Tricyclic boronic acid derivatives and methods for their preparation and use

Abstract

The present invention discloses tricyclic boronic acid derivatives and their preparation and use, and in particular, discloses a compound represented by formula (I), its optical isomers and pharma- ceutically acceptable salts, as well as the use of said compounds as β-lactamase inhibitors and compositions as antibacterial medicaments. JPEG2024540953000125.jpg2950

Description

[Technical Field]

[0001] The present invention belongs to the field of medicinal chemistry, and specifically relates to a compound represented by formula (I), its optical isomers and pharmaceutically acceptable salts thereof, as well as the use of the compound as a β-lactamase inhibitor and the composition as an antibacterial medicament. [Background technology]

[0002] This application claims priority to: CN202111217905.0, the filing date is October 19, 2021; CN202211255968.X, filing date is October 13, 2022.

[0003] The widespread use and overuse of antibiotics has led to the rapid evolution of pathogenic bacteria's ability to resist antimicrobial drugs, resulting in the emergence of numerous drug-resistant, multidrug-resistant, and even superbug strains. Bacterial drug resistance has become a major challenge to global public health. According to the 2014 "The Review on Antimicrobial Resistance," 700,000 people currently die each year from antibiotic resistance. China's bacterial resistance rate is much higher than that of Western countries, at approximately 45%. More than 80,000 people die each year from drug-resistant bacterial infections in China. If the current situation does not improve and new antibiotics for drug-resistant bacteria are not developed, it is expected that by 2050, China will experience one million deaths each year and a GDP loss of more than $20 trillion.

[0004] Beta-lactam antibiotics are currently the most important antibacterial drugs in clinical practice, accounting for more than 50% of the total market. Beta-lactam antibiotics refer to a large class of antibiotics with a beta-lactam ring in their chemical structure. These include the most commonly used penicillins and cephalosporins, as well as other atypical beta-lactam antibiotics such as carbapenems and monocyclic beta-lactams. This type of antibiotic has the advantages of potent bactericidal activity, low toxicity, a wide range of indications, and excellent clinical efficacy. The mechanism of action of beta-lactam antibiotics is similar: they inhibit the synthesis of cell wall mucin by inhibiting cell wall mucin synthesis enzymes, i.e., penicillin-binding proteins, resulting in bacterial cell wall defects and swelling and lysis of bacterial cells.

[0005] One of the major mechanisms of bacterial resistance to β-lactam antibiotics is the production of β-lactamases. Over 2,800 β-lactamases have been reported to date. They differ in many aspects, including source, substrate, inhibitor, and structure. In 1980, Ambler classified β-lactamases into four categories based on their molecular structure, based on amino acid sequence analysis: Category A penicillinases, Category B metallo-β-lactamases, Category C cephalosporinases, and Category D oxacillinases. The active groups of Categories A, C, and D are serine (SBL), while those of Category B are metal zinc ions (MBL).

[0006] β-lactamase inhibitors can bind to and inactivate β-lactamase enzymes. Clinically, combining them with β-lactam antibiotics can inhibit drug-resistant bacteria, reduce dosage, broaden the antibacterial spectrum, and enhance antibacterial activity. To date, six β-lactamase inhibitors have been approved by the FDA, but all have significant limitations and are unable to effectively treat MBL-mediated superbug resistance. Clavulanic acid, sulbactam, and tazobactam inhibit only some 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 antibiotics except for monocyclic β-lactams, including penicillin, cephalosporins, extended-spectrum cephalosporins, and carbapenems. According to the China Bacterial Resistance Surveillance Network (CHINET), resistance to carbapenem antibiotics such as meropenem accounted for 26.3%, 25.8%, and 73.9% of Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter strains clinically isolated in China in 2018. Among these, the resistance rate to meropenem increased from 2.9% in 2005 to 26.3%, while the resistance rate for Acinetobacter baumannii increased from 41.3% in 2005 to 73.9%. Acinetobacter baumannii possesses a strong ability to acquire and clonally spread drug resistance, making it an important pathogen in hospital-acquired infections. The WHO's priority list for developing effective drugs against antibiotic-resistant bacteria ranks carbapenem-resistant Acinetobacter baumannii at a very high priority. Carbapenems are the last line of defense against bacterial infections, but the emergence of drug resistance has left available options severely limited and in some cases even unavailable. Therefore, there is an urgent clinical need for new antibiotics to overcome the treatment dilemma and solve the increasingly prominent challenge of drug resistance.

[0007] There are many mechanisms underlying bacterial resistance, which can be summarized as follows: (1) Changes in the permeability of the bacterial cell wall or outer membrane, such as decreased expression of porins and increased expression of efflux pumps, prevent or limit the penetration of β-lactam antibiotics into the bacterial cell wall. The outer membrane of Gram-negative bacteria is the first barrier limiting the penetration of β-lactam antibiotics into the bacterial cell. (2) Mutations in target proteins can lead to decreased antibiotic binding, increased target proteins, or the production of new target proteins. For example, methicillin-resistant Staphylococcus aureus exhibits high resistance due to the generation of a new PBP2' between the original PBP2 and PBP3, while low and moderate resistance is caused by increased production of PBPs or decreased affinity for methicillin. (3) Bacteria produce β-lactamases to hydrolyze and inactivate antibiotics, or they bind to the antibiotic and remain in the extracellular space, preventing it from entering the cell and binding to the target protein. The main resistance mechanism for Gram-positive bacteria is the generation of β-lactamases and PBP mutations, whereas the main resistance mechanism for Gram-negative bacteria is the generation of β-lactamases. Summary of the Invention

[0008] In a first aspect, the present invention provides a compound represented by formula (I), an optical isomer thereof, and a pharmaceutically acceptable salt thereof. [ka] where: X is selected from S, S(=O) and S(=O)2; L1 is a single bond, C 1-6 Alkyl and C 1-6 heteroalkyl, wherein C 1-6 Alkyl or C 1-6 heteroalkyl is optionally substituted by 1, 2 or 3 R; L2 is a single bond, C 3-6 cycloalkyl and 4- to 9-membered heterocycloalkyl, 3-6the cycloalkyl or 4- to 9-membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; L3 is a single bond, C 1-6 Alkyl, C 1-6 heteroalkyl and 4- to 9-membered heterocycloalkyl, 1-6 Alkyl, C 1-6 heteroalkyl or 4- to 9-membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; R1 is NH2, [ka] , -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 cycloalkyl, 4- to 8-membered heterocycloalkyl, partially unsaturated 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; 1-6 Alkyl, C 3-6 The cycloalkyl, 4- to 8-membered heterocycloalkyl, partially unsaturated 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heteroaryl is optionally substituted by 1, 2, or 3 R; R, R a , R b , R b1 , R b2 are independently H, F, Cl, Br, OH, NH2, CN, and C 1-6 Alkyl and C 3-6 cycloalkyl, wherein C 1-6 Alkyl or C 3-6 cycloalkyl is optionally substituted by 1, 2 or 3 R'; R' is independently selected from F, Cl, Br, I, NH, OH, and Me; Said C 1-6Heteroalkyl, 4- to 9-membered heterocycloalkyl, partially unsaturated 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heteroaryl contains one, two, or three heteroatoms or heteroatom groups independently selected from O, NH, S, C(=O), C(=NH), C(=O)O, S(=O), S(=O)2, and N.

[0009] In some embodiments of the present invention, the compound represented by formula (I), its optical isomer, and pharmaceutically acceptable salt thereof is selected from the compounds represented by formulas (IA) and (IB), their optical isomer, and pharmaceutically acceptable salt thereof. [ka] where: X, L1, L2, L3 and R1 are as defined above. In some embodiments of the invention, each R is independently selected from R, F, Cl, Br, OH, NH, CH, [ka] wherein CH3, [ka] is optionally substituted by 1, 2 or 3 R', and the remaining variables are as defined herein.

[0010] In some embodiments of the invention, each R is independently F, Cl, Br, OH, NH2, CH3, [ka] and the remaining variables are as defined herein.

[0011] In some embodiments of the present invention, L is a single bond, C 1-3 Alkyl, -C 1-3 Alkyl-O-, -C1-3 Alkyl-S-, -C 1-3 Alkyl-NH- and -C 1-3 alkyl-C(=O)-, wherein C 1-3 Alkyl, -C 1-3 Alkyl-O-, -C 1-3 Alkyl-S-, -C 1-3 Alkyl-NH- or -C 1-3 The alkyl-C(=O)- is optionally substituted with 1, 2, or 3 R, and the remaining variables are as defined herein.

[0012] In some embodiments of the invention, L1 is a single bond, CH2, [ka] wherein CH2 is selected from [ka] is optionally replaced by 1, 2 or 3 R, and the remaining variables are as defined herein.

[0013] In some embodiments of the invention, L1 is a single bond, CH2, [ka] and the remaining variables are as defined herein.

[0014] 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 said cyclobutyl, cyclopentyl, azetidinyl, piperidinyl, piperazinyl, morpholinyl, or 2,6-diazaspiro[3.3]heptyl is optionally substituted by one, two, or three R, and the remaining variables are as defined herein.

[0015] In some embodiments of the invention, L2 is a single bond, [ka] and the remaining variables are as defined herein.

[0016] 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 alkyl-C(=O)NH-, 1-3 Alkyl, -C 1-3 Alkyl-C(=O)- or -C 1-3 The alkyl-C(=O)NH- is optionally substituted by 1, 2, or 3 R, and the remaining variables are as defined herein.

[0017] In some embodiments of the present invention, L3 is a single bond, C(=O), [ka] and the remaining variables are as defined herein.

[0018] In some embodiments of the present invention, R1 is NH2, [ka] , C 1-3Alkyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, morpholinyl, piperidinyl, piperazinyl, octahydrocyclopentadiene[c]pyrrolyl, 4,5-dihydro-1H-imidazolyl, imidazolyl, 4,5-dihydro-1H-imidazolyl, imidazolin-2-imino, tetrahydropyranyl imidine-2(1H)-imino, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 2,6-diazaspiro[3.4]octyl, 3,6-diazabicyclo[3.1.1]heptyl, and 2,5-diazabicyclo[2.2.1]heptyl; 1-3 Alkyl, cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, morpholinyl, 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-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 2,6-diazaspiro[3.4]octyl, 3,6-diazabicyclo[3.1.1]heptyl or 2,5-diazabicyclo[2.2.1]heptyl is optionally substituted by 1, 2 or 3 R, and the remaining variables are as defined herein.

[0019] In some embodiments of the present invention, R1 is NH2, [ka] wherein Me is selected from [ka] is optionally replaced by 1, 2 or 3 R, and the remaining variables are as defined herein.

[0020] In some embodiments of the present invention, R1 is NH2, Me, CF3, [ka] and the remaining variables are as defined herein.

[0021] In some embodiments of the present invention, the structural unit [ka] ,Me,CF3, [ka] [ka] and the remaining variables are as defined herein.

[0022] In a second aspect, the present invention also provides a compound of the following formula selected from the following formulae, its optical isomers and pharmaceutically acceptable salts thereof: [ka] [ka] [ka] [ka]

[0023] In another aspect of the present invention, the present invention also provides compounds of the following formula selected from the following formulae, their optical isomers and pharmaceutically acceptable salts thereof: [ka] [ka] [ka]

[0024] In a further aspect, the present invention further provides the use of the compounds described above, their optical isomers and pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating a bacterial infection. Some embodiments of the present invention further include combinations of the above-described compounds, their optical isomers, and pharmaceutically acceptable salts thereof with other β-lactam antibiotics.

[0025] In some embodiments of the invention, the β-lactam antibiotic is selected from penicillins, cephalosporins, carbapenems, monocyclic β-lactam antibiotics, or combinations thereof. In some embodiments of the invention, the penicillin is selected from acid-resistant penicillin, enzyme-resistant penicillin, ampicillin, amoxicillin, pivampicillin, carbenicillin, sulfenicillin, ticarcillin, furbenicillin, azlocillin, and piperacillin.

[0026] In some embodiments of the invention, the cephalosporin is selected from cephalexin, cephradine, cefazolin, cefuroxime, cefamandole, cefaclor, cefotaxime, ceftazidime, ceftriazine, cefoperazone, ceftizoxime, cefepime, cefpirome, and ceftolozane. In some embodiments of the invention, the carbapenem is selected from imipenem, meropenem, panipenem, biapenem, ertapenem, and faropenem. In some embodiments of the invention, the monocyclic β-lactam is selected from aztreonam. <Definitions and Explanations> Unless otherwise explained, the following terms and phrases used herein are intended to have the following meanings: A particular term or phrase should not be considered indefinite or unclear in the absence of a specific definition, but should be understood in its ordinary sense. Where trade names are mentioned herein, it is intended to refer to the corresponding product or its active ingredients.

[0027] For purposes of the present invention, the phrase "at least one," when used in reference to a list of one or more elements, should be understood to mean at least one element selected from any one or more elements in the list of elements, but need not include at least one of each of the elements specifically named in the list of elements, and does not exclude any combination of elements in the list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether related to the specifically identified elements or not.

[0028] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, may be used for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem or complication and which are commensurate with a reasonable benefit / risk ratio.

[0029] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention prepared with a compound having specific substituents discovered by the present invention and a relatively non-toxic acid or base. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of base in pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of acid in solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc., and organic acid salts including similar acids such as 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, and further include salts of amino acids (e.g., arginine) and salts of organic acids such as glucuronic acid. Some specific compounds of the present invention contain basic and acidic functional groups and can therefore be converted into any base or acid addition salt.

[0030] The pharmaceutically acceptable salts of the present invention can be synthesized from a parent compound that contains an acidic or basic group by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both.

[0031] The compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, and all such mixtures are included within the scope of the present invention. Other asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers and mixtures thereof are included within the scope of the claimed invention.

[0032] The compounds of the present invention may exist in specific forms. Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can rapidly interconvert. If tautomers are possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via the migration of a proton, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via recombination of some bond electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0033] The compounds of the present invention may contain unnatural atomic isotopes at one or more atoms that constitute the compounds. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I), C-14( 14The compound of the present invention can be labeled with a radioactive isotope such as CI (C). Alternatively, for example, deuterium can be replaced with hydrogen to form a deuterated drug, where the bond formed between deuterium and carbon is stronger than that formed between normal hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have the advantages of reduced toxic side effects, increased drug stability, enhanced efficacy, and extended biological half-life. Conversion of the isotopic composition of the compounds of the present invention, whether radioactive or not, is included within the scope of the present invention. The terms "optional" and "optionally" mean that the following items or circumstances are possible but not necessarily present, and the description includes cases where the described items or circumstances do not occur even when the described items or circumstances occur.

[0034] " [ka] " , the valence bond of the group is marked with a dotted line " [ka] ", the dotted line indicates the point at which the group is attached to the rest of the molecule. [ka] " to a single bond. [ka] ", the dotted line represents a single bond or the absence of a single bond, and " [ka] " is a single bond " [ka] " or double bond " [ka] " means to represent.

[0035] The term "substituted" or "substituted by" refers to the replacement of any one or more hydrogen atoms at a particular atom with a substituent, and may include variations of deuterium and hydrogen, provided that the particular valence state is normal and the compound is stable after substitution. The term "optionally substituted" or "optionally substituted by" may or may not be substituted, and unless otherwise defined, the type and number of substituents are optional as long as they are chemically stable and feasible.

