmosphere, compounds 17F A diazomethane ether solution (2.5 mL, 2.5 mmol) was added to tetrahydrofuran (6 mL) in which palladium acetate (130.0 mg, 0.25 mmol) and 5.50 mg, 0.024 mmol) were dissolved, and the mixture was stirred continuously for 10 minutes. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure to separate and purify the crude product by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain the compound. A3-7 (105.0 mg, yield: 79.0%) was obtained. MS (ESI) m / z (M+ H) + = 540.2

[0359] 17G (220 mg, 0.41 mmol) was split using a chiral preparative column to obtain 4 compounds 17G-a (30.5 mg, retention time t=8.843), 17G-b (35.2 mg, retention time t=10.024), 17G-c (26.5 mg, retention time t=11.146), 17G-d (36.5 mg, retention time t=13.983) was obtained.

[0360] Chiral Splitting Conditions: Chromatography Column: Daicel CHIRALPAK® IB250×30mm, 10μm; Mobile Phase A: n-hexane; Mobile Phase B: Ethanol; Detection Wavelength: 254nm; Flow Rate: 25mL / min; Isothermal Elution Procedure: Mobile Phase A:Mobile Phase B=95:05(V / V).

[0361] Chiral Splitting Conditions: Chromatography Column: Daicel CHIRALPAK® IB 250×4.6 mm, 5 μm; Mobile Phase A: n-hexane; Mobile Phase B: Ethanol; Detection Wavelength: 254 nm; Flow Rate: 1 mL / min; Column Temperature: 30 ℃; Time: 20 min; Isothermal Elution Procedure: Mobile Phase A:Mobile Phase B=95:05 (V / V).

[0362] Step 7: Preparation of Compounds 17-a, b, c, and d

[0363] At room temperature, compounds 17G-a After adding 150 μL of a 3M NaOH solution to a mixed solution of 0.6 mL of acetonitrile and 0.2 mL of water in which 25 mg (46.3 μmol) was dissolved, the mixture was heated to 60°C and stirred for 1.5 hours. In an ice bath, 0.2 mL of triethylsilane, 1 mL of trifluoroacetic acid, and 9.41 mg (92.34 μmol) of isobutylboric acid were sequentially added to the mixed solution and stirred at room temperature for 1 hour. After the reaction was complete, the crude product obtained by concentrating under reduced pressure was separated and purified by HPLC. 17-a (10.42 mg) was obtained.

[0364] 1 ¹H NMR (400 MHz, Methanol-d4) δ 7.23 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 3.98 - 3.72 (m, 2H), 3.33 - 3.23 (m, 2H), 3.11-3.00 (m, 1H), 2.26-2.15 (m, 1H), 1.71 - 1.53 (m, 3H), 1.49 - 1.23 (m, 3H), 1.11 (d, J = 6.8 Hz 3H), 0.55-0.45 (m, 1H), 0.31-0.25 (m, 1H). MS (ESI) m / z (M-1)-=347.0.

[0365] HPLC 100.00%(254nM); retention time: t=2.70min.

[0366] Separation conditions: Chromatography column: Welch Xtimate ® C18 21.2×250 mm; Column temperature: 25℃; Mobile phase A: Water (10.0 mM / L ammonium bicarbonate solution); Mobile phase B: Acetonitrile; Gradient: 0 to 45%, 15 min; Flow rate 18.0 mL / min,

[0367] Analysis conditions: Chromatography column: Waters X Bridge 4.6×100 mm, 3.5 μm; column temperature: 40 ℃; mobile phase A: water (10.0 mM / L ammonium bicarbonate solution); mobile phase B: acetonitrile; gradient: 5% to 95%, 7 min; flow rate 1.0 mL / min.

[0368] 17-b was manufactured using 17G-b as a raw material and 20.46 mg was obtained in the same way as 17-a.

[0369] 1 H NMR (400 MHz, Methanol -d4)δ 7.21 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.0 Hz, 1H), 3.93 - 3.73 (m, 2H), 3.35 - 3.23 (m, 2H), 3.12-3.01 (m, 1H), 2.18-2.07(m, 1H), 1.71-1.55 (m, 3H), 1.46 - 1.17 (m, 3H), 1.11 (d, J = 6.8 Hz, 3H), 0.53-0.39 (m, 1H), 0.33-0.24 (m, 1H).

[0370] 17-c was manufactured using 17G-c as a raw material and 7.91 mg was obtained in the same way as 17-a.

[0371] 1 ¹H NMR (400 MHz, Methanol-d4) δ 7.23 (d, J = 7.9 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 3.88 - 3.82 (m, 2H), 3.29 - 3.23 (m, 2H), 3.07 - 3.02 (m, 1H), 2.19 (dt, J = 8.0, 4.0 Hz, 1H), 1.62 (tt, J = 8.6, 3.2 Hz, 3H), 1.37 (dtd, J = 11.0, 3.3, 1.7 Hz, 2H), 1.31 - 1.26 (m, 1H), 1.12 (d, J = 6.9 Hz, 3H), 0.50 (ddd, J = 10.4, 8.1, 6.1 Hz, 1H), 0.28 (dt, J = 6.2, 3.9 Hz, 1H). MS (ESI) m / z (M- H) - =306.8.

[0372] 17-d was manufactured using 17G-d as a raw material and 9.32 mg was obtained in the same way as 17-a.

[0373] 1 ¹H NMR (400 MHz, Methanol-d4)δ 7.23 (d, J = 7.9 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 3.88 - 3.82 (m, 2H), 3.27 (dtd, J = 11.9, 5.9, 2.0 Hz, 2H), 3.06 (dd, J = 7.0, 5.0 Hz, 1H), 2.19 (td, J = 8.0, 4.1 Hz, 1H), 1.67 - 1.58 (m, 3H), 1.43 - 1.33 (m, 2H), 1.31 - 1.25 (m, 1H), 1.12 (d, J = 6.9 Hz, 3H), 0.50 (ddd, J = 10.5, 8.1, 6.2 Hz, 1H), 0.28 (dt, J = 6.2, 3.8 Hz, 1H). MS (ESI) m / z (M-H)-=306.8.

[0374] Example 18: Synthesis of Compound 18

[0375]

[0376]

[0377] Step 1: Preparation of Compound 18B

[0378] compound 18A (1.0 g, 8.62 mmol) and dimethylhydroxylamine hydrochloride (930.0 mg, 9.48 mmol, 1.1 equiv) were dissolved in a dichloromethane (20.0 mL) solution, N,N'-carbonyldiimidazole (1536.0 mg, 9.48 mmol, 1.1 equiv) was added to the reaction solution in batches, and stirred at room temperature for 16.0 hours. After the reaction was complete, the mixture was quenched with hydrochloric acid (1.0 N), extracted with ethyl acetate (40 mL × 3), the organic phase was collected, washed with an aqueous sodium hydroxide solution (100.0 mL, 1.0 N), dried, filtered, and concentrated to obtain the crude product. 18B (1.0g, yield: 73.0%, colorless liquid) was obtained and used directly in the next step without the need for further purification.

[0379] 1 1H NMR (400 MHz, Chloroform- d ) δ 4.75 - 4.62 (m, 1H), 3.85 - 3.72 (m, 2H), 3.67 (s, 3H), 3.09 (s, 3H), 2.15 - 2.03 (m, 1H), 1.92 - 1.73 (m, 3H).