[0036] When any variable (e.g., R) occurs more than one time in any composition or structure of a compound, its definition is independent at each occurrence. So, for example, if a group is substituted with one, two, or three R', then said group is optionally substituted with one, two, or three R', and each occurrence of R' is independently optional. Also, combinations of substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0037] If one of the variables is a single bond, it means that the two groups connected by it are directly connected, for example, [ka] If L1 in represents a single bond, this structure is actually [ka] becomes.

[0038] When a given substituent does not specify through which atom it is linked to a substituted substituent, such substituent may be linked through any atom thereof; for example, a pyridyl group as a substituent may be linked to the substituent through any carbon atom of the pyridine ring.

[0039] If the listed linking group does not specify any other linking direction, the linking direction is arbitrary, for example: [ka] The linking group L in the formula is -CH2O-, where -CH2O- connects the phenyl and cyclopentyl in the same direction as reading from left to right. [ka] It is also possible to construct a phenyl and a cyclopentyl by linking them in the reverse order of reading from left to right. [ka] Combinations of the above linking groups, substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0040] Unless otherwise defined, the number of atoms in a ring is generally defined as the number of ring members, for example, a "3- to 6-membered ring" refers to a "ring" with 3 to 6 atoms arranged around it.

[0041] Unless otherwise defined, "C 1-6 The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group of 1 to 6 carbon atoms. 1-6 Alkyl is C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6 and C5 alkyl, and the like, and may be monovalent (e.g., CH3), divalent (-CH2-) or polyvalent (e.g., [ka] ) may be used. C 1-6 Examples of alkyl are CH3, [ka] Including, but not limited to, the following:

[0042] Unless otherwise defined, the term "C 1-4 "Alkyl" refers to a saturated hydrocarbon group consisting of 1 to 4 carbon atoms, either straight or branched. 1-4 Alkyl is C 1-2 , C 1-3 , C 3-4 and C 2-3 alkyl, etc., and may be monovalent (e.g., CH3), divalent (-CH2-) or polyvalent (e.g., [ka] ) can be. C 1-4 Examples of alkyl are CH3, [ka] Including, but not limited to, the following:

[0043] Unless otherwise defined, the term "heteroalkyl," by itself or in combination with other terms, refers to a stable linear or branched alkyl group or combination thereof consisting of the specified number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatom is selected from B, O, N, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom 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 selected from -C(=O)O-, -C(=O)-, -C(=O)-, -C(=O)N(H)-, -C(=NH)-, -S(=O)2N(H)-, and -S(=O)N(H)-. 1-6 heteroalkyl, and in another embodiment, the heteroalkyl is C 1-3Although the heteroatom or heteroatom group can be placed at any interior position of the heteroalkyl, including the position at which the alkyl is attached to the remainder of the molecule, the term "alkoxy" is a convention and refers to an alkyl attached to the remainder of the molecule via an oxygen atom. Examples of heteroalkyl include, but are not limited to, -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, where up to two heteroatoms may be consecutive, e.g., -CH2-NH-OCH3. Unless otherwise defined, "C 1-6 The term "alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms attached to the remainder of the molecule through an oxygen atom. 1-6 Alkoxy is C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4 and C3 alkoxy, etc. 1-6 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, and the like.

[0044] Unless otherwise defined, "C 1-3 The term "alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom. 1-3 Alkoxy is C 1-3 , C 1-2 , C 2-3, C1, C2 and C3 alkoxy, etc. 1-3 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0045] Unless otherwise defined, "C 1-6 The term "alkylamino" refers to an alkyl group containing 1 to 6 carbon atoms attached to the rest of the molecule through an amino group. 1-6 Alkylamino is C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6, C5, C4, C3 and C2 alkylamino, etc. 1-6 Examples of alkylamino include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -N(CH2CH3)(CH2CH3), -NHCH2CH2CH3, -NHCH2(CH3)2, -NHCH2CH2CH2CH3, and the like.

[0046] Unless otherwise defined, "C 1-3 The term "alkylamino" refers to an alkyl group containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group. 1-3 Alkylamino is C 1-3 , C 1-2 , C 2-3 , C1, C2 and C3 alkylamino, etc. 1-3 Examples of alkylamino include, but are not limited to, -NHCH3, -N(CH3)2, -NHCH2CH3, -N(CH3)CH2CH3, -NHCH2CH2CH3, -NHCH2(CH3)2, and the like.

[0047] Unless otherwise defined, "C 1-6 The term "alkylthio" refers to an alkyl group containing 1 to 6 carbon atoms attached to the remainder of the molecule through a sulfur atom. 1-6 Alkylthio is C 1-4 , C 1-3 , C 1-2 , C2-6 , C 2-4 , C6, C5, C4, C3 and C2 alkylthio, etc. 1-6 Examples of alkylthio include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0048] Unless otherwise defined, the term "C 1-3 "Alkylthio" refers to an alkyl group containing 1 to 3 carbon atoms connected to the remainder of the molecule through a sulfur atom. 1-3 Alkylthio is C 1-3 , C 1-2 , C 2-3 , C1, C2 and C3 alkylthio, etc. 1-3 Examples of alkylthio include, but are not limited to, -SCH3, -SCH2CH3, -SCH2CH2CH3, -SCH2(CH3)2, and the like.

[0049] Unless otherwise defined, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (either at the specified endpoints or between any two endpoints, 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 (e.g., 3, 4, 5, or 6) carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cycloalkyl, and polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls.

[0050] Unless otherwise defined, "C 3-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group of 3 to 6 carbon atoms, including monocyclic and bicyclic ring systems, 3-6 Cycloalkyl is C 3-5 , C4-5 and C 5-6 C includes cycloalkyl and the like and can be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0051] The term "heterocyclyl" refers to a heterocyclyl group containing 3 to 20 ring atoms, one or more of which may be nitrogen, oxygen, or S(O). m (m is an integer of 0 to 2), but does not include an -OO-, -OS-, or -SS- ring moiety, and the remaining ring atoms are carbon. Preferably, it contains 3 to 12 ring atoms (which may be a specific end point or the interval between any two end points, e.g., 3, 4, 5, or 6 ring atoms, 4 to 11 ring atoms, or 6 to 12 ring atoms), of which 1 to 4 are heteroatoms, preferably 3 to 8 ring atoms, of which 1 to 3 are heteroatoms, and more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, etc., preferably tetrahydropyranyl, piperidinyl, pyrrolidinyl. Polycyclic heterocyclyls include spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl.

[0052] Unless otherwise defined, the term "3- to 6-membered heterocyclyl," by itself or in combination with other terms, refers to a saturated cyclic group composed of 3 to 6 ring atoms, of which 1, 2, 3, or 4 ring atoms are independently selected from O, S, and N heteroatoms, and the remainder are carbon atoms, in which the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O)). p, p is 1 or 2.) This includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spirocycles, fused rings, and bridged rings. Furthermore, for "3- to 6-membered heterocyclyl," a heteroatom can occupy the position at which the heterocyclyl is attached to the remainder of the molecule. The 3- to 6-membered heterocyclyl includes 4- to 6-membered, 5- to 6-membered, 4-membered, 5-membered, and 6-membered heterocyclyl, etc. Examples of 3- to 6-membered heterocyclyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperidinyl.

[0053] The term "aryl" refers to a 6- to 20-membered all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated π-electron system, preferably 6- to 10-membered, more preferably 6-membered, such as phenyl and naphthyl. The aryl includes the above aryls fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, where the ring attached to the parent structure is an aryl ring, non-limiting examples of which are: [ka] Includes:

[0054] Aryl can be substituted or unsubstituted, and when substituted, the substituents are preferably substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0055] The term "heteroaryl" refers to a heteroaromatic system containing 1 to 4 heteroatoms and 5 to 20 ring atoms, where the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10-membered and contains 1 to 3 heteroatoms, more preferably 5 or 6-membered and contains 1 to 3 heteroatoms, non-limiting examples of which include pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl, or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which are: [ka] Includes.

[0056] Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably substituted with one or more substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio. Unless otherwise defined, the terms "5- to 6-membered heteroaromatic ring" and "5- to 6-membered heteroaryl" of the present invention can be used interchangeably, and the term "5- to 6-membered heteroaryl" refers to a monocyclic group having a conjugated π-electron system consisting of 5 to 6 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(O)). p and p is 1 or 2). The 5- to 6-membered heteroaryl can be attached to the remainder of the molecule via a heteroatom or a carbon atom. The 5- to 6-membered heteroaryl includes 5- and 6-membered heteroaryls. Examples of 5- to 6-membered heteroaryls include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl). thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, etc.), pyrazinyl, or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0057] Unless otherwise defined, C n-n+m or C n -C n+m includes any one of the specific cases of n to n+m carbons, for example, C 1-12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 and C12 and any range between n and 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 Similarly, n- to n+m-membered rings indicate that the number of atoms on the ring is n to n+m, and for example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range of n to n+m, and for example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 5- to 10-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, a 6- to 9-membered ring, and a 6- to 10-membered ring, etc.

[0058] The term "leaving group" refers to a functional group or atom that can be displaced 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, iodine; sulfonate esters such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate, etc.; acyloxy such as acetoxy, trifluoroacetoxy, etc.

[0059] The term "protecting group" includes, but is not limited to, an "amino-protecting group," a "hydroxy-protecting group," or a "mercapto-protecting group." The term "amino-protecting group" refers to a protecting group suitable for preventing side reactions at an amino nitrogen. Representative amino-protecting groups include, but are not limited to, formyl; acyl such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl such as benzyl (Bn), trityl (Tr), 1,1-bis(4'-methoxyphenyl)methyl; silyl such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS). The term "hydroxy-protecting group" refers to a protecting group suitable for preventing side reactions of hydroxy. Representative hydroxy protecting groups include, but are not limited to, alkyl such as methyl, ethyl, and tert-butyl; acyl such as alkanoyl (e.g., acetyl); arylmethyl such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (DPM); silyl such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and the like.

[0060] The compounds of the present invention can be prepared by a variety of synthetic methods familiar to those skilled in the art, including the specific embodiments listed below, embodiments in combination with other chemical synthetic methods, and equivalent alternative methods familiar to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

[0061] Compounds were named according to their usual names in the art or ChemDraw® software, and for commercially available compounds the manufacturer's catalogue names were used. DETAILED DESCRIPTION OF THE INVENTION

[0062] The present application will be specifically described below by way of examples, but is not intended to limit the present invention in any way. The present application has been described in detail herein, and specific embodiments thereof have also been disclosed, and it will be apparent to those skilled in the art that various changes and modifications can be made in the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0063] All raw materials used in the present invention are commercially available unless otherwise specified. Experimental materials and reagents used in the following examples are commercially available unless otherwise specified. The following abbreviations are used in this invention: 9-BBN represents 9-borabicyclo(3.3.1)nonane; Boc2O represents di-tert-butyl dicarbonate; B2Pin2 represents bis(pinacolato)diboron; DCM represents dichloromethane; DMAP represents 4-dimethylaminopyridine; DMF represents N,N-dimethylformamide; DIEA represents N,N-diisopropylethylamine; DMP represents Dess-Martin reagent; HATU represents 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; HBF4PCy3 represents 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; NMM represents N-methylmorpholine; PhI(OAc) represents iodosobenzene diacetate; Pd(OAc) represents palladium acetate; Pd(dppf)Cl represents [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II); THF represents tetrahydrofuran; and Ti(OEt) represents ethyl titanate.

[0064] Example 1: Synthesis of Compound 1 [ka] [ka]

[0065] Step 1: Preparation of Compound 1B 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 allowed to react at 100 °C for 16 h. The solvent was removed by spin evaporation, and ethyl acetate was added. NaHSO3 solution was added and stirred, and the color changed from black to yellow. The mixture was extracted twice with ethyl acetate, dried, filtered, and spun dry under reduced pressure. Compound 1B (22.4 g, 72%) was obtained by column chromatography (9 / 1 pentane / ethyl acetate). 1 H NMR (400 MHz, DMSO-d6) 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).

[0066] Step 2: Preparation of Compound 1C Under argon gas protection, compound 1B (13.8 g, 38.76 mmol) was dissolved in tert-butanol (20 mL), and DMAP (470 mg, 3.87 mmol) and BocO (50 mL, 193.8 mmol) were added, followed by stirring at 80° C. for 2 hours. The mixture was spin-dried under reduced pressure and separated by column chromatography (9 / 1 pentane / ethyl acetate) to give compound 1C (31.4 g, 87%). 1 H 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).

[0067] Step 3: Preparation of Compound 1D Compound 1C (6 g, 14.5 mmol, 1 eq) was dissolved in toluene (50 mL), and KSAc (6 g, 52 mmol, 3 eq), o-phenanthroline (0.3 eq), and CuI (0.3 eq) were added. The mixture was protected with N2 and reacted at 100 °C for 2 days. The mixture was then spun dry under reduced pressure and separated by column chromatography (9 / 1 pentane / ethyl acetate) to give compound 1D (3.7 g, 54%). 1 H NMR (400 MHz, DMSO-d6) 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).

[0068] Step 4: Preparation of Compound 1E Compound 1D (2.2 g, 6.11 mmol) was dissolved in methanol (30 mL), cesium carbonate (3.0 g, 9.17 mmol) was added, and the mixture was incubated at room temperature for 10 minutes under argon gas protection. The substrate, methyl iodide (4.3 g, 30.56 mmol), was added, and the mixture was stirred at 40°C for 2 hours. The inorganic salts were filtered off with diatomaceous earth, spin-dried under reduced pressure, and separated by column chromatography (9 / 1 pentane / ethyl acetate) to give compound 1E (5.5 g, 85%). MS (ESI) m / z = 333.1 [M+H] + .

[0069] Step 5: Preparation of Compound 1F Compound 1E (5.5 g, 16.5 mmol) was dissolved in DCM (30 mL) and, under nitrogen gas protection, boron tribromide (50 mL, 50 mmol, 1 M dichloromethane solution) was added dropwise at -78 °C and stirred at room temperature for 60 min. After quenching with deionized water (50 mL), the DCM was removed by spin-drying under reduced pressure, and the aqueous phase was extracted three times with ethyl acetate. The mixture was dried, filtered, and spun under reduced pressure to give compound 1F (2.6 g, 60%). MS (ESI) m / z = 263.0 [M+H] + .

[0070] Step 6: Preparation of Compound 1G At room temperature, compound 1F (2.6 g, 10.0 mmol) was added to trifluoroacetic acid (150 mL), and acetone (3.5 g, 60 mmol, 44.1 mL) and trifluoroacetic anhydride (6.5 g, 31.2 mmol, 44.1 mL) were simultaneously injected using a syringe pump at 80 °C. The flow rate was 0.0306 mL / min. After the injection was completed, the reaction solution was concentrated, diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate, washed with water, and the organic phase was dried and concentrated. The sample was loaded by dry method and subjected to silica gel column chromatography (9 / 1 petroleum ether / ethyl acetate) to obtain compound 1G (1.3 g, 43%). MS (ESI) m / z = 305.1 [M+H] + .

[0071] Step 7: Preparation of Compound 1H Compound 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) at room temperature and stirred at 120 °C under argon gas protection for approximately 6 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and the sample was loaded by dry method. Compound 1H (0.5 g, 52%) was obtained by silica gel column chromatography (9 / 1 petroleum ether / ethyl acetate). MS (ESI) m / z = 295.2 [M+H] + .

[0072] Step 8: Preparation of Compound 1I At 0 °C, Br2 (0.92 g, 5.75 mmol) was added dropwise to a solution of compound 1H (1.7 g, 5.25 mmol) in chloroform (40 mL), and the mixture was allowed to react for 0.5 h. LCMS showed the disappearance of the starting material. The reaction solution was concentrated to give compound 1I (2.6 g, 100%), which was used directly in the next step.

[0073] Step 9: Preparation of Compound 1J EtN (0.64 g, 6.3 mmol) was added dropwise to a solution of compound 1I (2.6 g, 5.25 mmol) in DMF (30 mL) at 0 °C, and the mixture was allowed to warm to room temperature and react for 2 h. Ethyl acetate was added, and the mixture was rinsed three times with 1 M HCl. The organic phase was concentrated and purified by column chromatography (0-5% ethyl acetate / pentane) to give compound 1J (580 mg, 31%). 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] + .

[0074] Step 10: Preparation of Compound 1K To a solution of compound 1J (550 mg, 1.7 mmol) in dioxane (8 mL) at room temperature, B2pin2 (637 mg, 2.5 mmol), KOAc (491 mg, 5.0 mmol), and Pd(PPh3)4 (193 mg, 0.17 mmol) were added sequentially. The mixture was purged with argon gas three times and reacted in an oil bath at 70 °C for 2 h. The reaction solution was filtered, concentrated, purified, and separated by column chromatography (0-10% ethyl acetate / pentane) to give compound 1K (510 mg, 81%). 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] + .

[0075] Step 11: Preparation of Compound 1L To a solution of compound 1K (510 mg, 1.4 mmol) in THF (8 mL), (1S,2S,3R,5S)-(+)-2,3-pinanediol (461 mg, 2.7 mmol) was added, and the mixture was allowed to react for 2 hours in an oil bath at 60°C. The reaction solution was concentrated and purified, and then separated by column chromatography (0-10% ethyl acetate / pentane) to obtain compound 1L (320 mg, 55%). 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] + .

[0076] Step 12: Preparation of Compound 1M A diethyl ether solution (50 mL, ∼0.8 M) of diazomethane was added to compound 1L (320 mg, 0.75 mmol) and Pd(OAc)2 in THF (4 mL) and reacted at room temperature for 4 hours. The reaction solution was filtered, concentrated, and purified by column chromatography (0-10% ethyl acetate / pentane) to give the crude product (250 mg), which was purified by HPLC to give compound 1M (130 mg, 39%). MS (ESI) m / z = 443.2 [M+H] + .

[0077] Step 13: Preparation of Compound 1 NaOH (1 mL, 3N aqueous solution) was added to compound 1M (110 mg, 0.25 mmol) in dioxane (2 mL), and the reaction solution was reacted in an oil bath at 40 °C for 2 hours. LCMS showed the disappearance of the starting material. The reaction solution was cooled to 0 °C, and TES (1 mL), TFA (5 mL), and isobutylboronic acid (200 mg) were added sequentially. The mixture was slowly warmed to room temperature and reacted for 1 hour. The reaction solution was concentrated, alkalized to pH 10 with 3N aqueous NaOH, concentrated, and purified by alkaline HPLC to give compound 1 (32 mg, 52%). 1 H NMR (400 MHz, D2O) 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] + .

[0078] Example 2: Synthesis of Compound 2 [ka]

[0079] Step 1: Preparation of Compound 2B Compound 2A (50.0 g, 262 mmol) was dissolved in dichloromethane (300 mL) at room temperature. DMAP (3.20 g, 26.2 mmol) was then added, followed by the slow dropwise addition of BocO (66.2 mL, 288 mmol). After the addition was completed, the mixture was stirred at room temperature for 2 hours. Saturated NaHCO solution and dichloromethane were added to the reaction solution, and the mixture was separated. The organic phase was further washed twice with saturated NaHCO solution, then once with water, twice with 2 M citric acid, and twice with saturated brine. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 2B (73.5 g, 97%), which was used directly in the next reaction. 1H 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).

[0080] Step 2: Preparation of Compound 2C Compound 2B (73.5 g, 252 mmol) was dissolved in ultra-dry tetrahydrofuran (400 mL) at room temperature, purged with nitrogen gas three times, and then cooled to -65 °C with dry ice and acetone. LDA solution (132 mL, 264 mmol, 2 M tetrahydrofuran solution) was slowly added dropwise, taking care not to exceed -60 °C during the addition. After the addition was completed, the mixture was stirred at the same temperature for 4 hours, slowly warmed to 0 °C, and saturated ammonium chloride solution (200 mL) was added. After separation, the aqueous phase was extracted three times with ethyl acetate. The combined organic phase was further washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 2C (65.0 g, 88%), which was used directly in the next reaction. 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).

[0081] Step 3: Preparation of Compound 2D Compound 2C (65.0 g, 223 mmol) was dissolved in dichloromethane (200 mL) at room temperature, then trifluoroacetic acid (100 mL) was added, stirred at room temperature for 2 hours, concentrated to remove the solvent, and then slurried with additional dichloromethane (50 mL), filtered, and the filtered solid was washed twice with small amounts of dichloromethane to give compound 2D (40.0 g, 76%). 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).

[0082] Step 4: Preparation of Compound 2E Compound 2D (40.0 g, 170 mmol) was added to trifluoroacetic acid (200 mL) at room temperature. The starting material was not dissolved, and the atmosphere was purged with nitrogen gas three times. Next, trifluoroacetic anhydride (71.0 mL, 511 mmol) was added via syringe. After stirring at room temperature for 10 minutes, acetone (62.6 mL, 851 mmol) was slowly added via syringe. The temperature was slowly raised to 100 °C (external temperature, internal temperature to 85 °C). The starting material gradually dissolved, and the solution turned yellow. Stirring was continued at this temperature for 48 hours. The mixture was cooled to room temperature and concentrated to remove the solvent. Ethyl acetate (300 mL) and saturated NaHCO3 solution (100 mL) were added, and the mixture was separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic phase was washed successively with saturated NaHCO3 solution and saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give product 2E (37.5 g, 80%). 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] + .

[0083] Step 5: Preparation of Compound 2F Compound 2E (500 mg, 1.818 mmol), vinylboronic acid pinacol ester (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) and reacted at 80 °C under argon gas protection for 16 hours (LC-MS detection). The reaction solution was directly concentrated, and the sample was loaded by dry method. Compound 2F (400 mg, 63%) was obtained by silica gel column chromatography. MS (ESI) m / z = 349.2 [M+H] + .

[0084] Step 6: Preparation of Compound 2G Compound 2F (400 mg, 1.149 mmol) and phenylalanine (782 mg, 4.60 mmol) were added to tetrahydrofuran (20 mL) and reacted at 65° C. for 4 hours (detected by LC-MS). The reaction solution was directly concentrated and purified by silica gel column chromatography to give compound 2G (400 mg, 88%). 1 H 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] + .

[0085] Step 7: Preparation of Compound 2H Compound 2G (200 mg, 0.500 mmol) was dissolved in dichloromethane (5.00 mL) at room temperature, followed by addition of IrPPy3 (33 mg, 0.050 mmol). The mixture was purged with nitrogen gas three times and irradiated with blue light (460-465 nm, 10 watts) at room temperature for 4 hours. The reaction solution was then directly subjected to column chromatography (0%-10% EA / PE) to obtain compound 2H (120 mg, 60%). 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] + .

[0086] Step 8: Preparation of Compound 2I Compound 2H (13.1 g, 32.8 mmol) was dissolved in ultra-dry THF (79 mL) at room temperature. Pd(OAc)2 (368 mg, 1.64 mmol) was then added, and the mixture was flushed with argon three times. The mixture was cooled to approximately 0 °C, and a diazomethane diethyl ether solution (200 mL, ~0.6 M) was slowly added via syringe. The reaction solution turned from yellow to black and bubbles appeared. The mixture was then slowly warmed to room temperature and stirred for 2 h. The reaction solution was concentrated at room temperature and purified by column chromatography (0-10% EA / PE) to give the crude product compound (10.9 g). This was purified by acidic HPLC to give compound 2I (4.3 g, 31%). MS (ESI) m / z = 415.0 [M+H] + .

[0087] Step 11: Preparation of Compound 2J Compound 2I (150 mg, 0.377 mmol) was dissolved in dimethyl sulfoxide (2 mL) at room temperature, cesium carbonate (246 mg, 0.754 mmol) was added, and the mixture was purged with argon gas three times. 2-Propanethiol (86.1 mg, 1.13 mmol) was added to the reaction mixture and stirred at 60 °C overnight. The mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), and extracted three times with water (3 mL). The combined organic phase was washed with brine (3 mL) and concentrated to give the crude product. The crude product was purified by column chromatography (0-8% EA / PE) to give compound 2J (64 mg, 36%). MS (ESI) m / z = 471 .1 [M+H] + .

[0088] Step 12: Preparation of Compound 2 Compound 2J (150 mg, 0.377 mmol) was dissolved in 1 mL of 1,4-dioxane at room temperature, and 3 M aqueous sodium hydroxide (1 mL, 0.816 mmol) was added. The mixture was stirred at room temperature for 3 hours. A spot plate showed the reaction was complete. Triethoxysilane (0.126 mL, 112 mg, 0.681 mmol), trifluoroacetic acid (0.628 mL), and isobutylboronic acid (27.7 mg, 0.272 mmol) were then added to the reaction mixture, followed by stirring at room temperature for 30 minutes. The mixture was then filtered and concentrated. The pH of the reaction mixture was adjusted to 5 with aqueous sodium bicarbonate and concentrated to give the crude product, which was purified by HPLC to give compound 2 (12.8 mg, 34%). 1 H NMR (400 MHz, D2O) 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] + .

[0089] Example 3: Synthesis of Compound 3 [ka]

[0090] Step 1: Preparation of Compound 3A Compound 2J (95.0 mg, 0.229 mmol) was dissolved in dichloromethane (2.00 mL) at room temperature, followed by the addition of m-chloroperoxybenzoic acid (119 mg, 0.688 mmol) and stirring overnight at room temperature. The mixture was diluted with ethyl acetate (10.0 mL), quenched with an appropriate amount of saturated aqueous sodium thiosulfate solution, washed three times with saturated aqueous sodium bicarbonate solution (3.0 mL), and once with water (3.0 mL). The combined organic phase was washed with brine (3.0 mL), concentrated, and the crude product was purified by column chromatography (8-10% EA / PE) to give compound 3A (35 mg, 30%). MS (ESI) m / z = 503.1 [M+H] + .

[0091] Step 2: Preparation of Compound 3 This was prepared according to the synthesis method of compound 2 in Example 2. Compound 3A (30 mg, 0.0597 mmol) gave product 3 (6.8 mg, 37%). 1 H NMR (400 MHz, D2O) 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] + .

[0092] Example 4: Synthesis of Compound 4 [ka]

[0093] Step 1: Preparation of Compound 4B This was prepared according to the synthesis method of compound 2J in Example 2. Compound 2I (100 mg, 0.241 mmol) and compound 4A (236 mg, 1.61 mmol) gave product 4B (120 mg, 99%). MS (ESI) m / z = 499.1 [M+H] + .

[0094] Step 2: Preparation of Compound 4 It was prepared according to the synthesis method of compound 2 in Example 2. Compound 4B (150 mg, 0.301 mmol) gave product 4 (36.8 mg, 40%). 1 H NMR (400 MHz, D2O+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] + .

[0095] Example 5: Synthesis of Compound 5 [ka]

[0096] Step 1: Preparation of Compound 5B This was prepared according to the synthesis method of compound 2J in Example 2. Compound 2I (200 mg, 0.483 mmol) and compound 5A (212 mg, 1.45 mmol) gave product 5B (210 mg, 87%). MS (ESI) m / z = 499.1 [M+H] + .

[0097] Step 2: Preparation of Compound 5 Produced according to the synthesis method of compound 2 in Example 2. Compound 5B (190 mg, 0.381 mmol) gave product 5 (91.5 mg, 78%). 1 H NMR (400 MHz, D2O+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] + .

[0098] Example 6: Synthesis of Compound 6 [ka]

[0099] Step 1: Preparation of Compound 6B This was prepared according to the synthesis method of compound 2J in Example 2. Compound 2I (150 mg, 0.36 mmol) and compound 6A (288 mg, 1.81 mmol) gave product 6B (144 mg, 78%). MS (ESI) m / z = 512.1 [M+H] + .

[0100] Step 2: Preparation of Compound 6 Produced according to the synthesis method of compound 2 in Example 2. Compound 6B (144 mg, 0.282 mmol) gave product 6 (8.4 mg, 9%). 1H NMR (400 MHz, D2O) 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] + .

[0101] Example 7: Synthesis of Compound 7 [ka]

[0102] Step 1: Preparation of Compound 7B This was prepared according to the synthesis method of compound 2J in Example 2. Compound 2I (200 mg, 0.483 mmol) and compound 7A (514 mg, 2.90 mmol) gave product 7B (180 mg, 65%). MS (ESI) m / z = 471 .1 [M+H] + .

[0103] Step 2: Preparation of Compound 7 Prepared according to the synthesis method of compound 2 in Example 2. Compound 7B (180 mg, 0.315 mmol) gave product 7 (40 mg, 46%). 1 H NMR (400 MHz, D2O) 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] + .

[0104] Example 8: Synthesis of Compound 8 [ka]

[0105] Step 1: Preparation of Compound 8 Compound 7 (40.0 mg, 0.143 mmol) was dissolved in dimethyl sulfoxide (4.0 mL) at room temperature, N,N-diisopropylethylamine (27.8 mg, 0.215 mmol) was added, and the mixture was purged with argon gas three times. Compound 8A (48.8 mg, 1.57 mmol) was then added to the reaction mixture and stirred at 60 °C overnight. The mixture was cooled 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 brine (3.0 mL) and concentrated to give the crude product. A 4 M solution of hydrochloric acid in methanol (4 mL) was added and the mixture was stirred overnight at room temperature. Purification by alkaline HPLC (0.1% NH4OH) afforded compound 8 (4.2 mg, 9%). 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] + .

[0106] Example 9: Synthesis of Compound 9 [ka]

[0107] Step 1: Preparation of Compound 9A Compound 7B (24.0 mg, 0.051 mmol) was dissolved in a solution of hydrogen chloride in ethyl acetate (4 M, 5.0 mL) at room temperature and stirred for 18 hours. TLC showed the reaction was complete. Concentration gave crude product compound 9A (26.0 mg), which was used directly in the next step. MS (ESI) m / z = 472.4 [M+H] + .

[0108] Step 2: Preparation of compound 9C Compound 9A (20 mg, 0.042 mmol) was dissolved in tetrahydrofuran (4.0 mL) at room temperature, sodium bicarbonate (7.0 mg, 0.085 mmol) was added, and the mixture was purged with argon gas. Compound 9B (21 mg, 0.085 mmol) was added to the reaction mixture and stirred at 70 °C overnight. The mixture was cooled 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 brine (3.0 mL) and concentrated to give the crude product. Separation and purification by column chromatography (MeOH / DCM = 1 / 9) gave compound 9C (18 mg, 79%). MS (ESI) m / z = 540 .0 [M+H] + .