[0380] Step 2: Preparation of Compound 18C

[0381] At 0°C, under an argon gas atmosphere, compounds 18B Methyl magnesium bromide (2.3 mL, 3.0 M in THF) was slowly added dropwise to a 10.0 mL solution of tetrahydrofuran (1.0 g, 6.28 mmol) dissolved therein, and the mixture was stirred continuously at 0°C for 1 hour. After the reaction was complete, the mixture was quenched with a saturated aqueous ammonium chloride solution, extracted with ethyl acetate (40 mL × 3), dried, filtered, and concentrated under reduced pressure to obtain the crude product. 18C (380.0 mg, yield: 53.0%, yellow liquid) was obtained and used directly in the next step without the need for further purification.

[0382] 1 1H NMR (400 MHz, Chloroform- d ) δ 4.27 - 4.22 (m, 1H), 3.84 - 3.75 (m, 2H), 2.10 (s, 3H), 2.09 - 2.01 (m, 1H), 1.86 - 1.73 (m, 3H).

[0383] Step 3: Preparation of Compound 18D

[0384] At 0℃, compound 18C Sodium borohydride (253.0 mg, 6.67 mmol, 2.0 equiv) was added in batches to a tetrahydrofuran (5.0 mL) solution in which (380.0 mg, 3.33 mmol) was dissolved, the temperature was slowly raised to room temperature, and the mixture was stirred overnight. After the reaction was complete, the mixture was quenched with hydrochloric acid (1.0 N), extracted with ethyl acetate (10 mL × 3), the organic phase was collected, dried, filtered, and concentrated under reduced pressure to obtain the crude product. 18D(126.0 mg, yield: 33.0%, yellow liquid) was obtained and used directly in the next step without the need for further purification.

[0385] 1 1H NMR (400 MHz, Chloroform- d ) δ 4.57 - 4.39 (m, 1H), 3.76 - 3.67 (m, 1H), 3.65 - 3.58 (m, 1H), 3.58 - 3.39 (m, 2H), 1.87 - 1.65 (m, 4H), 1.04 - 0.97 (m, 3H).

[0386] Step 4: Preparation of Compound 18E

[0387] compound 18D (6.0 g, 51.72 mmol) and triethylamine (14.35 mL, 103.44 mmol, 2.0 equiv) were dissolved in dichloromethane (50.0 mL), 4-dimethylaminopyridine (634.0 mg, 5.2 mmol, 0.1 equiv) and p-toluenesulfonyl chloride (19.757 g, 103.44 mmol, 2.0 equiv) were added sequentially, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, the crude product obtained by vacuum concentration was separated and purified (ethyl acetate / petroleum ether = 0 to 10%) by column chromatography to obtain the compound. 18E (7.0g, yield: 50.1%, colorless liquid) was obtained. MS (ESI) m / z (M+ H) + = 271.

[0388] Step 5: Preparation of Compound 18F

[0389] Under an argon gas atmosphere, compounds 15B After stirring an N,N-dimethylformamide (10.0 mL) solution containing dissolved cesium carbonate (1.0 g, 3.46 mmol) and cesium carbonate (2256.0 mg, 6.92 mmol, 2.0 equiv) at room temperature for 5.0 minutes, 18E(1.4g, 5.19mmol, 1.5 equiv) was added and stirred at room temperature for 1.0 hour. After the reaction was complete, the mixture was quenched with a saturated aqueous ammonium chloride solution (100.0mL), extracted with ethyl acetate (30mL × 3), the organic phase was collected, dried with anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product, which was then purified by column chromatography (ethyl acetate / petroleum ether = 0 to 10%) to obtain a compound. 18F (1.0g, yield: 75.0%, yellow liquid) was obtained. MS (ESI) m / z (M+ H) + = 388.8.

[0390] Step 6: Preparation of Compound 18G

[0391] At room temperature, (1S,2S,3R,5S)-(+)-2,3-pinandiol (1.3g, 7.79mmol) was added to tetrahydrofuran (10mL) in which pinacol vinylboronate (1g, 6.49mmol) was dissolved, and the mixture was stirred for 20 hours. After the reaction was complete, the crude product obtained by concentrating under reduced pressure was separated and purified by column chromatography (PE:EA=9:1) to obtain the compound 18G (1.3g, yield: 97.15%) was obtained.

[0392] Step 7: Preparation of Compound 18H

[0393] compound 18F (1.0g, 2.58mmol), 18GA solution of acetonitrile (20.0 mL) containing tris[dibenzylideneacetone]dipalladium (738 mg, 3.1 mmol, 1.2 equiv), tri-tert-butylphosphine tetrafluoroborate (297.0 mg, 1.03 mmol, 0.4 equiv), and diisopropylethylamine (0.674 mL, 3.87 mmol, 1.5 equiv) was purged with argon gas four times, heated to 100°C, and stirred for 1.0 hour. After the reaction was complete, the mixture was filtered and concentrated under reduced pressure to separate and purify the crude product by column chromatography (ethyl acetate / petroleum ether = 0 to 15%) to obtain the compound. 18H (1.2g, yield: 90.8%) was obtained. MS (ESI) m / z (M+ H) + = 513.0

[0394] Step 8: Preparation of Compound 18I

[0395] compound 18H Tris(2-phenylpyridine)iridium (15.0 mg) was added to dichloromethane (6.0 mL) in which (300.0 mg) was dissolved, and after purging with argon gas four times, the mixture was stirred at room temperature for 2.0 hours under irradiation with blue light at a wavelength of 460 to 465 nm. After the reaction was completed, the crude product obtained by vacuum concentration was separated and purified (ethyl acetate / petroleum ether = 0 to 15%) by column chromatography to obtain the compound 18I (175.0 mg, yield: 58%) was obtained. MS (ESI) m / z (M+ H) + = 513.0

[0396] Step 10: Preparation of Compounds 18J-a, 18J-b, 18J-c, and 18J-d

[0397] compound 18IDiazomethane ether solution (40 mmol) was added to a tetrahydrofuran solution (60.0 mL) in which palladium acetate (92 mg, 0.41 mmol, 0.1 equiv) was dissolved (2.1 g, 4.1 mmol), and stirred at room temperature for 15 minutes. After the reaction was completed, the residue obtained by concentration under reduced pressure was separated and purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 0 to 5%), and the crude product obtained was further separated and purified by chiral chromatography. 18J-a (324.0mg), 18J-b (167.0 mg) was obtained.

[0398] Chiral separation conditions: Chromatography column: Daicel CHIRALPAK® IE250×30mm, 10μm; Mobile phase: n-hexane (0.2% DEA)-ethanol (0.2% DEA); ratio of mobile phase n-hexane to ethanol: 90:10 (V / V); flow rate 25.0 mL / min]

[0399] 18J-c (232.0mg), 18J-d (284.0mg)

[0400] Chiral separation conditions: Chromatography column: Daicel CHIRALPAK® IE250×30mm, 10μm; Mobile phase: [n-hexane(0.2%DEA)-ethanol(0.2%DEA)]; Ratio of n-hexane to ethanol in mobile phase: 95:05(V / V); Flow rate 25.0mL / min.