[0109] Step 3: Preparation of Compound 9 Compound 9 (1.8 mg, 15%) was obtained from compound 7B (18 mg, 0.033 mmol) according to the synthesis method of compound 2 in Example 2. 1 H NMR (400 MHz, D2O) 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] + .

[0110] Example 10: Synthesis of Compound 10 [ka]

[0111] Step 1: Preparation of Compound 10B Aqueous ammonia (20 mL) was added to a sealed canister containing 10A (4.0 g, 46.5 mmol) at room temperature, purged with argon gas for 1 minute, spun down, and stirred at 110 °C for 14 h. TLC (PE:EA = 5:1) showed the disappearance of the starting material. Concentration gave racemic compound 10B (4.8 g, 100%). The crude product was used directly in the next reaction without further purification.

[0112] Step 2: Preparation of Compound 10C Racemic compound 10B (4.8 g, 46.5 mmol) was dissolved in tetrahydrofuran (50 mL) at room temperature. Then, BocO (12.8 mL, 55.8 mmol) and NaOH solution (31 mL, 93 mmol, 3M) were added and stirred at room temperature for 2 h. TLC (PE / EA = 5:1) showed the disappearance of the starting material. Ethyl acetate and saturated brine were added to the reaction solution, and the mixture was separated. The aqueous phase was extracted twice with ethyl acetate. The combined organic phase was washed three times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give racemic compound 10C (6.0 g, 64%). The crude product was used directly in the next reaction without further 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).

[0113] Step 3: Preparation of Compound 10D At room temperature, compound 10C (1.0 g, 4.92 mmol) was dissolved 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. MsCl (0.46 mL, 5.90 mmol) was then slowly added dropwise. After the addition was completed, the mixture was warmed to room temperature and stirred for 2 hours. Saturated brine was added to the reaction solution, separated, and the organic phase was washed twice more with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 10D (1.3 g, 94%). The crude product was used directly in the next reaction without further purification.

[0114] Step 4: Preparation of Compound 10E Compound 10D (1.3 g, 4.62 mmol) was dissolved in ultra-dry DMF (30 mL) at room temperature and purged with argon gas three times. Potassium thioacetate (792 mg, 6.93 mmol) was then added in batches. The reaction mixture was yellow and slowly heated to 65 °C and stirred for 18 h. The starting material was almost consumed, the reaction mixture turned black, and a large amount of solid was formed. After cooling to room temperature, water (200 mL) and ethyl acetate (50 mL) were added and the mixture was separated. The aqueous phase was extracted three times with ethyl acetate. The combined organic phase was washed four times with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography (0-50% EA / PE) to give compound 10E (570 mg, 47%). 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] + .

[0115] Step 5: Preparation of Compound 10F This compound was prepared according to the synthesis method for compound 2J in Example 2. Compound 2I (150 mg, 0.362 mmol) and compound 10E (284 mg, 1.09 mmol) gave crude racemic compound 10F (a mixture of 10F_1 and 10F_2, 130 mg). This was purified and separated by alkaline HPLC to give compound 10F_P1 (isomer 10F_1 or 10F_2, 30 mg, 13.5%) and compound 10F_P2 (isomer 10F_2 or 10F_1, 32 mg, 14.4%). Compound 10F_P1: MS (ESI) m / z = 636.2 [M+Na] + ;Compound 10F_P2:MS (ESI) m / z=636.2 [M+Na] + .

[0116] Step 6: Preparation of Compound 10 It was prepared according to the synthesis method of compound 2 in Example 2. Compound 10F_P1 (30 mg, 0.0489 mmol) gave compound 10-P1 (isomer 10_1 or 10_2, 6.9 mg, 44%). 1 H NMR (400 MHz, D2O) 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] + .

[0117] Compound 10F_P2 (30 mg, 0.0489 mmol) gave compound 10-P2 (isomer 10_1 or 10_2, 13.6 mg, 87%). 1H NMR (400 MHz, D2O) 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] + .

[0118] Example 11: Synthesis of Compound 11 [ka]

[0119] Step 1: Preparation of Compound 11A Compound 10C (2.0 g, 9.85 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature. 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. Diethyl azodicarboxylate (2.06 g, 11.8 mmol) was then slowly added dropwise. After the addition was complete, the mixture was warmed to room temperature and stirred for 16 hours. Ethyl acetate and water were added to the reaction solution, and the mixture was separated. The organic phase was washed twice more with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography (0-20% EA / PE) to give compound 11A (1.00 g, 29%). MS (ESI) m / z = 338.0 [M-14]. + .

[0120] Step 2: Preparation of Compound 11B Compound 11A (1.00 g, 2.84 mmol) was dissolved in methanol (10 mL) at room temperature. Lithium hydroxide monohydrate (357 mg, 8.51 mmol) dissolved in water (2 mL) was then added and stirred at room temperature for 2 hours. TLC (EA / PE = 3:7) showed that the starting material had completely reacted. Ethyl acetate and water were added to the reaction solution, and the mixture was separated. The organic phase was washed twice with saturated aqueous sodium bicarbonate solution, then with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 11B (512 mg, 89%). The crude product was used directly in the next reaction without further purification.

[0121] Step 3: Preparation of Compound 11C This was prepared according to the synthesis method for compound 10D in Example 10. Compound 11C (590 mg, 83.2%) was obtained from compound 11B (512 mg, 2.52 mmol). MS (ESI) m / z=181.0 [M-100] + .

[0122] Step 4: Preparation of Compound 11D Produced according to the synthesis method of compound 10E in Example 10. Compound 11D (250 mg, 46%) was obtained from compound 11C (590 mg, 2.10 mmol). MS (ESI) m / z=284.0 [M+Na] + .

[0123] Step 5: Preparation of Compound 11E This compound was prepared according to the synthesis method of compound 2J in Example 2. Compound 2I (132 mg, 0.319 mmol) and compound 11D (250 mg, 0.958 mmol) gave racemic compound 11E (a mixture of isomers 10E_1 and 10E_2, 120 mg). This was purified and separated by alkaline HPLC to give compound 11E_P1 (isomer 11E_1 or 11E_2, 50 mg, 26%) and compound 11E_P2 (isomer 11E_2 or 11E_1, 40 mg, 21%). Compound 11E_P1: MS (ESI) m / z=636.3 [M+Na] + ;Compound 11E_P2:MS (ESI) m / z=636.3 [M+Na] + .

[0124] Step 6: Preparation of Compound 11 It was prepared according to the synthesis method of compound 2 in Example 2. Compound 11E_P1 (50 mg, 0.0815 mmol) gave product 11-P1 (isomer 11_1 or 11_2, 23.2 mg, 89%). 1 H NMR (400 MHz, D2O) 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] + .

[0125] Compound 11E_P2 (40 mg, 0.0652 mmol) gave product 11-P2 (isomer 11_1 or 11_2, 18.4 mg, 88%). 1H NMR (400 MHz, D2O) 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] + .

[0126] Example 12: Synthesis of Compound 12 [ka]

[0127] Step 1: Preparation of Compound 12B This was prepared according to the synthesis method of compound 10C in Example 10. Compound 12B (1.9 g, 96%) was obtained from compound 12A (1.0 g, 9.7 mmol). 1 H NMR (400 MHz, DMSO-d6) 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).

[0128] Step 2: Preparation of Compound 12C Produced according to the synthesis method of compound 10D in Example 10. Compound 12C (688 mg, 100%) was obtained from compound 12B (500 mg, 2.46 mmol). MS (ESI) m / z=181.2 [M-100] + .

[0129] Step 3: Preparation of Compound 12D Produced according to the synthesis method of compound 10E in Example 10. Compound 12D (430 mg, 67%) was obtained from compound 12C (688 mg, 2.46 mmol). MS (ESI) m / z=206.2 [M+H-56] + .

[0130] Step 4: Preparation of Compound 12E Compound 12D (430 mg, 1.65 mmol) and sodium hydroxide (400 mg, 10.0 mmol) were dissolved in methanol (10 mL), purged with argon gas, and reacted at 0 ° C for 0.5 hours. 0.5 M diluted hydrochloric acid was added to adjust the pH to 6, extracted twice with ethyl acetate, dried over anhydrous sodium sulfate, concentrated, and separated by column chromatography (PE / EA = 80:20) to give compound 12E (320 mg, 59%). MS (ESI) m / z = 164.2 [M + H -56] + .

[0131] Step 5: Preparation of Compound 12F Compound 12F (100 mg, 58%) was obtained from compound 2I (100 mg, 0.24 mmol) and compound 12E (110 mg, 0.5 mmol) according to the synthesis method of compound 2J in Example 2. MS (ESI) m / z = 514.4 [M+H-100] + .

[0132] Step 6: Preparation of Compound 12G To a solution of compound 12F (100 mg, 0.163 mmol) in tetrahydrofuran (1 mL), hydrogen chloride in dioxane (2 mL) was added and stirred at 0° C. for 2 hours. After completion of the reaction, the mixture was concentrated to give compound 12G (90 mg, 100%). The crude product was used directly in the next reaction without further purification. MS (ESI) m / z=514.4 [M+H] + .

[0133] Step 7: Preparation of Compound 12H Compound 12G (90 mg, 0.163 mmol), compound 8A (186 mg, 0.6 mmol), and DIPEA (78 mg, 0.6 mmol) were dissolved in acetonitrile (4.0 mL), stirred overnight at room temperature, and separated using a reverse-phase column to give compound 12H (110 mg, 89%). MS (ESI) m / z = 756.6 [M+H] + .

[0134] Step 8: Preparation of Compound 12I 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 adjusted to pH 3-4 with trifluoroacetic acid. Trifluoroacetic acid (1.0 mL), triethylsilane (0.3 mL), and isobutylboronic acid (51 mg, 0.5 mmol) were added sequentially at 0°C. Stirring was continued for 2 hours at 0°C. After the reaction was complete, the mixture was adjusted to pH 9 with sodium hydroxide at 0°C. Compound 12I (50 mg, 38%) was obtained by alkaline HPLC. MS (ESI) m / z = 402.1 [M+H-100] + .

[0135] Step 9: Preparation of Compound 12 Compound 12I (8 mg, 0.018 mmol) was dissolved in tetrahydrofuran (0.1 mL), and hydrogen chloride in dioxane (0.3 mL) was added and stirred for 2 hours at 0° C. After completion of the reaction, the product was purified by alkaline HPLC to give compound 12 (1.1 mg, 17%). 1H NMR (400 MHz, D2O) 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] + .

[0136] Example 13: Synthesis of Compound 13 [ka]

[0137] Step 1: Preparation of Compound 13B Compound 13A (10.0 g, 142.8 mmol) was dissolved in tert-butanol (50 mL), and sodium tert-butoxide (14.4 g, 150 mmol) and nitromethane (9.2 g, 150 mmol) were added in batches at 0 °C. The mixture was stirred at 0 °C for 2 hours, diluted with ethyl acetate (500 mL), and the cloudy solution was filtered. The mother liquor was washed with 1 M aqueous HCl. The organic phase was washed once with saturated NaCl solution, dried over anhydrous sodium sulfate, and concentrated to give compound 13B (18.7 g, 100%). The crude product was used directly in the next reaction without further purification. MS (ESI) m / z = 114.1 [M + H -18] + .

[0138] Step 2: Preparation of Compound 13C Compound 13B (18.1 g, 142.8 mmol) and Pd / C (1.0 g) were dissolved in methanol (300 mL), purged with hydrogen gas, and stirred at room temperature overnight. The mixture was filtered through diatomaceous earth and directly concentrated to give compound 13C (14.4 g, 100%). MS (ESI) m / z = 102.4 [M+H] + .

[0139] Step 3: Preparation of Compound 13D Produced according to the synthesis method of compound 10C in Example 10. Compound 13D (13.2 g, 46%) was obtained from compound 13C (14.4 g, 142.8 mmol). MS (ESI) m / z = 202.6 [M+H] + .

[0140] Step 4: Preparation of Compound 13E Produced according to the synthesis method of compound 10D in Example 10. Compound 13D (10.0 g, 49.5 mmol) gave compound 13E (11.0 g, 70%). MS (ESI) m / z=180.2 [M+H-100] + .

[0141] Step 5: Preparation of Compound 13F Produced according to the synthesis method of compound 10E in Example 10. Compound 13F (6.8 g, 66%) was obtained from compound 13E (11.0 g, 39.6 mmol). MS (ESI) m / z=160.2 [M+H-100] + .

[0142] Step 6: Preparation of Compound 13G Produced according to the synthesis method of compound 12E in Example 12. Compound 13G (200 mg, 24%) was obtained from compound 13F (1.0 g, 3.86 mmol). MS (ESI) m / z=218.2 [M+H] + .

[0143] Step 7: Preparation of Compound 13H This was prepared according to the synthesis method for compound 2J in Example 2. Compound 13H (30 mg, 32%) was obtained from compound 2I (60 mg, 0.145 mmol) and compound 13G (110 mg, 0.5 mmol). MS (ESI) m / z = 512.0 [M+H-100] + .

[0144] Step 8: Preparation of Compound 13I Produced according to the synthesis method of compound 12I in Example 12. Compound 13I (8 mg, 38%) was obtained from compound 13H (30 mg, 0.047 mmol). MS (ESI) m / z=320.2 [M+H-100] + .

[0145] Step 10: Preparation of Compound 13 This was prepared according to the synthesis method of compound 12 in Example 12. Compound 13 (0.7 mg, 9%) was obtained from compound 13I (10 mg, 0.0238 mmol). 1 H NMR (400 MHz, D2O) 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] + .

[0146] Example 14: Synthesis of Compound 14 [ka]

[0147] Step 1: Preparation of Compound 14B Produced according to the synthesis method of compound 13B in Example 13. Compound 14B (16.1 g, 100%) was obtained from compound 14A (10.0 g, 100 mmol). MS (ESI) m / z = 161.60 [M+H] + .

[0148] Step 2: Preparation of Compound 14C This was prepared according to the synthesis method of compound 13C in Example 13. Compound 14C (13.1 g, 100%) was obtained from compound 14B (16.1 g, 100 mmol). MS (ESI) m / z = 131.60 [M+H] + .

[0149] Step 3: Preparation of Compound 14D Produced according to the synthesis method of compound 10C in Example 10. Compound 14C (13.1 g, 100 mmol) gave compound 14D (15.2 g, 66%). MS (ESI) m / z=231.6 [M+H] + .

[0150] Step 4: Preparation of Compound 14E Produced according to the synthesis method of compound 10D in Example 10. Compound 14D (10.0 g, 43.3 mmol) gave compound 14E (13.5 g, 100%). MS (ESI) m / z = 210.0 [M+H-100] + .

[0151] Step 5: Preparation of Compound 14F Produced according to the synthesis method of compound 10E in Example 10. Compound 14F (8.7 g, 69%) was obtained from compound 14E (13.5 g, 43.7 mmol). MS (ESI) m / z=190.2 [M+H-100] + .

[0152] Step 6: Preparation of Compound 14G Produced according to the synthesis method of compound 12E in Example 12. Compound 14F (1.0 g, 3.45 mmol) gave compound 14G (500 mg, 59%). MS (ESI) m / z = 248.0 [M+H] + .