[0401] 18J-a : Retention time: t=25.930 min, HPLC: 99.72%;

[0402] 18J-b : Retention time: t=29.544 min, HPLC: 97.48%;

[0403] 18J-c : Retention time: t=5.123 min, HPLC: 91.2%;

[0404] 18J-d : Retention time: t=5.650 min, HPLC: 98.83%;

[0405] MS (ESI) m / z (M+ H) + = 527.0

[0406] Step 11: Preparation of Compounds 18-a, b, c, and d

[0407] compound 18J-a An aqueous sodium hydroxide solution (0.3 mL, 3.0 N) was added to acetonitrile (0.5 mL) in which (50.0 mg) was dissolved, and the mixture was stirred in an oil bath at 65°C for 3.0 hours. After the reaction was complete, the mixture was returned to room temperature, the pH was adjusted to 1 to 2 with hydrochloric acid, isobutylboric acid (30.0 mg) was added, and stirring continued for 10 minutes. After the reaction was complete, the mixture was separated and purified by high-performance preparative liquid chromatography to obtain the compound 18-a (16.7 mg) was obtained.

[0408] HPLC separation conditions Chromatography column: Welch Xtimate ® C18 21.2×250 mm; Column temperature: 25℃; Mobile phase: [Water (10.0 mM / L formic acid solution)-Acetonitrile]; Mobile phase acetonitrile ratio: 40% to 45%, 15 min; Flow rate 18.0 mL / min.

[0409] 1 ¹H NMR (400 MHz, DMSO-d6)δ 12.97 (s, 1H), 9.33 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 7.9 Hz, 1H), 3.84 - 3.70 (m, 2H), 3.61 (dt, J = 8.0, 6.6 Hz, 1H), 3.32 - 3.29 (m, 1H), 2.28 (td, J = 8.0, 4.0 Hz, 1H), 1.96 - 1.86 (m, 1H), 1.86 - 1.77 (m, 2H), 1.73 - 1.60 (m, 1H), 1.33 (ddd, J = 10.9, 7.9, 3.3 Hz, 1H), 1.14 (d, J = 6.9 Hz, 3H), 0.53 (ddd, J = 10.4, 8.0, 6.0 Hz, 1H), 0.32 (dt, J = 6.1, 3.7 Hz, 1H). MS (ESI) m / z (M+ H-18) + = 317.0

[0410] The synthesis of compound 18-b was performed using 18J-b as a starting material, and 15.9 mg of 18-b was obtained using the same manufacturing process as 18-a.

[0411] 1 ¹H NMR (400 MHz, DMSO-d6) δ 12.96 (s, 1H), 9.33 (s, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.11 (d, J = 7.9 Hz, 1H), 3.74 (dq, J = 14.2, 6.9 Hz, 2H), 3.63 (td, J = 7.6, 5.9 Hz, 1H), 3.24 (p, J = 6.7 Hz, 2H), 2.28 (td, J = 8.0, 4.0 Hz, 1H), 1.93 (dtd, J = 11.9, 7.1, 4.9 Hz, 1H), 1.85 - 1.74 (m, 2H), 1.66 - 1.56 (m, 1H), 1.33 (ddd, J = 11.0, 7.9, 3.4 Hz, 1H), 1.15 (d, J = 6.8 Hz, 3H), 0.54 (ddd, J = 10.5, 8.1, 6.1 Hz, 1H), 0.31 (dt, J = 6.4, 3.7 Hz, 1H). MS (ESI) m / z (M+ H-18) + = 317.0

[0412] The synthesis of compound 18-c was performed using 18J-c as the starting material, and 15.4 mg of 18-c was obtained using the same manufacturing process as 18-a.

[0413] 1 ¹H NMR (400 MHz, DMSO-d6) δ 12.97 (s, 1H), 9.33 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.11 (d, J = 8.0 Hz, 1H), 3.80 - 3.69 (m, 2H), 3.63 (td, J = 7.7, 5.9 Hz, 1H), 3.25 (t, J = 6.7 Hz, 1H), 2.28 (td, J = 7.9, 4.0 Hz, 1H), 2.00 - 1.85 (m, 1H), 1.86 - 1.72 (m, 3H), 1.65 - 1.55 (m, 1H), 1.33 (ddd, J = 10.9, 7.9, 3.4 Hz, 1H), 1.15 (d, J = 6.8 Hz, 3H), 0.53 (ddd, J = 10.5, 8.0, 6.1 Hz, 1H), 0.32 (dt, J = 6.0, 3.7 Hz, 1H). MS (ESI) m / z (M+ H-18) + = 317.0

[0414] The synthesis of compound 18-b was performed using 18J-d as a starting material, and 17.3 mg of 18-d was obtained using the same manufacturing process as 18-a.

[0415] 1 ¹H NMR (400 MHz, DMSO-d6)δ 12.97 (s, 1H), 9.33 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 3.88 - 3.69 (m, 2H), 3.61 (dt, J = 8.0, 6.6 Hz, 1H), 3.33 (s, 1H), 2.28 (td, J = 7.9, 4.0 Hz, 1H), 1.97 - 1.87 (m, 1H), 1.81 (dtt, J = 10.1, 7.3, 4.9 Hz, 2H), 1.73 - 1.62 (m, 1H), 1.33 (ddd, J = 11.0, 7.9, 3.4 Hz, 1H), 1.13 (d, J = 6.9 Hz, 3H), 0.53 (ddd, J = 10.5, 8.1, 6.1 Hz, 1H), 0.31 (dt, J = 6.0, 3.7 Hz, 1H). MS (ESI) m / z (M+ H-18) + = 317.0

[0416] Example 19: Synthesis of Compound 19

[0417]

[0418]

[0419]

[0420] Step 1: Preparation of Compound 19B

[0421] At room temperature, compounds 19A N,N-carbonyldiimidazole (8.74 g, 54 mmol) was added to a 100 mL solution of dichloromethane in which N,O-dimethylhydroxylamine hydrochloride (5.00 g, 49 mmol) and N,O-dimethylhydroxylamine hydrochloride (4.78 g, 49 mmol) were dissolved, and the mixture was stirred at room temperature for 16 hours. After the reaction was complete, water (100 mL) was added to quench the mixture, it was extracted with ethyl acetate (80 mL × 3), the organic phase was collected, washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to separate and purify the crude product by column chromatography (petroleum ether:ethyl acetate = 0 to 100%) to obtain the compound. 19B(6g, yield: 84.5%) was obtained.

[0422] Step 2: Preparation of Compound 19C

[0423] At 0°C, under a nitrogen gas atmosphere, compounds 19B A methyl magnesium bromide solution (13.1 mL, 1N, 13.1 mmol) was slowly added dropwise to a tetrahydrofuran solution (20 mL) in which 950 mg (6.55 mmol) of magnesium bromide was dissolved, and the mixture was stirred continuously for 2 hours. After the reaction was complete, the mixture was returned to room temperature, quenched with water (20 mL), extracted with ethyl acetate (30 mL × 3), the organic phase was collected, washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to separate and purify the crude product by column chromatography (petroleum ether:ethyl acetate = 1:1) to obtain the compound. 19C (650mg, yield: 90%) was obtained.

[0424] 1 ¹H NMR (400 MHz, CDCl3-d) δ 4.78 (m, 4H), 3.9 (m, 1H), 2.15 (s, 3H).

[0425] Step 3: Preparation of Compound 19D

[0426] At 0℃, compound 19C Sodium borohydride (451 mg, 11.88 mmol) was added in batches to a methanol (15 mL) solution in which [substance] was dissolved, and the mixture was stirred for 1 hour. After the reaction was complete, water (5 mL) was added to quench the mixture, it was extracted with ethyl acetate (30 mL × 3), the organic phase was combined, dried, filtered, and concentrated under reduced pressure to separate and purify the crude product by column chromatography (dichloromethane:methanol = 10:1) to obtain the compound. 19D (1.1g, yield: 70.5%) was obtained.

[0427] 1 ¹H NMR (400 MHz, DMSO-d6)δ 4.72-4.70 (d, 1H), 4.57-4.54 (m, 2H), 4.45-4.42 (t, 1H), 4.30-4.26 (t, 1H), 3.86-3.78 ((m, 1H), 2.85-2.76 (m, 1H), 0.97-0.95 (d, 3H).

[0428] Step 4: Preparation of Compound 19E

[0429] In an ice bath, compounds 19D Methylsulfonyl chloride (1.09 g, 9.56 mmol) was added to dichloromethane (6 mL) in which (750 mg, 7.35 mmol) and triethylamine (1.18 g, 11.76 mmol) were dissolved, and the mixture was stirred for 2 hours. After the reaction was complete, water was added to quench the mixture, extracted with ethyl acetate (50 mL × 3), washed with saturated saline solution, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. 19E (1.14g, yield: 86.4%) was obtained.

[0430] 1 ¹H NMR (400 MHz, DMSO-d6) δ 5.00 (m, 1H). 4.57-4.61 (m, 2H), 4.44-4.47 (t, 1H), 4.36-4.39 (t, 1H), 3.22 (s, 3H),3.24-3.15 ((m, 1H), 1.28-1.26 (d, 3H).

[0431] Step 5: Preparation of Compound 19F

[0432] Under a nitrogen gas atmosphere, compounds 19E (1.11g, 6.2mmol), 15BA 30 mL solution of N,N-dimethylformamide containing dissolved potassium carbonate (1.78 g, 6.2 mmol), potassium carbonate (1.71 g, 12.4 mmol), and potassium iodide (103 mg, 0.62 mmol) was heated to 90 °C and stirred continuously for 2 hours. After the reaction was complete, the mixture was cooled to room temperature, poured into ice water, extracted with ethyl acetate (150 mL × 3), the organic phase was combined, washed with saturated saline solution, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to separate and purify the crude product by column chromatography (petroleum ether / ethyl acetate = 5:1) to obtain the compound. 19F (1.67g, yield: 72.2%) was obtained. MS (ESI) m / z (M+ H) + = 375.0

[0433] Step 6: Preparation of Compound 19G

[0434] compound 19F A 30 mL solution of acetonitrile containing dissolved pinacol vinylboronate (1.5 g, 4.03 mmol), tris[dibenzylideneacetone]dipalladium (735 mg, 0.804 mmol), tri-tert-butylphosphine tetrafluoroborate (465 mg, 1.608 mmol), and diisopropylethylamine (777 mg, 6.06 mmol) was stirred at 90°C for 1 hour under a nitrogen gas atmosphere. After the reaction was complete, the solution was returned to room temperature, filtered, and concentrated under reduced pressure to separate and purify the crude product by column chromatography (petroleum ether / ethyl acetate = 4:3) to obtain the compound 19G (1.36g, yield: 75.9%) was obtained. MS (ESI) m / z (M+ H) + = 447.0

[0435] Step 7: Preparation of Compound 19H

[0436] At room temperature, compounds 19G(1R,2R,3S,5S)-(-)-2,3-pinandiol (2.06 g, 12.1 mmol) was added to (1.35 g, 3.03 mmol) of dissolved (tetrahydrofuran (30 mL))) and stirred for 16 hours. After the reaction was complete, the crude product obtained by concentration under reduced pressure was separated and purified using (petroleum ether / ethyl acetate = 5:1) to obtain the compound 19H (900 mg, yield: 59.6%) was obtained. MS(ESI)m / z:(M+H)+ = 499.0

[0437] Step 8: Preparation of Compound 19I

[0438] compound 19H Tris(diphenylpyridine)iridium (24 mg, 0.36 mmol) was added to dichloromethane (7 mL) in which (900 mg, 1.8 mmol) was dissolved, and irradiated with blue light (wavelength: 460 to 465 nm, 10 W) for 70 minutes under a nitrogen gas atmosphere. After the reaction was completed, the crude product obtained by vacuum concentration was separated and purified by column chromatography (petroleum ether / ethyl acetate = 3:1). 19I (550 mg, yield: 61%) was obtained. MS(ESI)m / z:(M+H)+ = 499.0

[0439] Step 9: Preparation of Compounds 19J-a, 19J-b, 19J-c, and 19J-d

[0440] At -20℃, under a nitrogen gas atmosphere, compounds 19I A diazomethane ether solution (20 mmol) was added to a THF (3 mL) solution in which (500 mg, 1 mmol) and Pd(OAc)2 (22 mg, 0.1 mmol) were dissolved, and the mixture was stirred for 16 hours. After the reaction was complete, the crude product obtained by concentration under reduced pressure was separated and purified (ethyl acetate / petroleum ether = 0 to 40%) by column chromatography to obtain the compound. 19J- A mixture (500 mg, yield: 97.6%) was obtained, which is a yellow oily substance, and was separated and purified by SFC to obtain four compounds.

[0441] 19J-a, 60mg, yellow solid, retention time: t=8.889min, MS(ESI)m / z:(M+H)+ = 513.0;

[0442] 19J-b , 69mg, yellow solid, retention time: t=9.890min, MS(ESI)m / z:(M+H)+ = 513.0;

[0443] 19J-c , 71mg, yellow solid, retention time: t=10.979min, MS(ESI)m / z:(M+H)+ =513.0;

[0444] 19J-d , 66mg, yellow solid, retention time: t=12.86min, MS(ESI)m / z:(M+H)+ = 513.0;

[0445] Chiral splitting condition: Chromatography column: Daicel CHIRALPAK® IB250×30mm, 10μm; Mobile phase A: n-hexane; Mobile phase B: isopropanol; Detection wavelength: 254nm; Flow rate: 25mL / min; Isothermal elution procedure: Mobile phase A:Mobile phase B=80:20(V / V).

[0446] Chiral splitting condition: Chromatography Column: Daicel CHIRALPAK® IB 250×4.6 mm, 5 μm; Mobile Phase A: n-hexane; Mobile Phase B: Ethanol; Detection Wavelength: 254 nm; Flow Rate: 1 mL / min; Column Temperature: 30 ℃; Time: 20 min; Isothermal Elution Procedure: Mobile Phase A:Mobile Phase B=80:20 (V / V).

[0447] Step 13: Preparation of Compounds 19-a, 19-b, 19-c, and 19-d

[0448] At room temperature, compounds 19J-aAn aqueous sodium hydroxide solution (3M, 330 μL) was added to a mixed solvent of acetonitrile (1 mL) and water (0.2 mL) in which (40 mg, 78.1 μmol) was dissolved, then the temperature was raised to 60°C and stirred for 3 hours. The reaction was cooled to room temperature, and triethylsilane (0.2 mL), trifluoroacetic acid (1.2 mL), and isobutylboric acid (24 mg, 0.234 mmol) were added to the reaction solution, and stirring was continued at room temperature for 1 hour. After the reaction was completed, the crude product obtained by vacuum concentration was separated and purified by HPLC to obtain the compound 19-a (18 mg, yield: 72%) was obtained.

[0449] 1 ¹H NMR (400 MHz, Methanol-d4) δ 7.25 (d, J = 7.9 Hz, 1H), 7.07 (d, J = 7.9 Hz, 1H), 4.63 (dd, J = 8.1, 6.2 Hz, 1H), 4.55 (dd, J = 7.9, 6.3 Hz, 1H), 4.37 (dt, J = 13.1, 6.5 Hz, 2H), 3.45 (dd, J = 9.9, 6.7 Hz, 1H), 3.05 - 2.91 (m, 1H), 2.20 (td, J = 8.0, 4.1 Hz, 1H), 1.28 (ddd, J = 10.3, 8.0, 3.6 Hz, 1H), 1.10 (d, J = 6.7 Hz, 3H), 0.51 (ddd, J = 10.4, 8.1, 6.2 Hz, 1H), 0.33 - 0.24 (m, 1H).HPLC 100.00%(254nM); retention time: t=5.379min. MS (ESI) m / z (M-1)- =321.3.