[0153] Step 7: Preparation of Compound 14H This was prepared according to the synthesis method of compound 2J in Example 2. Compound 2I (60 mg, 0.145 mmol) and compound 14G (124 mg, 0.5 mmol) gave compound 14H_P1 (isomer 14H_1 or 14H_2, 32 mg, 34%) and compound 14H_P2 (isomer 14H_2 or 14H_1, 30 mg, 32%). 14H_P1: MS (ESI) m / z = 542.0 [M + H -100] + ;14H_P2:MS (ESI) m / z=542.0 [M+H-100] + .

[0154] Step 8: Preparation of Compound 14I This was prepared according to the synthesis method of compound 12I in Example 12. Compound 14H_P1 (32 mg, 0.05 mmol) gave compound 14I_1 (isomer 14I_1 or 14I_2, 9 mg, 40%); compound 14H_P2 (30 mg, 0.05 mmol) gave compound 14I_P2 (isomer 14I_2 or 14I_1, 8 mg, 38%). 14I_P1: MS (ESI) m / z = 350.2 [M + H -100] + ;14I_P2:MS (ESI) m / z=350.2 [M+H-100] + .

[0155] Step 10: Preparation of Compound 14 This was prepared according to the synthesis method of compound 12 in Example 12. Compound 14I_P1 (9 mg, 0.02 mmol) gave compound 14_P1 (isomer 14_1 or 14_2, 5.5 mg, 78%). 1 H NMR (400 MHz, D2O)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] + .

[0156] Compound 14I_P2 (8 mg, 0.018 mmol) gave compound 14_P2 (isomer 14_2 or 14_1, 1.1 mg, 17%). 1H NMR (400 MHz, D2O) 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] + .

[0157] Example 15: Synthesis of Compound 15 [ka]

[0158] Step 1: Preparation of Compound 15A Compound 2E (5 g, 18.2 mmol) was dissolved in N,N-dimethylformamide (100 mL). 4-Methoxybenzyl mercaptan (4.2 g, 27.3 mmol) and cesium carbonate (17.7 g, 54.6 mmol) were added under a nitrogen atmosphere and stirred at room temperature for 16 hours. After completion of the reaction, the mixture was filtered, the cake was washed with ethyl acetate, the filtrate was combined, concentrated under reduced pressure, 50 mL of methanol was added, and the mixture was stirred for 10 minutes. The mixture was filtered, the cake was washed with methanol, and dried under reduced pressure to give white solid 15A (5.7 g, 76.1% yield). 1 H 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).

[0159] Step 2: Preparation of Compound 15B Compound 15A (3 g, 7.3 mmol) was dissolved in dichloromethane (30 mL), and trifluoromethanesulfonic acid (2 mL) was added at 0 °C. Stirring was continued for 1 hour. After the reaction was completed, sodium bicarbonate solution was added to adjust the pH to neutral, and the mixture was extracted with dichloromethane (50 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 3 g of crude 15B, which was used directly in the next step without purification. MS (ESI) m / z: (M+H)+ = 288.80.

[0160] Step 3: Preparation of Compound 15C Compound 15B (3 g, 7.3 mmol) was dissolved in N,N-dimethylformamide (30 mL) at room temperature, potassium carbonate (1.5 g, 10.95 mmol) and 2-(4-morpholine)ethyl bromide (2.0 g, 7.3 mmol) were added, and the mixture was stirred for 2 h. After completion of the reaction, the mixture was washed with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:3) to give compound 15C (2.6 g, 88.4% yield for two steps). MS (ESI) m / z: (M+H) = 401.8.

[0161] Step 4: Preparation of Compound 15D 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 mixture was purged with nitrogen three times, heated to 100 °C, and stirred for 16 h. After the reaction was completed, the mixture was cooled to room temperature, water (50 mL) was added, and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (dichloromethane / methanol = 10:1) to give compound 15D (1.1 g, yield: 70.5%). MS (ESI) m / z (M+ H) +=394.0.

[0162] Step 5: Preparation of Compound 15E Compound 15D (676 mg, 1.72 mmol) was dissolved in chloroform (6 mL), acetic acid (2 mL) was added in an ice bath, and then liquid bromine (330 mg, 2.06 mmol) was slowly added dropwise. The mixture was stirred at 0 °C for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure to give a solid residue. N,N-dimethylformamide (6 mL) was added, followed by triethylamine (347.4 mg, 3.44 mmol) at room temperature. Stirring was continued for 1 h. After completion of the reaction, the mixture was diluted with ethyl acetate (20 mL), washed with water (50 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:3) to give compound 15E (488 mg, yield: 66.4%). MS (ESI) m / z: (M+H)+ = 428.0.

[0163] Step 6: Preparation of Compound 15F Compound 15E (1.3 g, 3.04 mmol) was dissolved in isopropyl acetate (10 mL), and bis(1S,2S,3R,5S)(+)-pinenediol diboron ester (1.63 g, 4.56 mmol), allylpalladium(II) chloride dimer (111.0 mg, 0.304 mmol), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (289.8 mg, 0.608 mmol), and potassium isooctanoate (1.2 g, 6.69 mmol) were added. The mixture was purged with argon gas four times, heated to 35°C, and stirred for 16 hours. After completion of the reaction, the mixture was washed with water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was separated and purified by column chromatography (petroleum ether / ethyl acetate = 5:3) to give compound 15F (372 mg, yield: 23.5%). MS (ESI) m / z: (M+H)+ = 528.2.

[0164] Step 7: Preparation of Compounds 15G-a and 15G-b A solution of compound 15F (97 mg, 183.89 μmol) and Pd(OAc) (4.13 mg, 18.39 μmol) in THF (3 mL) was added to a solution of CHN (0.2 M, 9.19 mL) in diethyl ether at -20 °C under a nitrogen atmosphere. The mixture was allowed to warm to room temperature and stirred for 16 h. After completion of the reaction, the crude product was concentrated under reduced pressure. This was then separated and purified by column chromatography (0-40% petroleum ether / ethyl acetate) to give a yellow oily mixture of compound 15G (60 mg, 60.25% yield), which was then separated and purified by SFC to give compounds 15G-a and 15G-b.

[0165] SFC separation conditions: Chiral column: Chiralpak IC-3 150 × 4.6 mm ID, 3 μm; mobile phase: 50% IPA (0.05% DEA) in CO2; flow rate: 2.5 mL / min; column temperature: 35 °C; ABPR: 1500 psi. 15G-a: Retention time: t=4.021min, HPLC: 91.78%; Retention time: t=4.52min, 25mg of white solid. 15G-b: Retention time: t=4.860min, HPLC: 94.11%; Retention time: t=4.58min, 25mg of white solid. MS (ESI) m / z (M+1)+=542.4.

[0166] Step 13: Preparation of Compounds 15-a and 15-b To a solution of compound 15G-a (25 mg, 46.17 μmol) in dioxane (1 mL), NaOH solution (3 M, 46.17 μL) was added and stirred at room temperature for 24 hours. The reaction solution was then cooled to 0°C, and triethylsilane (0.1 mL), trifluoroacetic acid (0.2 mL), and isobutylboronic acid (9.41 mg, 92.34 μmol) were added sequentially and stirred for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure, and the crude product was separated and purified by HPLC to obtain 15-a (5 mg, yield: 31.01%).

[0167] 1 H NMR (400MHz, 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.

[0168] HPLC separation and purification conditions: Chromatography column: Welch Xtimate C18 100 × 40 mm × 3 μm; Mobile phase: [water (TFA)-acetonitrile]; B%: 8% to 38%, 8 min); HPLC 99.92%; retention time: t=1.82min.

[0169] 15-b was produced using 15G-b as a raw material in the same manner as 15-a to obtain 5 mg. 1H NMR (400MHz, 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. HPLC 99.89%; retention time: t=1.69min.

[0170] Example 16: Synthesis of Compound 16 [ka] [ka]

[0171] Step 1: Preparation of Compound 16B Liquid bromine (2.05 g, 12.79 mmol) was slowly added to a solution of compound 16A (1.00 g, 11.62 mmol) and triphenylphosphine (3.35 g, 12.79 mmol) in toluene (10 mL) at -20°C, and stirring was continued for 2 h. After completion of the reaction, the mixture was allowed to warm to room temperature, filtered, and washed with toluene (2 mL) to give a toluene solution of compound 16B (11 mL, 1.06 N), which was used directly in the next step without further purification.

[0172] Step 2: Preparation of Compound 16C A toluene solution of 16B (0.4 mL) was slowly added dropwise to a solution of 15B (100 mg, 0.346 mmol) and potassium carbonate (96.0 mg, 0.69 mmol) in N,N-dimethylformamide (3 mL) at room temperature under a nitrogen atmosphere. The mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was quenched with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give 16C (50 mg, 41% yield). MS (ESI) m / z: (M+H) = 357.0.

[0173] Step 3: Preparation of Compound 16D A solution of 16C (200 mg, 0.56 mmol), pinacol vinylborate (260 mg, 1.68 mmol), tris(dibenzylideneacetone)dipalladium(0) (50.0 mg, 0.056 mmol), tri-tert-butylphosphonium tetrafluoroborate (32.0 mg, 0.11 mmol), and N,N-diisopropylethylamine (215 mg, 1.68 mmol) in toluene (3.0 mL) was stirred at 115 °C for 1 h under a nitrogen atmosphere. After completion of the reaction, the reaction was quenched with water (15 mL) and extracted with ethyl acetate (5 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and directly concentrated under reduced pressure to give the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 20:1) to give compound 16D (140 mg, yield: 58%). MS(ESI) m / z: (M+H)+ = 431.2.

[0174] Step 4: Preparation of Compound 16E To a solution of compound 16D (1.05 g, 2.43 mmol) in tetrahydrofuran (12 mL) at room temperature, (1S,2S,3R,5S)-(+)-2,3-pinanediol (2.00 g, 12.2 mmol) was added and stirred for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure, and the crude product was separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 16E (1.00 g, yield: 85.4%). MS (ESI) m / z (M- H) = 483.2.

[0175] Step 5: Preparation of Compound 16F Compound 16E (80.0 mg, 0.166 mmol) was dissolved in acetonitrile (8 mL), tris(2-phenylpyridinato)iridium (8.00 mg) was added at room temperature, and the mixture was irradiated with LED blue light (wavelength = 450 nM, 10 W) under nitrogen gas for 1.5 hours. The reaction solution was then concentrated under reduced pressure to obtain the crude product, which was then separated and purified by column chromatography (petroleum ether: ethyl acetate = 20:1) to obtain compound 16F (36 mg, yield: 45%). MS (ESI) m / z (M+ H) + =483.2

[0176] Step 7: Preparation of Compound 16G-a or 16G-b Compound 16F (400 mg, 829.12 μmol) was subjected to preparative chiral separation to give white solid compound 16G-a (120 mg, yield: 30.00%) with a retention time of t=3.700 min. 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 increased from 5% to 40% within 5 min, then decreased from 40% to 5% within 30 s and maintained for 1.5 min; Flow rate: 2.5 mL / min; Column temperature: 35 °C; ABPR: 1500 psi; Retention time: t = 3,700 min.

[0177] 16G-b (130mg, yield: 32.50%), white solid, retention time: t=4.046min. SFC separation conditions: Chiral column: Chiralcel OD-3 150 mm x 4.6 mm ID, 3 μm; Mobile phase: A: CO2, B: Isopropanol (0.05% DEA); Gradient: Mobile phase B increased from 5% to 40% within 5 min, then decreased from 40% to 5% within 30 s and held for 1.5 min; Flow rate: 2.5 mL / min; Column temperature: 35 °C; ABPR: 1500 psi; Retention time: t = 4.046 min.

[0178] Step 8: Preparation of Compounds 16H-aa, ab, ba, and bb To a solution of compound 16G-a (120 mg, 248.74 μmol) in tetrahydrofuran (10 mL) was added Pd(OAc) (55.84 mg, 248.74 μmol) at −20° C., followed by the slow dropwise addition of CHN (0.2 M, 6.22 mL) and the reaction mixture was allowed to react at room temperature for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure to give the crude product, which was then purified by column chromatography (ethyl acetate / petroleum ether = 15%) to give the crude product. Further chiral separation afforded compound 16H-aa (45 mg, yield: 36.44%) as a white solid and compound 16H-ab (40 mg, yield: 32.39%) as a white solid.

[0179] 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.

[0180] 16H-ab (40 mg, yield: 32.39%), white solid. 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.

[0181] SFC separation conditions: Chiral column: Chiralpak IC-3 100 mm × 4.6 mm ID, 3 μm; Mobile phase: A:CO₂B:methanol (0.05% DEA); Gradient: Mobile phase B increased from 5% to 40% within 4 min and maintained for 2.5 min, then mobile phase B was maintained at 5% for 1.5 min; Flow rate: 2.8 mL / min; Column temperature: 35°C; ABPR: 1500 psi; Retention time: t = 2.873 min.

[0182] HPLC conditions: Mobile phase: 2.75 mL / 4 L TFA / water (mobile phase A), 2.5 mL / 4 L TFA / acetonitrile (mobile phase B), increasing from 30% to 90% within 6 minutes using mobile phase B and holding for 2 minutes; flow rate: 1.2 mL / min; chromatography column: Ultimate C18 3.0 x 50 mm, 3 μm; wavelength: UV 220 nm, 215 nm, 254 nm; column temperature: 40 °C; retention time: t = 6.36 min. To a solution of compound 16G-b (120.00 mg, 248.74 μmol) and Pd(OAc) (55.84 mg, 248.74 μmol) in tetrahydrofuran (20 mL) was added CHN (10.45 mg, 248.74 μmol) at -20 °C and the mixture was allowed to react for 16 h at room temperature. After completion of the reaction, the mixture was concentrated under reduced pressure to give the crude product, which was then separated and purified by column chromatography (ethyl acetate / petroleum ether = 15%). Further chiral separation afforded compound 16H-ba (45 mg, yield: 36.44%, retention time: t = 3.711 min), a white solid, and compound 16H-bb (40 mg, yield: 32.39%, retention time: t = 4.242 min), a white solid.

[0183] SFC conditions: Chiral column: (S,S) Whelk-01 100 × 4.6 mm ID, 5.0 μm; Mobile phase: A:CO₂B:ethanol (0.05% DEA); Gradient: Mobile phase B increased from 5% to 40% within 4.5 min and maintained for 1.5 min; Flow rate: 2.5 mL / min; Column temperature: 40 °C; ABPR: 100 bar;

[0184] 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), increasing from 30% to 90% within 6 minutes using mobile phase B and maintaining 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 °C.

[0185] Step 9: Preparation of compounds 16-a, b, c, and d Compound 16H-aa (40 mg, 80 μmol) was dissolved in a mixed solvent of acetonitrile (1 mL) and water (0.5 mL) at room temperature, and aqueous sodium hydroxide (3 M, 80 μL) was added. The mixture was then heated to 60°C and stirred for 2 hours. The reaction mixture was cooled to room temperature, and isobutylboronic acid (41 mg, 0.4 mmol) and hydrochloric acid (100 μL) were added to the reaction solution. The mixture was stirred at room temperature for 30 minutes. After completion of the reaction, the mixture was concentrated under reduced pressure to give the crude product, which was then separated and purified by HPLC (chromatography column: Boston Green ODS 150 × 30 mm × 5 μm; mobile phase: [water(HCl)-ACN]; B%: 40%-60%, 10 min) to give compound 16-a (10 mg, yield: 41%).

[0186] 1 H 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.

[0187] 16b was synthesized using 16H-ab as the starting material in the same manner as 16-a, yielding 17.88 mg: 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.

[0188] 16-c was synthesized using 16H-ba as the starting material in the same manner as 16-a, yielding 15.4 mg: 1 H 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.

[0189] 16-d was synthesized using 16H-bb as the starting material, and the synthesis method was the same as that for 16-a, yielding 21.66 mg: 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.

[0190] Example 17: Synthesis of Compound 17 [ka]

[0191] Step 1: Preparation of Compound 17B Methanesulfonyl chloride (210 mg, 1.84 mmol) was slowly added dropwise to a solution of compound 17A (200 mg, 1.54 mmol) and triethylamine (233 mg, 2.31 mmol) in dichloromethane (4 mL) at -10°C and stirred for 1 hour. After the reaction was completed, the mixture was allowed to return to room temperature, washed with water (10 mL), extracted with dichloromethane (20 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 17B (319 mg, yield: 99%).

[0192] Step 2: Preparation of Compound 17C Compound 15B (70 mg, 0.24 mmol) and potassium carbonate (50.0 mg, 0.36 mmol) were dissolved in N,N-dimethylformamide (1.5 mL) at room temperature. A DMF solution of 17B (60.0 mg, 0.28 mmol) was added dropwise under a nitrogen atmosphere. After the addition was complete, the mixture was heated to 100 °C and stirred for 1 h. After the reaction was complete, the mixture was washed with water and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to give compound 17C (45 mg, 46% yield). MS (ESI) m / z: (M+H) = 401.0.

[0193] Step 3: Preparation of Compound 17D 17C (40.0 mg, 0.1 mmol), pinacol vinyl boronate (46.0 mg, 0.3 mmol), tris(dibenzylideneacetone)dipalladium(0) (9.15 mg, 0.1 mmol), tri-tert-butylphosphonium tetrafluoroborate (6.0 mg, 0.02 mmol), and N,N-diisopropylethylamine (40 mg, 0.3 mmol) were dissolved in toluene (1.5 mL) at room temperature. The mixture was purged with nitrogen three times, heated to 115 °C, and stirred for 2 h. After the reaction was completed, the mixture was cooled to room temperature, washed with water, and extracted with ethyl acetate (3 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and directly concentrated under reduced pressure to give the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to give compound 17D (26 mg, yield: 55%). MS(ESI) m / z: (M+H)+ = 475.2.

[0194] Step 4: Preparation of Compound 17E To a solution of compound 17D (550.0 mg, 1.16 mmol) in tetrahydrofuran (6 mL) was added (1S,2S,3R,5S)-(+)-2,3-pinanediol (591.0 mg, 3.48 mmol) at room temperature and stirred for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound 17E (520.0 mg, 85.2% yield). MS (ESI) m / z (M-H) = 527.2.

[0195] Step 5: Preparation of Compound 17F 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 the mixture was irradiated with LED blue light under a nitrogen atmosphere for 1.5 hours. The mixture was then concentrated under reduced pressure to obtain the crude product, which was then separated and purified by column chromatography (petroleum ether:ethyl acetate = 5:1) to obtain compound 17F (55 mg, yield: 55%). MS (ESI) m / z (M+ H) + =527.2.

[0196] Step 6: Preparation of Compound 17G In an ice bath under a nitrogen atmosphere, compound 17F (130.0 mg, 0.25 mmol) and palladium acetate (5.50 mg, 0.024 mmol) were dissolved in tetrahydrofuran (6 mL) and a diazomethane diethyl ether solution (2.5 mL, 2.5 mmol) was added, followed by stirring for 10 minutes. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to obtain the crude product, which was then separated and purified by column chromatography (petroleum ether:ethyl acetate = 10:1) to obtain compound A3-7 (105.0 mg, yield: 79.0%). MS (ESI) m / z (M+ H) + =540.2

[0197] 17G (220 mg, 0.41 mmol) was separated using a chiral preparative column to give four 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), and 17G-d (36.5 mg, retention time t = 13.983).

[0198] Chiral separation conditions: Chromatography column: Daicel CHIRALPAK® IB 250 × 30 mm, 10 μm; Mobile phase A: n-hexane; Mobile phase B: ethanol; Detection wavelength: 254 nm; Flow rate: 25 mL / min; Isocratic elution program: Mobile phase A: Mobile phase B = 95:05 (V / V).

[0199] Chiral analysis 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 °C; Time: 20 min; Isocratic elution program: Mobile phase A: Mobile phase B = 95:05 (V / V).

[0200] Step 7: Preparation of compounds 17-a, b, c, and d To a solution of compound 17G-a (25 mg, 46.3 μmol) dissolved in acetonitrile (0.6 mL) and water (0.2 mL) at room temperature, NaOH solution (3 M, 150 μL) was added, and the mixture was heated to 60°C and stirred for 1.5 hours. In an ice bath, triethylsilane (0.2 mL), trifluoroacetic acid (1 mL), and isobutylboronic acid (9.41 mg, 92.34 μmol) were added sequentially to the above mixture, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product, which was separated and purified by HPLC to obtain 17-a (10.42 mg).

[0201] 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.

[0202] HPLC 100.00%(254nM); Retention time: t=2.70min. Separation conditions: Chromatography column: Welch Xtimate (registered trademark) C18 21.2 × 250 mm; column temperature: 25 ° C; 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. Analytical conditions: Chromatography column: Waters X Bridge 4.6 × 100 mm, 3.5 μm; column temperature: 40 °C; 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. 17-b was produced using 17G-b as the raw material in the same manner as 17-a, yielding 20.46 mg.

[0203] 1H NMR (400MHz, 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).

[0204] 17-c was produced using 17G-c as the raw material in the same manner as 17-a, yielding 7.91 mg. 1 H 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). - =306.8.

[0205] 17-d was produced using 17G-d as the raw material in the same manner as 17-a, yielding 9.32 mg. 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, MS (ESI) m / z (M- H)-=306.8.

[0206] Example 18: Synthesis of Compound 18 [ka] [ka]

[0207] Step 1: Preparation of Compound 18B Compound 18A (1.0 g, 8.62 mmol) and dimethylhydroxylamine hydrochloride (930.0 mg, 9.48 mmol, 1.1 equiv) were dissolved in dichloromethane (20.0 mL). 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 h. After completion of the reaction, the mixture was quenched with hydrochloric acid (1.0 N) and extracted with ethyl acetate (40 mL × 3). The combined organic phases were washed with aqueous sodium hydroxide (100.0 mL, 1.0 N), dried, filtered, and concentrated to give crude product 18B (1.0 g, yield: 73.0%, colorless liquid), which was used directly in the next step without further purification. 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).

[0208] Step 2: Preparation of Compound 18C Methylmagnesium bromide (2.3 mL, 3.0 M in THF) was slowly added dropwise to a solution of compound 18B (1.0 g, 6.28 mmol) in tetrahydrofuran (10 mL) at 0° C. under an argon atmosphere, and the mixture was stirred for 1 h at 0° C. After completion of the reaction, the mixture was quenched with saturated aqueous ammonium chloride solution, extracted with ethyl acetate (40 mL × 3), dried, filtered, and concentrated under reduced pressure to give crude product 18C (380 mg, yield: 53.0%, yellow liquid), which was used directly in the next step without further purification.

[0209] 1 H 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).

[0210] Step 3: Preparation of Compound 18D To a solution of compound 18C (380.0 mg, 3.33 mmol) in tetrahydrofuran (5.0 mL) was added sodium borohydride (253.0 mg, 6.67 mmol, 2.0 equiv) in a batchwise manner at 0 °C, and the mixture was allowed to warm slowly to room temperature and stirred overnight. After completion of the reaction, the mixture was quenched with hydrochloric acid (1.0 N) and extracted with ethyl acetate (10 mL × 3). The combined organic phases were dried, filtered, and concentrated under reduced pressure to give crude product 18D (126.0 mg, yield: 33.0%, yellow liquid), which was used directly in the next step without further purification.

[0211] 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).

[0212] Step 4: Preparation of Compound 18E 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 completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by column chromatography (ethyl acetate / petroleum ether = 0-10%) to obtain compound 18E (7.0 g, yield: 50.1%, colorless liquid). MS (ESI) m / z (M+ H) + =271.

[0213] Step 5: Preparation of compound 18F A solution of compound 15B (1.0 g, 3.46 mmol) and cesium carbonate (2256 mg, 6.92 mmol, 2 equiv) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 5 min under an argon atmosphere. 18E (1.4 g, 5.19 mmol, 1.5 equiv) was then added and stirred at room temperature for 1 h. After completion of the reaction, the mixture was quenched with saturated aqueous ammonium chloride (100 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to give the crude product. The crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-10%) to give compound 18F (1.0 g, yield: 75.0%, yellow liquid). MS (ESI) m / z (M+ H) + =388.8.

[0214] Step 6: Preparation of Compound 18G (1S,2S,3R,5S)-(+)-2,3-Pinanediol (1.3 g, 7.79 mmol) was added to pinacol vinylboronate (1 g, 6.49 mmol) in tetrahydrofuran (10 mL) at room temperature and stirred for 20 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by column chromatography (PE:EA=9:1) to obtain compound 18G (1.3 g, yield: 97.15%).

[0215] Step 7: Preparation of Compound 18H A solution of compound 18F (1.0 g, 2.58 mmol), 18G (738 mg, 3.1 mmol, 1.2 equiv), tris(dibenzylideneacetone)dipalladium (473 mg, 0.517 mmol, 0.2 equiv), tri-tert-butylphosphonium tetrafluoroborate (297 mg, 1.03 mmol, 0.4 equiv), and diisopropylethylamine (0.674 mL, 3.87 mmol, 1.5 equiv) in acetonitrile (20 mL) was purged with argon gas four times, heated to 100 °C, and stirred for 1.0 h. After completion of the reaction, the mixture was filtered and concentrated under reduced pressure to obtain the crude product. This crude product was purified by column chromatography (ethyl acetate / petroleum ether = 0-15%) to obtain compound 18H (1.2 g, yield: 90.8%). MS (ESI) m / z (M+ H) + =513.0

[0216] Step 8: Preparation of Compound 18I Compound 18H (300.0 mg) was dissolved in dichloromethane (6.0 mL) and tris(2-phenylpyridine)iridium (15.0 mg) was added. The mixture was purged with argon gas four times, and then stirred at room temperature for 2.0 hours under blue light irradiation at 460-465 nm. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by column chromatography (ethyl acetate / petroleum ether = 0-15%) to obtain compound 18I (175.0 mg, yield: 58%). MS (ESI) m / z (M+ H) += 513.0

[0217] Step 10: Preparation of compounds 18J-a, 18J-b, 18J-c, and 18J-d A solution of compound 18I (2.1 g, 4.1 mmol) and palladium acetate (92 mg, 0.41 mmol, 0.1 equiv) in tetrahydrofuran (60 mL) was added to a diethyl ether solution of diazomethane (40 mmol) and stirred at room temperature for 15 minutes. After completion of the reaction, the mixture was concentrated under reduced pressure to give the residue, which was then separated and purified by column chromatography (ethyl acetate / petroleum ether (v / v) = 0-5%) to give the crude product, which was further purified by chiral separation to give 18J-a (324 mg) and 18J-b (167 mg).

[0218] Chiral separation conditions: Chromatography column: Daicel CHIRALPAK® IE250 × 30 mm, 10 μm; Mobile phase: n-hexane (0.2% DEA)-ethanol (0.2% DEA); Ratio of n-hexane to ethanol in the mobile phase: 90:10 (V / V); Flow rate: 25.0 mL / min. 18J-c (232.0mg), 18J-d (284.0mg) Chiral separation conditions: Chromatography column: Daicel CHIRALPAK® IE250×30 mm, 10 μm; Mobile phase: [n-hexane (0.2% DEA)-ethanol (0.2% DEA)]; Ratio of mobile phase n-hexane and ethanol: 95:05 (V / V); Flow rate: 25.0 mL / min.

[0219] 18J-a: Retention time: t=25.930min, HPLC:99.72%; 18J-b: Retention time: t=29.544min, HPLC:97.48%; 18J-c: Retention time: t=5.123min, HPLC: 91.2%; 18J-d: Retention time: t=5.650min, HPLC:98.83%; MS (ESI) m / z (M+ H) + =527.0

[0220] Step 11: Preparation of compounds 18-a, b, c, and d Compound 18J-a (50.0 mg) was dissolved in acetonitrile (0.5 mL) and sodium hydroxide solution (0.3 mL, 3.0 N) was added, followed by stirring in an oil bath at 65°C for 3.0 hours. After the reaction was completed, the mixture was returned to room temperature, the pH was adjusted to 1-2 with hydrochloric acid, isobutylboronic acid (30.0 mg) was added, and stirring was continued for 10 minutes. After the reaction was completed, the mixture was separated and purified by high-performance preparative liquid chromatography to obtain compound 18-a (16.7 mg).

[0221] HPLC separation conditions: Chromatography column: Welch Xtimate (registered trademark) C18 21.2 × 250 mm; column temperature: 25 °C; mobile phase: [water (10.0 mM / L formic acid solution)-acetonitrile]; mobile phase to acetonitrile ratio: 40% to 45%, 15 min; flow rate: 18.0 mL / min.

[0222] 1 H 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, MS (ESI) m / z (M+ H-18) + =317.0

[0223] Compound 18-b was synthesized using 18J- as the starting material, and the preparation process was similar to that of 18-a to obtain 15.9 mg of 18-b. 1 H 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

[0224] Compound 18-c was synthesized using 18J-c as the starting material, and the preparation process was similar to that of 18-a to obtain 15.4 mg of 18-c. 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

[0225] Compound 18-b was synthesized from the starting raw materials used in 18J-d, and the manufacturing process was the same as 18-a and 17.3 mg was obtained from 18-d. 1 H 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, MS (ESI) m / z (M+ H-18)+ =317.0

[0226] Example 19: Synthesis of Compound 19 [ka] [ka] [ka]

[0227] Step 1: Preparation of Compound 19B To a solution of compound 19A (5.00 g, 49 mmol) and N,O-dimethylhydroxylamine hydrochloride (4.78 g, 49 mmol) in dichloromethane (100 mL) was added N,N-carbonyldiimidazole (8.74 g, 54 mmol) and stirred at room temperature for 16 hours. After completion of the reaction, the mixture was quenched with water (100 mL) and extracted with ethyl acetate (80 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (petroleum ether:ethyl acetate = 0-100%) to give compound 19B (6 g, yield: 84.5%).

[0228] Step 2: Preparation of Compound 19C At 0°C under a nitrogen atmosphere, compound 19B (950 mg, 6.55 mmol) was dissolved in tetrahydrofuran (20 mL) and methylmagnesium bromide (13.1 mL, 1N, 13.1 mmol) solution was slowly added dropwise and stirred for 2 hours. After the reaction was completed, the mixture was allowed to return to room temperature, quenched by adding water (20 mL), extracted with ethyl acetate (30 mL x 3), and the combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was separated and purified by column chromatography (petroleum ether:ethyl acetate = 1:1) to give compound 19C (650 mg, yield: 90%).