[0450] HPLC separation conditions: Chromatography column: Welch Xtimate ® C18 21.2×250 mm; Column temperature: 25℃; Mobile phase: [Water-Acetonitrile]; Mobile phase acetonitrile ratio: 30% to 35%, 15 min; Flow rate 18.0 mL / min.

[0451] Analysis conditions: Chromatography column: Waters X Bridge 4.6×100 mm, 3.5 μm; Column temperature: 40 ℃; Mobile phase A: Water (10.0 mM / L ammonium bicarbonate solution); Mobile phase B: Acetonitrile; Gradient: 5% to 95%, 7 min; Flow rate 1.0 mL / min.

[0452] The synthesis of compound 19-b was performed using 19J-b as a starting material, and 22 mg of 19-b was obtained using the same manufacturing process as 19-a.

[0453] 1 ¹H NMR (400 MHz, Methanol-d4) δ 7.26 (d, J = 7.9 Hz, 1H), 7.08 (d, J = 7.9 Hz, 1H), 4.64 (dd, J = 8.1, 6.2 Hz, 1H), 4.56 (dd, J = 7.9, 6.3 Hz, 1H), 4.37 (dt, J = 13.2, 6.5 Hz, 2H), 3.45 (dd, J = 9.9, 6.7 Hz, 1H), 3.05 - 2.94 (m, 1H), 2.21 (td, J = 8.0, 4.1 Hz, 1H), 1.30 (ddd, J = 10.4, 7.9, 3.6 Hz, 1H), 1.10 (d, J = 6.7 Hz, 3H), 0.52 (ddd, J = 10.4, 8.1, 6.2 Hz, 1H), 0.29 (dt, J = 6.2, 3.8 Hz, 1H). MS (ESI) m / z (M+ H-18) + = 321.3

[0454] The synthesis of compound 19-c was performed using 19J-c as the starting material, and 12 mg of 19-c was obtained using the same manufacturing process as 19-a.

[0455] 1 ¹H NMR (400 MHz, Methanol-d4)δ 7.25 (d, J = 7.9 Hz, 1H), 7.08 (d, J = 7.9 Hz, 1H), 4.63 (dd, J = 8.1, 6.2 Hz, 1H), 4.55 (dd, J = 7.9, 6.3 Hz, 1H), 4.36 (dt, J = 18.3, 6.4 Hz, 2H), 3.45 (dd, J = 9.9, 6.7 Hz, 1H), 2.98 (dddd, J = 9.8, 8.0, 6.6, 1.4 Hz, 1H), 2.21 (td, J = 8.0, 4.2 Hz, 1H), 1.29 (ddd, J = 11.1, 8.0, 3.6 Hz, 1H), 1.10 (d, J = 6.7 Hz, 3H), 0.52 (ddd, J = 10.4, 8.1, 6.2 Hz, 1H), 0.28 (dt, J = 6.2, 3.9 Hz, 1H). MS (ESI) m / z (M+ H-18) + = 321.3.

[0456] The synthesis of compound 19-d was performed using 19J-d as a starting material, and 7 mg of 19-d was obtained using the same manufacturing process as 19-a.

[0457] 1 ¹H NMR (400 MHz, Methanol-d4) δ 7.24 (d, J = 7.9 Hz, 1H), 7.05 (d, J = 7.9 Hz, 1H), 4.63 (dd, J = 8.1, 6.2 Hz, 1H), 4.55 (dd, J = 7.9, 6.3 Hz, 1H), 4.36 (dt, J = 17.6, 6.5 Hz, 2H), 3.45 (dd, J = 9.9, 6.7 Hz, 1H), 3.01 - 2.91 (m, 1H), 2.18 (td, J = 8.0, 4.0 Hz, 1H), 1.26 (ddd, J = 11.2, 7.9, 3.5 Hz, 1H), 1.10 (d, J = 6.7 Hz, 3H), 0.50 (ddd, J = 10.4, 8.2, 6.2 Hz, 1H), 0.28 (dt, J = 6.2, 3.8 Hz, 1H). MS (ESI) m / z (M+ H-18) + = 321.3.

[0458] Example 20: Synthesis of Compound 20

[0459]

[0460] Step 1: Preparation of Compound 20B

[0461] At 0℃, compound 20A Sodium borohydride (782 mg, 21 mmol) was added to a methanol (500 mL) solution in which 4 g (20 mmol) was dissolved, and the mixture was stirred for 2 hours. After the reaction was complete, the methanol was removed by concentration under reduced pressure, a potassium hydroxide solution was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phase was washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to separate and purify the crude product using column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the compound. 20B (3.7g, yield: 91.57%) was obtained.

[0462] Step 2: Preparation of Compound 20C

[0463] At 0℃, compound 20B Carbon tetrabromide (7.3g, 22.1mmol) was added in batches to dichloromethane (50mL) in which (3.7g, 18.4mmol) and triphenylphosphine (5.8g, 22.1mmol) were dissolved, then the temperature was slowly raised to room temperature and stirred continuously for 16 hours. After the reaction was complete, the crude product obtained by concentrating under reduced pressure was separated and purified by column chromatography (petroleum ether / ethyl acetate = 5:1). 20C (3.3g, yield: 67.95%) was obtained.

[0464] Step 3: Preparation of Compound 20D

[0465] compound 20C (3.3g, 12.5mmol) and 15B (3.6g, 12.5mmol) dissolved N,N-Potassium carbonate (5.2 g, 37.5 mmol) was added to a dimethylformamide (50 mL) solution, the mixture was replaced with nitrogen gas, heated to 60°C, and stirred for 6 hours. After the reaction was complete, the solution was diluted with ethyl acetate, filtered, and concentrated under reduced pressure to separate and purify the crude product using column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain the compound. 20D (3.9g, yield: 66.09%) was obtained. MS (ESI) m / z (M- H) + = 472.0

[0466] Step 4: Preparation of Compound 20E

[0467] compound 20D A solution of acetonitrile (9 mL) containing dissolved tri-tert-butylphosphine tetrafluoroborate (870 mg, 1.8 mmol), N,N-diisopropylethylamine (250 mg, 1.9 mmol), tri-tert-butylphosphine tetrafluoroborate (213 mg, 0.7 mmol), tris[dibenzylideneacetone]dipalladium (337 mg, 0.4 mmol), and pinacol vinylboronate (1.42 g, 9.2 mmol) was reacted by heating at 90°C for 1 hour under a nitrogen gas atmosphere. After the reaction was complete, the compound was diluted with ethyl acetate, filtered, and concentrated under reduced pressure. 20E The crude product (1g) was used directly in the next step without the need for purification. MS (ESI) m / z (M- H) + = 546.2

[0468] Step 5: Preparation of Compound 20F

[0469] compound 20E A 20 mL solution of tetrahydrofuran in which (1.5 g, 2.8 mmol) and (1S,2S,3R,5S)-(+)-2,3-pinandiol (2.3 g, 13.8 mmol) were dissolved was stirred at room temperature for 4 hours. After the reaction was complete, the compound obtained by concentrating under reduced pressure 20FThe crude product is purified using a C18 reverse-phase column (MeCN:0.2% NH4HCO3 = 5% to 95%), and the obtained crude product is separated and purified using normal-phase column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the compound 20F (1g, yield: 60.86%) was obtained. MS (ESI) m / z (M- H) + = 598.2