[0229] 1 H NMR (400 MHz, CDCl3-d) δ 4.78 (m, 4H), 3.9 (m, 1H), 2.15 (s, 3H).

[0230] Step 3: Preparation of Compound 19D Sodium borohydride (451 mg, 11.88 mmol) was added batchwise to a solution of compound 19C in methanol (15 mL) at 0°C and stirred for 1 hour. After completion of the reaction, the mixture was quenched with water (5 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic phases were dried, filtered, and concentrated under reduced pressure to give the crude product, which was then purified by column chromatography (dichloromethane:methanol = 10:1) to give compound 19D (1.1 g, yield: 70.5%). 1 H 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).

[0231] Step 4: Preparation of Compound 19E Compound 19D (750 mg, 7.35 mmol) and triethylamine (1.18 g, 11.76 mmol) were dissolved in dichloromethane (6 mL) and methanesulfonyl chloride (1.09 g, 9.56 mmol) was added in an ice bath and stirred for 2 h. After completion of the reaction, the mixture was quenched with water, extracted with ethyl acetate (50 mL × 3), washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give crude product 19E (1.14 g, 86.4% yield). 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).

[0232] Step 5: Preparation of compound 19F A solution of compound 19E (1.11 g, 6.2 mmol), 15B (1.78 g, 6.2 mmol), potassium carbonate (1.71 g, 12.4 mmol), and potassium iodide (103 mg, 0.62 mmol) in N,N-dimethylformamide (30 mL) was heated to 90 °C under a nitrogen atmosphere and stirred for 2 h. After completion of the reaction, the mixture was cooled to room temperature, poured into ice water, and extracted with ethyl acetate (150 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, which was purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give compound 19F (1.67 g, 72.2% yield). MS (ESI) m / z (M+ H) + =375.0

[0233] Step 6: Preparation of Compound 19G A solution of compound 19F (1.5 g, 4.03 mmol), pinacol vinyl boronate (3.09 g, 20.2 mmol), tris(dibenzylideneacetone)dipalladium (735 mg, 0.804 mmol), tri-tert-butylphosphonium tetrafluoroborate (465 mg, 1.608 mmol), and diisopropylethylamine (777 mg, 6.06 mmol) in acetonitrile (30 mL) was stirred at 90 °C under a nitrogen atmosphere for 1 h. After completion of the reaction, the mixture was allowed to warm to room temperature, filtered, and concentrated under reduced pressure to obtain the crude product. This crude product was then purified by column chromatography (petroleum ether / ethyl acetate = 4:3) to give compound 19G (1.36 g, 75.9% yield). MS (ESI) m / z (M+ H) + =447.0

[0234] Step 7: Preparation of Compound 19H Compound 19G (1.35 g, 3.03 mmol) was dissolved in tetrahydrofuran (30 mL) and (1R,2R,3S,5S)-(-)-2,3-pinanediol (2.06 g, 12.1 mmol) was added at room temperature. The mixture was stirred for 16 hours. After the reaction was completed, the mixture was concentrated under reduced pressure to obtain the crude product. This was then separated and purified using petroleum ether / ethyl acetate (5:1) to obtain compound 19H (900 mg, 59.6% yield). MS (ESI) m / z: (M+H)+ = 499.0

[0235] Step 8: Preparation of Compound 19I Compound 19H (900 mg, 1.8 mmol) dissolved in dichloromethane (7 mL) was added to tris(diphenylpyridine)iridium (24 mg, 0.36 mmol) and irradiated with blue light (wavelength: 460-465 nm, 10 W) for 70 minutes under a nitrogen atmosphere. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by column chromatography (petroleum ether / ethyl acetate = 3:1) to obtain 19I (550 mg, yield: 61%). MS (ESI) m / z: (M+H)+ = 499.0

[0236] Step 9: Preparation of Compounds 19J-a, 19J-b, 19J-c, and 19J-d A diazomethane diethyl ether solution (20 mmol) was added to a THF (3 mL) solution of compound 19I (500 mg, 1 mmol) and Pd(OAc)2 (22 mg, 0.1 mmol) at -20 °C under a nitrogen atmosphere, and the mixture was stirred for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure to give the crude product, which was separated and purified by column chromatography (ethyl acetate / petroleum ether = 0-40%) to give a mixture of compound 19J- (500 mg, yield: 97.6%) as a yellow oil. This mixture was separated and purified by SFC to give four compounds.

[0237] 19J-a, 60mg, yellow solid, retention time: t=8.889min, MS(ESI) m / z:(M+H)+=513.0; 19J-b, 69mg, yellow solid, retention time: t=9.890min, MS(ESI) m / z:(M+H)+=513.0; 19J-c, 71mg, yellow solid, retention time: t=10.979min, MS(ESI) m / z:(M+H)+=513.0; 19J-d, 66mg, yellow solid, retention time: t=12.86min, MS(ESI) m / z:(M+H)+=513.0;

[0238] Chiral separation conditions: Chromatography column: Daicel CHIRALPAK® IB 250 × 30 mm, 10 μm; Mobile phase A: n-hexane; Mobile phase B: isopropanol; Detection wavelength: 254 nm; Flow rate: 25 mL / min; Isocratic elution procedure: Mobile phase A: Mobile phase B = 80:20 (V / V). Chiral analysis 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 °C; Time: 20 min; Isocratic elution procedure: Mobile phase A: Mobile phase B = 80:20 (V / V).

[0239] Step 13: Preparation of Compounds 19-a, 19-b, 19-c, and 19-d Compound 19J-a (40 mg, 78.1 μmol) was dissolved in a mixed solvent of acetonitrile (1 mL) and water (0.2 mL) at room temperature, and aqueous sodium hydroxide (3 M, 330 μL) was added. The mixture was then heated to 60°C and stirred for 3 hours. The reaction mixture was cooled to room temperature, and triethylsilane (0.2 mL), trifluoroacetic acid (1.2 mL), and isobutylboronic acid (24 mg, 0.234 mmol) were added to the reaction solution, followed by stirring at room temperature for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by HPLC to obtain compound 19-a (18 mg, yield: 72%).

[0240] 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, HPLC 100.00%(254nM); Retention time: t=5.379min. MS (ESI) m / z (M-1)-=321.3.

[0241] HPLC separation conditions: Chromatography column: Welch Xtimate (registered trademark) C18 21.2 × 250 mm; column temperature: 25 °C; mobile phase: [water-acetonitrile]; mobile phase to acetonitrile ratio: 30% to 35%, 15 min; flow rate: 18.0 mL / min.

[0242] Analytical conditions: Chromatography column: Waters X Bridge 4.6 × 100 mm, 3.5 μm; column temperature: 40 °C; 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.

[0243] Compound 19-b was synthesized using 19J-b as a starting material, and the preparation process was similar to that of 19-a to obtain 22 mg of 19-b. 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

[0244] Compound 19-c was synthesized from the starting raw materials used in 19J-c, and the manufacturing process was the same as 19-a and 12mg was obtained from 19-c. 1 H 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.

[0245] Compound 19-d was synthesized using 19J-d as the starting material, and 7 mg of 19-d was obtained in the same manner as in 19-a. 1 H 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, MS (ESI) m / z (M+ H-18) +=321.3.

[0246] Example 20: Synthesis of Compound 20 [ka]

[0247] Step 1: Preparation of Compound 20B Sodium borohydride (782 mg, 21 mmol) was added to a solution of compound 20A (4 g, 20 mmol) in methanol (500 mL) at 0°C and stirred for 2 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to remove methanol, potassium hydroxide solution was added, and the mixture was extracted with ethyl acetate (100 mL × 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, which was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to give compound 20B (3.7 g, yield: 91.57%).

[0248] Step 2: Preparation of compound 20C To a solution of compound 20B (3.7 g, 18.4 mmol) and triphenylphosphine (5.8 g, 22.1 mmol) in dichloromethane (50 mL) at 0 °C, carbon tetrabromide (7.3 g, 22.1 mmol) was added in batches, and the mixture was then slowly warmed to room temperature and stirred for 16 h. After completion of the reaction, the mixture was concentrated under reduced pressure to give the crude product, which was then separated and purified by column chromatography (petroleum ether / ethyl acetate = 5:1) to give 20C (3.3 g, yield: 67.95%).

[0249] Step 3: Preparation of Compound 20D Potassium carbonate (5.2 g, 37.5 mmol) was added to a solution of compound 20C (3.3 g, 12.5 mmol) and 15B (3.6 g, 12.5 mmol) in N,N-dimethylformamide (50 mL). The mixture was purged with nitrogen gas, heated to 60°C, and stirred for 6 hours. After completion of the reaction, the mixture was diluted with ethyl acetate, filtered, and concentrated under reduced pressure to obtain the crude product. This was then separated and purified by column chromatography (petroleum ether / ethyl acetate = 2:1) to obtain compound 20D (3.9 g, yield: 66.09%). MS (ESI) m / z (M- H) + =472.0

[0250] Step 4: Preparation of Compound 20E A solution of compound 20D (870 mg, 1.8 mmol), N,N-diisopropylethylamine (250 mg, 1.9 mmol), tri-tert-butylphosphonium tetrafluoroborate (213 mg, 0.7 mmol), tris(dibenzylideneacetone)dipalladium (337 mg, 0.4 mmol), and pinacol vinyl boronate (1.42 g, 9.2 mmol) in acetonitrile (9 mL) was heated to 90 °C under a nitrogen atmosphere for 1 hour. After completion of the reaction, the mixture was diluted with ethyl acetate, filtered, and concentrated under reduced pressure to give crude compound 20E (1 g), which was used directly in the next step without further purification. MS (ESI) m / z (M-H) + =546.2

[0251] Step 5: Preparation of Compound 20F A solution of compound 20E (1.5 g, 2.8 mmol) and (1S,2S,3R,5S)-(+)-2,3-pinanediol (2.3 g, 13.8 mmol) in tetrahydrofuran (20 mL) was stirred at room temperature for 4 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to give crude compound 20F. The crude product was purified using a C18 reverse-phase column (MeCN: 0.2% NH4HCO3 = 5% to 95%) to give the crude product. The crude product was then further separated and purified using normal-phase column chromatography (petroleum ether / ethyl acetate = 4:1) to give compound 20F (1 g, yield: 60.86%). MS (ESI) m / z (M- H) + =598.2

[0252] Step 6: Preparation of Compound 20G Compound 20F (200 mg, 0.33 mmol) and tris(2-phenylpyridine)iridium (11 mg, 0.02 mmol) were dissolved in acetonitrile (6 mL), purged with nitrogen gas, and stirred at room temperature for 1 hour under 10 W blue light. After the reaction was complete, the mixture was concentrated under reduced pressure to obtain the crude product, which was then separated and purified by column chromatography (petroleum ether / ethyl acetate = 4:1) to obtain compound 20G (105 mg, yield: 52.50%). MS (ESI) m / z (M- H) + = 598.2

[0253] Step 7: Preparation of compounds 20H-a, 8b, 8c, and 8d Compound 20G (645 mg, 1.1 mmol) and palladium acetate (24 mg, 0.1 mmol) were dissolved in tetrahydrofuran (15 mL). The atmosphere was purged with nitrogen gas, and then a diethyl ether solution of diazomethane (7.2 mL, 21.6 mmol) was added at 0 °C. The mixture was stirred at room temperature for 1 h. After completion of the reaction, the mixture was diluted with dichloromethane and filtered to remove solids. The filtrate was concentrated under reduced pressure to give the crude product. The crude product was separated and purified by column chromatography (petroleum ether / ethyl acetate = 4.5:1) to give the crude product (550 mg, yield: 83.32%). Further chiral separation gave 94 mg of 20H-a; 50 mg of 20H-b; 54 mg of 20H-c; and 112 mg of 20H-d. MS (ESI) m / z (M- H) +=612.2. Holding time: 20H-a:t=10.620min;20H-b:t=9.075min;20H-c:t=10.741min;20H-d:t=14.542min.

[0254] Chiral separation conditions for 20H-a and 20H-d: 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; Isocratic elution procedure: Mobile phase A: Mobile phase B = 85:15 (V / V).

[0255] 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; Isocratic elution procedure: Mobile phase A: Mobile phase B = 85:15 (V / V).

[0256] 20H-b, 20H-c chiral separation 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; Isocratic elution procedure: Mobile phase A: Mobile phase B = 60:40 (V / V).

[0257] 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; Isocratic elution procedure: Mobile phase A: Mobile phase B = 60:40 (V / V) (V / V).

[0258] Step 8: Preparation of Compounds 20I-a, b, c, and d To a solution of compound 20H-a (60 mg, 0.1 mmol) in dichloromethane (3 mL) was added 2,6-dimethylpyridine (42 mg, 0.39 mmol) and trimethylsilyl trifluoromethanesulfonate (106 mg, 0.59 mmol) sequentially at 0°C and stirred for 2 h. After completion of the reaction, the mixture was concentrated under reduced pressure to give the crude product, which was then separated and purified by column chromatography (DCM:MeOH (0.1% NH) = 9:1) to give compound 20I-a (50 mg, yield: 99.64%).

[0259] Step 9: Preparation of Compounds 20I-a, b, c, and d A solution of compound 20I-a (50 mg, 0.1 mmol) in dichloromethane (1 mL) was added with aqueous formaldehyde (0.3 mL) at room temperature. After stirring at room temperature for 1 hour, sodium triacetoxyborohydride (41 mg, 0.2 mmol) was added to the reaction solution, and stirring was continued for 1 hour. After completion of the reaction, the mixture was quenched with saturated sodium bicarbonate solution and extracted with ethyl acetate (10 mL × 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by column chromatography (DCM:MeOH (0.1% NH3) = 9:1) to obtain compound 20I-a (33 mg, yield: 64.24%). MS (ESI) m / z (M- H) + =526.0

[0260] Step 10: Preparation of Compounds 20-a, b, c, and d To a solution of compound 20I-a (33 mg, 0.06 mmol) in acetonitrile (1 mL), water (0.1 mL) and 3N sodium hydroxide (188 μL, 0.57 mmol) were added sequentially and stirred at 60°C for 4 hours. TFA (0.5 mL), triethylsilane (0.1 mL), and isobutylboronic acid (19 mg, 0.19 mmol) were added sequentially and stirred for 1 hour. After completion of the reaction, the pH was adjusted to approximately 6, and the mixture was concentrated under reduced pressure to obtain the crude product. This was then purified by HPLC to obtain the crude product compound (12 mg, yield: 72.6%). 0.5 mL of water was added, followed by 3M sodium hydroxide (19.8 μL, 0.059 mmol), and the mixture was stirred at 60°C for 1 hour. Purification using a C18 reverse-phase column (separation conditions: chromatography column: Redi-GOLD (registered trademark) C18 10 μm 33 × 147 mm; mobile phase: [water-acetonitrile]; flow rate: 30 mL / min) gave compound 20-a (6.59 mg, yield: 26.6%). 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.

[0261] Using the same method as in the synthesis of Example 20-a, Examples 20-b to 34-b were synthesized, as shown in Table 1 below: [Table 1-1]

[0262] Table 1-2

[0263] Table 1-3

[0264] Table 1-4

[0265] Table 1-5

[0266] Table 1-6

[0267] Table 1-7

[0268] Table 1-8

[0269] Table 1-9

[0270] Table 1-10

[0271] Table 1-11

[0272] [Table 1-12]

[0273] [Table 1-13]

[0274] [Table 1-14]

[0275] [Table 1-15]

[0276] [Table 1-16]

[0277] [Table 1-17]

[0278] Test Example 1: Enzyme activity test Compound stock solutions: Compounds were prepared in 50 mM stock solutions in DMSO. The positive control compound VNRX-5133 was prepared in 50 mM stock solutions in DMSO. Compound stock solutions were aliquoted and stored at -20°C. Preparation and storage of antibiotic substrate stock solution: The antibiotic fluorescent substrate FC5 was synthesized in-house, prepared to a 2 mM stock solution, aliquoted, and stored at -20°C.

[0279] Storage of β-lactamase: Each β-lactamase was synthesized by Genscript Biotech Corporation and stored at −80°C after aliquoting to avoid repeated freezing and thawing.

[0280] Preparation of enzyme activation reaction buffer: SBL buffer: PBS pH 7.4, 0.01% (v / v) Triton X-100; MBL buffer: 50 mM HEPES in PBS pH 7.2, 1 μM ZnSO, 1 μg / mL BSA, 0.01% v / v Triton X-100 The buffer was stored at 4°C.

[0281] Experimental steps: a) The test compound and buffer solution were removed and allowed to warm to room temperature. b) Each compound was diluted in DMSO and buffer to an initial experimental concentration (Table 2), and then the compound was diluted 3-fold for a total of 10 concentrations. c) Diluted compounds were added to wells 1-20 of a 384-well black plate in duplicate at each concentration, 5 μL per well. 5 μL of DMSO was added to each of wells 21-24. d) Each enzyme was diluted to the experimental concentration (Table 2) with SBL and MBL buffers, and finally added to a total of 22 wells at 35 μL / well. 35 μL of buffer was added to wells 23-24. Here, wells 21-22 were set as the highest test value (Max), and wells 23-24 were set as the lowest test value (Min). e) Quickly centrifuged and incubated at room temperature for 10 minutes. f) The antibiotic substrate FC5 was diluted in buffer to the experimental concentration for each enzyme (Table 2). g) After incubation, the 384-well plate was removed, and 10 μL of FC-5 was added to each of wells 1 to 24. After quick centrifugation, the plate was immediately transferred to a microplate reader and read. h) Fluorescence intensity at an excitation wavelength of 355 nm / emission wavelength of 460 nm was measured 10 times in total every 3 minutes using a microplate reader.

[0282] The experimental concentrations are as shown in Table 2. [Table 2] Initial enzyme reaction velocity (V): The background reading (Min well) without enzyme was subtracted from each fluorescence intensity reading, and a linear regression analysis was performed for each compound concentration group. The slope of the regression line was the initial enzyme reaction velocity (V) at each compound concentration.

[0283] Compound dose-effect curves and IC 50 Calculation of IC: The initial rate of the enzyme reaction under the influence of each concentration of compound was fitted by nonlinear regression to obtain the formula IC 50 IC = (1-Vi / V0) x 100 (Vi: initial enzyme reaction velocity at each compound concentration, V0: initial enzyme reaction velocity without compound (Maxwell)) 50 was calculated using Graphpad Prism 8 software.

[0284] [Table 3] As shown in Table 3, the compounds of the present invention can effectively inhibit four types of β-lactamase compounds, A, B, C, and D, and have significant advantages in inhibitory activity compared with compound VNRX-5133. The commercially available drug avibactam has good activity against A and C class serine β-lactamases (SBLs), but has no inhibitory effect against B class metal zinc ion β-lactamases (MBLs), and also shows low inhibitory effect against D class serine β-lactamases.

[0285] Test Example 2: Minimum Inhibitory Concentration (MIC) Test of Compounds Against Bacterial Growth (1) Main reagents and consumables: (2) [Table 4]

[0286] (2) Strains: [Table 5]

[0287] (3) Experimental method Preparation of strains: Test strains were streaked onto Mueller Hinton II Agar plates from glycerol tubes at -80°C, and cultured in a 37°C incubator for 18 to 24 hours.

[0288] Culture medium preparation: CAMHB (Mueller Hinton II Broth): 22 g of powder was dissolved in 1 L of purified water and sterilized at 121°C for 10 minutes before use. Saline: 8.5 g of NaCl was dissolved in 1 L of purified water and sterilized at 121°C for 30 minutes before use. Preparation of compound and antibiotic mother solution: Compound and antibiotic were dissolved in DMSO or water to a concentration of 12.8 mg / mL.

[0289] Two-fold gradient antibiotic dilution: 300 μL of CAMHB medium was added to columns 2 to 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 evenly to achieve a concentration of 512 μg / mL. 300 μL of antibiotic solution was transferred from column 1 to column 2 and mixed evenly. This process was repeated until columns 11 and 12 were used as blank controls.

[0290] Dilution of combination compounds: Compounds were diluted 400-fold to 32 ug / ml in CAMHB medium. Dispense working solution: Use a pipette to dispense 25 µL of antibiotic into a 96-U bottom plate, then add 25 µL of combination compound to each well. If antibiotic was used alone, add 25 µL of CAMHB medium.

[0291] Preparation of inoculum solution: Five to six single colonies were picked from the plate and suspended in saline. Using a turbidity meter, the bacterial suspension was adjusted to a turbidity of 0.2 (i.e., McFarland turbidity 0.5), with a bacterial concentration of approximately 1–2 × 10. 8 The bacterial suspension was diluted 100-fold with CAMHB medium for use.

[0292] Inoculation: Using a pipette, 50 μL of inoculation solution was transferred to the 50 μL compound plate above. Culture: The 96-U bottom plate was placed in a 37°C incubator and cultured for 18 to 20 hours.

[0293] (4) MIC evaluation: After incubation was completed, bacterial growth was visually observed, and photographs of the test plates were taken, recorded, and archived. The minimum compound concentration at which bacterial growth was completely inhibited was defined as the minimum inhibitory concentration (MIC).

[0294] [Table 6-1]

[0295] [Table 6-2]

[0296] [Table 6-3]

[0297] [Table 6-4]

[0298] [Table 6-5]

[0299] [Table 6-6]

[0300] [Table 6-7]

[0301] [Table 6-8]

[0302] [Table 6-9]

[0303] As shown in Table 6, the compounds of the present invention can effectively restore the activity of the antibiotics cefepime / meropenem / biapenem against carbapenem-resistant Acinetobacter baumannii strains. VNRX5133 + cefepime / meropenem was essentially ineffective against all drug-resistant strains of Acinetobacter baumannii (MIC ≥ 32 μg / mL), while the compounds of the present invention + meropenem / biapenem were effective against all drug-resistant strains and were significantly more advantageous in activity and inhibition spectrum than the VNRX5133 + cefepime combination. (Addendum) The invention of the present disclosure includes the following aspects. <Item 1> A compound represented by formula (I), its optical isomer, and a pharmaceutically acceptable salt thereof. [ka] (where, X is S, S(=O) and S(=O) 2 is selected from L 1 is a single bond, C 1-6 Alkyl and C 1-6 heteroalkyl, wherein C 1-6 Alkyl or C 1-6 heteroalkyl is optionally substituted by 1, 2 or 3 R; L 2 is a single bond, C 3-6 cycloalkyl and 4- to 9-membered heterocycloalkyl, 3-6 the cycloalkyl or 4- to 9-membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; L 3 is a single bond, C 1-6 Alkyl, C 1-6 heteroalkyl and 4- to 9-membered heterocycloalkyl, 1-6 Alkyl, C 1-6 heteroalkyl or 4- to 9-membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; R 1 NH 2 、

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

change

Claims

1. A compound represented by formula (I), its optical isomers and pharmaceutically acceptable salts thereof. 【Chemistry 1】 (where, X is S, S(=O) and S(=O) ２ is selected from L １ is C １－６ Alkyl and C １－６ heteroalkyl, wherein C １－６ Alkyl or C １－６ heteroalkyl is optionally substituted by 1, 2 or 3 R; L ２ is a single bond, C ３－６ cycloalkyl and 4- to 9-membered heterocycloalkyl, ３－６ the cycloalkyl or 4- to 9-membered heterocycloalkyl is optionally substituted by 1, 2, or 3 R; L ３ is a single bond, C １－６ Alkyl and C １－６ heteroalkyl, wherein C １－６ Alkyl or C １－６ heteroalkyl is optionally substituted by 1, 2 or 3 R; R １ is NH ２ , -NR ａ C(=NH)R ｂ , -NR ａ C(=NH)NR ｂ１ R ｂ２ , —C(═NH)R ｂ , C ３－６ cycloalkyl, 4- to 8-membered heterocycloalkyl, partially unsaturated 4- to 8-membered heterocycloalkyl, and 5- to 6-membered heteroaryl; ３－６ the cycloalkyl, 4- to 8-membered heterocycloalkyl, partially unsaturated 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heteroaryl is optionally substituted by 1, 2, or 3 R; R is independently H, F, Cl, Br, OH, or NH ２ , CN and C １－６ alkyl, R a , R b1 and R b2 are each independently selected from H and C 1-6 alkyl; each R b is independently selected from H, NH 2 and C 1-6 alkyl; Said C １－６ Heteroalkyl, 4- to 9-membered heterocycloalkyl, partially unsaturated 4- to 8-membered heterocycloalkyl, or 5- to 6-membered heteroaryl may be selected from the group consisting of one, two, or three independently selected from O, NH, S, C(=O), C(=NH), C(=O)O, S(=O), S(=O) ２ and N.

2. The compound represented by formula (I) according to claim 1, its optical isomer, and its pharmaceutically acceptable salt, which are selected from the compounds represented by formulas (IA) and (IB), their optical isomers, and their pharmaceutically acceptable salts. 【Chemistry 2】 (where, X, L １ , L ２ , L ３ and R １ is as defined in claim 1.

3. R is independently F, Cl, Br, OH, or NH ２ , C.H. ３ , and 【Transformation 3】 The compound of claim 1, its optical isomers and pharmaceutically acceptable salts thereof, selected from:

4. L １ is C １－３ Alkyl, —C １－３ Alkyl-O-, -C １－３ Alkyl-S-, -C １－３ Alkyl-NH- and -C １－３ alkyl-C(=O)-, wherein said C １－３ Alkyl, —C １－３ Alkyl-O-, -C １－３ Alkyl-S-, -C １－３ Alkyl-NH- or -C １－３ The compound of claim 1, its optical isomers and pharmaceutically acceptable salts thereof, wherein alkyl-C(=O)- is optionally substituted by 1, 2 or 3 R.

5. L １ is CH ２ , 【Chemistry 4】 is optionally substituted by one, two or three R, its optical isomers and pharmaceutically acceptable salts thereof.

6. L １ is CH ２ , 【Transformation 5】 The compound according to claim 5, its optical isomers and pharmaceutically acceptable salts thereof, selected from:

7. L ２ is selected from a single bond, 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 optionally substituted by one, two, or three R, its optical isomers, and pharmaceutically acceptable salts thereof.

8. L ２ is a single bond, 【Transformation 6】 The compound according to claim 7, its optical isomers and pharmaceutically acceptable salts thereof, selected from:

9. L ３ represents a single bond, C(=O), C １－３ Alkyl, —C １－３ Alkyl-C(=O)- and -C １－３ alkyl-C(=O)NH-, １－３ Alkyl, —C １－３ Alkyl-C(=O)- or -C １－３ 2. The compound of claim 1, its optical isomers and pharmaceutically acceptable salts thereof, wherein alkyl-C(=O)NH- is optionally substituted by 1, 2 or 3 R.

10. L ３ is a single bond, C(=O), 【Transformation 7】 The compound according to claim 9, its optical isomers and pharmaceutically acceptable salts thereof, selected from:

11. R １ is NH ２ , 【Transformation 8】 Cyclopropyl, cyclobutyl, oxetanyl, azetidinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-2H-pyranyl, morpholinyl, piperidinyl, piperazinyl, octahydrocyclopentadiene[c]pyrrolyl, 4,5-dihydro-1H-imidazolyl, imidazolyl, imidazoline-2-imino, tetrahydropyrimidine-2(1H)-imino, 2,6-diazaspirillum cyclopropyl, cyclobutyl, oxetanyl, azetyl, 2-oxa-6-azaspiro[3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 2,6-diazaspiro[3.4]octyl, 3,6-diazabicyclo[3.1.1]heptyl and 2,5-diazabicyclo[2.2.1]heptyl; dihydro-1H-imidazolyl, imidazolyl, imidazoline-2-imino, tetrahydropyrimidine-2(1H)-imino, 2,6-diazaspiro[3.3]heptyl, 2-oxa-6-azaspiro[ 3.3]heptyl, 2,6-diazaspiro[3.4]octyl, 6-oxa-2-azaspiro[3.4]octyl, 2,6-diazaspiro[3.4]octyl, 3,6-diazabicyclo[3.1.1]heptyl, or 2,5-diazabicyclo[2.2.1]heptyl is optionally substituted by one, two, or three R, its optical isomers, and pharmaceutically acceptable salts thereof.

12. R １ is NH ２ , 【Chemistry 9】 and 【Chemistry 10】 is optionally substituted by 1, 2 or 3 R, its optical isomers and pharmaceutically acceptable salts thereof.

13. R １ is NH ２ , 【Chemistry 11】 13. The compound of claim 12, its optical isomers and pharmaceutically acceptable salts thereof, selected from:

14. Structural Unit 【Chemistry 12】 【Chemistry 13】 【Chemistry 14】 【Chemistry 15】 14. The compound of claim 13, its optical isomers and pharmaceutically acceptable salts thereof, selected from:

15. A compound represented by the following formula, an optical isomer thereof, and a pharmaceutically acceptable salt thereof, selected from the following formulas: 【Chemistry 16】 【Chemistry 17】 [Chemistry 18] 【Chemistry 19】

16. A compound represented by the following formula, an optical isomer thereof, and a pharmaceutically acceptable salt thereof, selected from the following formulas: 【Chemistry 20】 【Chemistry 21】

17. Use of the compound according to any one of claims 1 to 16, its optical isomers and pharmaceutically acceptable salts thereof in the manufacture of a medicament for treating a bacterial infection.

18. The use according to claim 17, characterized in that it comprises a combination of the compound, its optical isomers and its pharmaceutically acceptable salts with other β-lactam antibiotics.

19. The use according to claim 18, characterized in that the β-lactam antibiotic is selected from penicillins, cephalosporins, carbapenems, monocyclic β-lactam antibiotics or combinations thereof.

20. The penicillin antibiotic is selected from acid-resistant penicillin, enzyme-resistant penicillin, ampicillin, amoxicillin, pivampicillin, carbenicillin, sulfenicillin, ticarcillin, fulvencillin, azlocillin, and piperacillin; Optionally, the cephalosporin antibiotic is selected from cephalexin, cephradine, cefazolin, cefuroxime, cefamandole, cefaclor, cefotaxime, ceftazidime, ceftriazine, cefoperazone, ceftizoxime, cefepime, cefpirome, and ceftolozane; Optionally, the carbapenem antibiotic is selected from imipenem, meropenem, panipenem, biapenem, ertapenem, and faropenem; 20. The use according to claim 19, optionally characterized in that the monocyclic β-lactam antibiotic is selected from aztreonam.

Images