[0470] Step 6: Preparation of Compound 20G

[0471] compound 20F (200 mg, 0.33 mmol) and tris(2-phenylpyridine)iridium (11 mg, 0.02 mmol) were dissolved in acetonitrile (6 mL), replaced with nitrogen gas, and stirred at room temperature for 1 hour under 10 W blue light. After the reaction was complete, the crude product obtained by vacuum concentration was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain the compound 20G (105 mg, yield: 52.50%) was obtained. MS (ESI) m / z (M- H) + = 598.2

[0472] Step 7: Preparation of Compounds 20H-a, 8b, 8c, and 8d

[0473] compound 20G (645 mg, 1.1 mmol) and palladium acetate (24 mg, 0.1 mmol) were dissolved in tetrahydrofuran (15 mL), and after purging with nitrogen gas, a diazomethane ether solution (7.2 mL, 21.6 mmol) was added at 0 °C and stirred at room temperature for 1 hour. After the reaction was complete, dichloromethane was added to dilute the mixture, the solid was removed by filtration, and the filtrate was concentrated under reduced pressure. The crude product obtained by separation and purification was then separated by column chromatography (petroleum ether / ethyl acetate = 4.5:1), and the crude product (550 mg, yield: 83.32%) was further subjected to chiral separation to obtain 94 mg of 20H-a , 50mg of 20H-b , 54mg of 20H-c , 112mg of 20H-d obtained. MS (ESI) m / z (M- H) + = 612.2. Time of stay: 20H-a : t=10.620min; 20H-b : t=9.075min; 20H-c : t=10.741min; 20H-d : t=14.542min.

[0474] 20H-a, 20H-d Chiral Splitting Conditions: Chromatography Column: Daicel CHIRALPAK® IE 250×30 mm, 10 μm; Mobile Phase A: n-hexane (0.2% DEA); Mobile Phase B: Isopropanol (0.2% DEA); Detection Wavelength: 254 nm; Flow Rate: 25 mL / min; Isothermal Elution Procedure: Mobile Phase A:Mobile Phase B = 85:15 (V / V).

[0475] Chiral Analysis Conditions: Chromatography Column: Daicel CHIRALPAK® IE 250×4.6 mm, 5 μm; Mobile Phase A: n-hexane (0.2% DEA); Mobile Phase B: isopropanol (0.2% DEA); Detection Wavelength: 254 nm; Flow Rate: 1 mL / min; Isothermal Elution Procedure: Mobile Phase A:Mobile Phase B = 85:15 (V / V).

[0476] 20H-b, 20H-c Chiral Splitting Conditions: Chromatography Column: Daicel CHIRALPAK® IC 250×30 mm, 10 μm; Mobile Phase A: n-hexane; Mobile Phase B: isopropanol; Detection Wavelength: 254 nm; Flow Rate: 25 mL / min; Isothermal Elution Procedure: Mobile Phase A:Mobile Phase B=60:40 (V / V).

[0477] Chiral Analysis Conditions: Chromatography Column: Daicel CHIRALPAK® IE 250×4.6 mm, 5 μm; Mobile Phase A: n-hexane (0.2% DEA); Mobile Phase B: Isopropanol (0.2% DEA); Detection Wavelength: 254 nm; Flow Rate: 1 mL / min; Isothermal Elution Procedure: Mobile Phase A:Mobile Phase B = 60:40 (V / V) (V / V).

[0478] Step 8: Preparation of Compounds 20I-a, b, c, and d

[0479] At 0℃, compound 20H-a 2,6-dimethylpyridine (42 mg, 0.39 mmol) and trimethylsilyl trifluoromethanesulfonate (106 mg, 0.59 mmol) were sequentially added to a 3 mL solution of dichloromethane in which 60 mg (0.1 mmol) was dissolved, and the mixture was stirred for 2 hours. After the reaction was completed, the crude product obtained by concentrating under reduced pressure was separated and purified by column chromatography (DCM:MeOH(0.1%NH3)=9:1) to obtain the compound 20I-a (50mg, yield: 99.64%) was obtained.

[0480] Step 9: Preparation of Compounds 20I-a, b, c, and d

[0481] At room temperature, compounds 20I-a An aqueous formaldehyde solution (0.3 mL) was added to a dichloromethane solution (1 mL) in which (50 mg, 0.1 mmol) was dissolved. After stirring at room temperature for 1 hour, sodium triacetylborohydride (41 mg, 0.2 mmol) was added to the reaction solution and stirring continued for 1 hour. After the reaction was complete, a saturated sodium bicarbonate solution was added to quench the mixture, extracted with ethyl acetate (10 mL × 3), the organic phase was combined, washed with saturated saline, dried with anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to separate and purify the crude product by column chromatography (DCM:MeOH(0.1%NH3)=9:1) to obtain the compound. 20I-a (33 mg, yield: 64.24%) was obtained. MS (ESI) m / z (M- H) + = 526.0

[0482] Step 10: Preparation of Compounds 20-a, b, c, and d

[0483] compound 20I-aWater (0.1 mL) and a 3N sodium hydroxide solution (188 μL, 0.57 mmol) were sequentially added to an acetonitrile (1 mL) solution in which (33 mg, 0.06 mmol) was dissolved, and the mixture was stirred at 60°C for 4 hours. TFA (0.5 mL), triethylsilane (0.1 mL), and isobutylboric acid (19 mg, 0.19 mmol) were sequentially added to the reaction system and stirred continuously for 1 hour. After the reaction was completed, the pH was adjusted to approximately 6, and the crude product obtained by vacuum concentration was separated and prepared by HPLC to obtain a crude product compound (12 mg, yield: 72.6%). 0.5 mL of water was added to this, and 3M sodium hydroxide (19.8 μL, 0.059 mmol) was further added, and the mixture was stirred at 60°C for 1 hour. The compound was purified using a C18 reversed-phase column (separation conditions: chromatography column: Redi-GOLD ® C18 10μm 33×147mm; mobile phase: [water-acetonitrile]; flow rate: 30mL / min). 20-a (6.59 mg, yield: 26.6%) was obtained. Retention time: t=1.798 min. 1 H NMR (400 MHz, Deuterium Oxide) δ 7.10 (d, J = 7.6 Hz, 1H), 6.90 (d, J = 7.8 Hz, 1H), 4.25 - 4.10 (m, 1H), 4.06 - 3.96 (m, 1H), 3.84 - 3.77 (m, 1H), 3.73 - 3.62 (m, 1H), 3.34 (dt, J = 21.6, 7.5 Hz, 1H), 2.97 - 2.84 (m, 1H), 2.74 (d, J = 25.9 Hz, 3H), 1.96 (s, 1H), 1.07 (dd, J = 15.2, 6.8 Hz, 4H), 0.31 (d, J = 26.1 Hz, 2H). MS (ESI) m / z (M- H) + = 334.2.

[0484] Examples 20-b to 34-b were synthesized similarly to the synthesis of Example 20-a, as shown in Table 1 below.

[0485]

[0486]

[0487]

[0488]

[0489]

[0490]

[0491]

[0492]

[0493]

[0494]

[0495]

[0496]

[0497]

[0498]

[0499]

[0500] Test Example 1: Enzyme Activity Test

[0501] Stock solution of the compound The compound was prepared with a 50 mM DMSO stock solution. The positive control compound VNRX-5133 was prepared with a 50 mM DMSO stock solution. The compound stock solutions were dispensed and stored at -20℃.

[0502] Preparation and Storage of Antibiotic Substrate Stock Solutions : The antibiotic fluorescent substrate FC5 was synthesized internally, prepared as a 2 mM stock solution, dispensed, and stored at -20℃.

[0503] Storage of β-lactamase Each β-lactamase was synthesized by GenScript Biotech Co., Ltd. and stored at -80℃ after dispensing to avoid repeated freezing and thawing.

[0504] Preparation of enzyme activation reaction bufferSBL buffer: PBS pH 7.4, 0.01% (v / v) Triton X-100; MBL buffer: 50 mM HEPES in PBS pH 7.2, 1 μM ZnSO4, 1 μg / mL BSA, 0.01% v / v Triton X-100

[0505] The buffer solution was stored at 4℃.

[0506] Experimental phase:

[0507] a) Take out the compound and buffer solution to be tested and raise the temperature to room temperature.

[0508] b) Each compound was diluted with DMSO and buffer to the initial experimental concentration (Table 2), and then the compounds were diluted three-fold to a total of 10 concentrations.

[0509] c) 5 μL of the diluted compound was added to wells 1 through 20 of a 384-well black plate at each concentration in double wells. 5 μL of DMSO was added to wells 21 through 24, respectively.

[0510] d) Each enzyme was diluted to the experimental concentrations (Table 2) in SBL and MBL buffers, and finally 35 μL / well was added, for a total of 22 wells. 35 μL of buffer was added to wells 23 to 24. Here, wells 21 to 22 were set as the maximum test value (Max), and wells 23 to 24 were set as the minimum test value (Min).

[0511] e) Rapidly centrifuge and incubate at room temperature for 10 minutes.

[0512] f) Antibiotic substrate FC5 was diluted in buffer solution to the experimental concentration of each enzyme (Table 2).

[0513] g) After removing the 384-well plate from which culture was complete, 10 μL of FC-5 was added to wells 1 to 24 per well. After rapid centrifugation, the plates were quickly transferred to a microplate reader for reading.

[0514] h) Fluorescence intensity was measured at 355 nm excitation light / 460 nm emission light using a microplate reader, and a total of 10 fluorescence intensity measurements were taken every 3 minutes.

[0515] The test concentrations are as shown in Table 2 below.

[0516]

[0517] Enzyme reaction initial rate V After subtracting the background reading (Min well) without enzyme from each fluorescence intensity reading, linear regression analysis was performed on the concentration group of each compound, and the slope is the initial rate (V) of the enzyme reaction at each compound concentration.

[0518] Compound Dose-Response Curve and IC50 50 Calculation of: Formula IC50 by nonlinear regression fitting of the initial enzyme reaction rate under the action of each compound concentration 50 IC50, the half-inhibition concentration of a compound, according to =(1-Vi / V0)x100(Vi: initial enzyme reaction rate at each compound concentration, V0: initial enzyme reaction rate without compound addition (Maxwell)). 50 It was calculated, and the software used was Graphpad Prism 8.

[0519]

[0520] As shown in Table 3, the compounds of the present invention can effectively inhibit four classes of β-lactamase compounds, A, B, C, and D, and were found to have a significant advantage in inhibitory activity compared to the compound VNRX-5133. Avibactam, a commercially available drug, showed better activity against class A and class C serine β-lactamase (SBL), but had no inhibitory effect against class B metal zinc ion β-lactamase (MBL) and was found to have lower inhibitory activity against class D serine β-lactamase.

[0521] Test Example 2: Minimum Inhibitory Concentration (MIC) Test of a Compound for Bacterial Growth

[0522] (1) Major reagents and consumables:

[0523]

[0524] (2) Strain:

[0525]

[0526] (3) Experimental method

[0527] Preparation of strains The strain to be tested was inoculated by streaking onto a Mueller Hinton II Agar plate in a glycerol tube at -80°C. It was placed in a 37°C incubator and cultured for 18 to 24 hours.

[0528] Preparation of badges : CAMHB (Mueller Hinton II Broth): 22g of powder was dissolved in 1L of pure water and sterilized at 121°C for 10 minutes for later use. Physiological saline: 8.5g of NaCl was dissolved in 1L of pure water and sterilized at 121°C for 30 minutes for later use.

[0529] Preparation of Compounds and Antibiotic Mother Solution: The compound and antibiotic were dissolved in DMSO or water at a concentration of 12.8 mg / mL.

[0530] 2-fold gradient dilution of antibiotics 300 μL of CAMHB medium was added to columns 2–12 of a 96-deep-well plate. 24 μL of antibiotic stock solution and 576 μL of CAMHB medium were added to column 1 and mixed uniformly, with a concentration of 512 μg / mL. 300 μL of antibiotic solution from column 1 was transferred to column 2 and mixed uniformly. This process was repeated up to column 11, and column 12 served as a blank control.

[0531] Dilution of co-administered compounds The compound was diluted 400-fold to 32 µg / ml in CAMHB medium.

[0532] Preparation of the working solutionUsing a pipette, 25 μL of antibiotic was dispensed onto a 96-U bottom plate, and 25 μL of the combination compound was added to each well. When using the antibiotic alone, 25 μL of CAMHB medium was added.

[0533] Preparation of inoculum solution Five to six single colonies were selected from the plate and suspended in physiological saline. Using a turbidimeter, the bacterial suspension was measured at 0.2 (i.e., McFarland turbidity 0.5, bacterial concentration approximately 1 to 2 x 10⁻⁶). 8 It was adjusted to (CFU / mL). The bacterial suspension was diluted 100-fold with CAMHB medium for later use.

[0534] inoculation : 50 μL of inoculum solution was transferred to the 50 μL compound plate using a pipette.

[0535] culture : 96-U bottom plates were placed in an incubator at 37°C and cultured for 18 to 20 hours.

[0536] (4) MIC Evaluation:

[0537] After the incubation was complete, bacterial growth was observed visually, and the test plates were photographed, recorded, and stored. The minimum concentration of a compound that completely inhibits bacterial growth was defined as the Minimum Inhibitory Concentration (MIC).

[0538]

[0539]

[0540]

[0541]

[0542]

[0543]

[0544]

[0545]

[0546]

[0547]

[0548] As shown in Table 6, the compounds of the present invention were found to be able to effectively restore the activity of the antibiotics cefepim / meropenem / viapenem against carbapenem-resistant Acinetobacter baumannii strains. VNRX5133 + cefepim / meropenem was basically ineffective against all Acinetobacter baumannii-resistant strains (MIC≥32μg / mL), while the compounds of the present invention + meropenem / viapenem were effective against all resistant strains and showed a significant advantage in the activity and inhibition spectrum compared to the combination of VNRX5133 + cefepim.

Claims

Claim 1 Compound of formula (I) below, its optical isomer, or its pharmaceutically acceptable salt: ,in the above equation, X is selected from S, S(=O) and S(=O)2; and L1 is C 1-6 Alkyl and C 1-6 Selected from heteroalkyl, and C 1-6 alkyl or C 1-6 The heteroalkyl group is optionally substituted by 1, 2, or 3 R groups; L2 is a single bond, C 3-6 Selected from cycloalkyl and quaternary to ninth-membered heterocycloalkyl, and said C 3-6 Cycloalkyl or quaternary to ninth-membered heterocycloalkyl is optionally substituted by 1, 2, or 3 Rs; L3 is a single bond, C 1-6 Alkyl, and C 1-6 Selected from heteroalkyl, and C 1-6 alkyl, or C 1-6 The heteroalkyl group is optionally substituted by 1, 2, or 3 R groups; R1 is NH2, -NR a C(=NH)R b , -NR a C(=NH)NR b1 R b2 , -C(=NH)R b , C 3-6 Selected from cycloalkyl, tetrocycloalkyl, partially unsaturated tetrocycloalkyl, and zetroaryl, and hexacycloalkyl, and C 3-6 The cycloalkyl, tetrocycloalkyl, partially unsaturated tetrocycloalkyl, or zetroaryl heterocycloalkyl is optionally substituted by 1, 2, or 3 Rs; R is independently H, F, Cl, Br, OH, NH2, CN, and C 1-6 Selected from alkyl;R a , R b1 , and R b2 H and C, respectively, independently 1-6 Selected from alkyl; R b is independently H, NH2, and C 1-6 Selected from alkyl; said C 1-6 The heteroalkyl, quaternary to ninth heterocycloalkyl, partially unsaturated quaternary to eighth heterocycloalkyl or quinary to sixth heteroaryl independently comprises one, two, or three heteroatoms or heteroatom groups selected from O, NH, S, C(=O), C(=NH), C(=O)O, S(=O), S(=O)2, and N. Claim 2 In claim 1, the compound of formula (I) is a compound of formula (IA) or formula (IB), and , , in the above formula, X, L1, L2, L3 and R1 are compounds as defined in claim 1, optical isomers thereof, or pharmaceutically acceptable salts thereof. Claim 3 In paragraph 1, R is each independently F, Cl, Br, OH, NH2, CH3, and A compound selected from, its optical isomer, or its pharmaceutically acceptable salt. Claim 4 delete Claim 5 In paragraph 1, L1 is C 1-3 Alkyl, -C 1-3 Alkyl-O-, -C 1-3 Alkyl-S-, -C 1-3 Alkyl-NH- and -C 1-3 Selected from alkyl-C(=O)-, and said C 1-3 Alkyl, -C 1-3 Alkyl-O-, -C 1-3 Alkyl-S-, -C 1-3 Alkyl-NH- or -C 1-3 Alkyl-C(=O)- is a compound optionally substituted by 1, 2, or 3 R groups, its optical isomers, or pharmaceutically acceptable salts thereof. Claim 6 In paragraph 5, L1 is CH2, , , , , , , and Selected from, and the above CH2, , , , , , , or is a compound optionally substituted by 1, 2, or 3 Rs, its optical isomer, or its pharmaceutically acceptable salt. Claim 7 In paragraph 6, L1 is CH2, , , , , , , , , , , and A compound selected from, its optical isomer, or its pharmaceutically acceptable salt. Claim 8 In claim 1, L2 is selected from single bonds, cyclobutyl, cyclopentyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, and 2,6-diazaspiro[3.3]heptyl, wherein said cyclobutyl, cyclopentyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, or 2,6-diazaspiro[3.3]heptyl is a compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof in which 1, 2, or 3 Rs are optionally substituted. Claim 9 In paragraph 8, L2 is a single combination, , , , , , and A compound selected from, its optical isomer, or its pharmaceutically acceptable salt. Claim 10 In paragraph 1, L3 is a single bond, C(=O), C 1-3 Alkyl, -C 1-3 Alkyl-C(=O)- and -C 1-3 Selected from alkyl-C(=O)NH-, and said C 1-3 Alkyl, -C 1-3 Alkyl-C(=O)- or -C 1-3 A compound in which alkyl-C(=O)NH- is optionally substituted by 1, 2 or 3 R groups, its optical isomers or pharmaceutically acceptable salts thereof. Claim 11 In Clause 10, L3 is a single bond, C(=O), , , , , and A compound selected from, its optical isomer, or its pharmaceutically acceptable salt. Claim 12 In paragraph 1, R1 is NH2, , , , , , , cyclopropyl, cyclobutyl, oxetanil, azetidinyl, pyrrolidinyl, tetrahydrofuranil, tetrahydro-2H-pyranil, morpholinil, piperidinyl, piperazinil, octahydrocyclopentadiene[c]pyrrolyl, 4,5-dihydro-1H-imidazolyl, imidazolyl, imidazoline-2-imino, tetrahydropyrimidine-2(1H)-imino, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 6-oxa-2-azspiro[3.4]octyl, 2,6-diazaspiro[3.4]octyl, Selected from 3,6-diazabicyclo[3.1.1]heptyl and 2,5-diazabicyclo[2.2.1]heptyl, and said cyclopropyl, cyclobutyl, oxetanil, azetidinyl, pyrrolidinyl, tetrahydrofuranil, tetrahydro-2H-pyranil, morpholinil, piperidinyl, piperazinyl, octahydrocyclopentadiene[c]pyrrolyl, 4,5-dihydro-1H-imidazolyl, imidazolyl, imidazoline-2-imino, tetrahydropyrimidine-2(1H)-imino, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 2,6-diazaaspiro[3.4]octyl, 3,6-diazabicyclo[3.1.1]heptyl or 2,5-diazabicyclo[2.2.1]heptyl are compounds optionally substituted by 1, 2 or 3 Rs, their optical isomers or pharmaceutically acceptable salts. Claim 13 In Paragraph 12, R1 is NH2, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and Selected from, and the above , , , , , , , , , , , , , , , , , , , , , , , , , , , , or is a compound optionally substituted by 1, 2, or 3 Rs, its optical isomer, or its pharmaceutically acceptable salt. Claim 14 In Paragraph 13, R1 is NH2, , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and A compound selected from, its optical isomer, or its pharmaceutically acceptable salt. Claim 15 In Paragraph 7, structural unit Is , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , and A compound selected from, its optical isomer, or its pharmaceutically acceptable salt. Claim 16 Compounds of the formula selected from the following, optical isomers thereof, or pharmaceutically acceptable salts thereof: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . Claim 17 Compounds of the formula selected from the following, optical isomers thereof, or pharmaceutically acceptable salts thereof: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , . Claim 18 A pharmaceutical composition for treating bacterial infectious diseases, wherein the pharmaceutical composition comprises a compound according to any one of claims 1 to 3 and claims 5 to 17, an optical isomer thereof, or a pharmaceutically acceptable salt thereof. Claim 19 In claim 18, the pharmaceutical composition further comprises another β-lactam antibiotic. Claim 20 In claim 19, the above-mentioned β-lactam antibiotic is selected from penicillin, cephalosporin, carbapenem, monocyclic β-lactam antibiotic, or a combination thereof, in a pharmaceutical composition. Claim 21 A pharmaceutical composition according to claim 20, wherein the penicillin antibiotic is selected from acid-resistant penicillin, enzyme-resistant penicillin, ampicillin, amoxicillin, pivampicillin, carbenicillin, sulbenicillin, ticarcillin, furbenicillin, azlocillin, and piperacillin; optionally, the cephalosporin antibiotic is selected from cephalexin, cefradine, cefazolin, ceproxim, cefamandol, cefachlor, cefotaxim, ceftazidime, ceftriaxone, cefoperazone, ceftizoxime, cefepim, cefpirom, and ceftolozane; optionally, the carbapenem antibiotic is selected from imipenem, meropenem, panipenem, viapenem, ertapenem, and paropenem; and optionally, the monocyclic β-lactam antibiotic is selected from aztreonam.

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