Boronic acid compounds

Abstract

The present invention provides novel boronic acid compounds, specifically compounds represented by formula (II) or (II'), pharmaceutically acceptable salts thereof, or stereoisomers thereof, and uses thereof in drugs for treating diseases associated with bacterial infections. TIFF2023538645000178.tif38170

Description

[Technical Field]

[0001] The present invention relates to novel boronic acid compounds, specifically compounds represented by formula (II) or (II'), pharmaceutically acceptable salts thereof or stereoisomers thereof, and their use in drugs for treating bacterial infection-related diseases. [Background technology]

[0002] Since British scientist Fleming first expressed penicillin in 1928, countless lives have been saved by β-lactam antibiotics. With the emergence of various β-lactamases, β-lactam antibiotics are increasingly losing their activity. For example, serine hydrolases ESBLs, KPCs, and metallo-β-lactamases (MBLs) are becoming increasingly prevalent in various bacteria, and the safety risks they pose to humans are becoming more serious. Compounds such as phenylboronic acid have a significant inhibitory effect on metallo-β-lactamases (MBLs).

[0003] The launch of combination drugs of antibiotics such as meropenem / vaborbactam and boronic acid β-lactamase inhibitors has led to expectations for the development of boronic acid β-lactamase inhibitors. Rempex Pharmaceuticals (WO2018 / 005662A1) has reported a boronic acid β-lactamase inhibitor obtained by modifying phenylboronic acid, and optimization of this series of compounds has resulted in the compound QPX7728, which is currently undergoing Phase 1 clinical development. This compound is currently being clinically tested by Qpex Biopharma. In addition, another compound currently under development for boronic acid β-lactamase inhibitors is VNRX-5133 (WO2014 / 089365) being developed by VenatoRx Pharmaceuticals, which is currently in Phase 3 clinical trials. [ka]

[0004] Based on the severe drug resistance situation, it is urgent to develop a new generation of broad-spectrum β-lactamase inhibitors to solve the current drug resistance problem. The boronic acid molecule in the present invention has corresponding potential in this regard.

Summary of the Invention

[0005] The present invention relates to formula (II) or (II’)

Chemical Formula

[0006] In some embodiments of the present invention, the above compound is of formula (II-1), (II'-1), (II-2), or (II'-2) [ka] [In the formula, R1, R2, R3, R4, R5, R6, and R7 are as defined in this invention.] It has the structure shown in [image / diagram].

[0007] In some embodiments of the present invention, the above compound is of formula (I) or (I') [ka] [In the formula, T, R1, R2, R3, R4, R5, and R6 are as defined in this invention.] It has the structure shown in [image / diagram].

[0008] The present invention relates to formula (I) [ka] [In the formula, B is boron.] T is -O-, -S-, or -Se-. R1 is -OH or C 1-3 It is an alkoxy group. R2 and R3 are each independently H or C 1-3 The alkyl group is, among others, the C 1-3 The alkyl group may be substituted with one, two, or three substituents independently selected from F, Cl, Br, I, -OH, and -OCH3. R4 is H, F, Cl, Br, or I. R5 is H, F, Cl, Br, I, or C 1-3 It is an alkoxy group. R6 is H, F, Cl, Br, I, -OR a or C 1-3 The alkyl group is, among others, the C 1-3 The alkyl group may be substituted with one, two, or three substituents independently selected from F, Cl, Br, I, -OH, and -OCH3. R a H or C 1-3 The alkyl group is, among others, the C 1-3 The alkyl group consists of 1, 2, or 3 independently selected elements from F, Cl, Br, I and [ka] It may be substituted with substituents selected from the following. The present invention provides the compound indicated by or a pharmaceutically acceptable salt thereof.

[0009] In some embodiments of the present invention, the above compound is of formula (I-1), (I'-1), (I-2), or (I'-2) [ka] [In the formula, R1, R2, R3, R4, R5, and R6 are as defined in this invention.] It has the structure shown in [image / diagram].

[0010] In some embodiments of the present invention, the above compound is of formula (I-1) or (I-2) [ka] [In the formula, R1, R2, R3, R4, R5, and R6 are as defined in this invention.] It has the structure shown in [image / diagram].

[0011] In some embodiments of the present invention, the pharmaceutically acceptable salt is of formula (I-3), (I-4), (I-5), or (I-6) [ka] [In the formula, R2, R3, R4, R5, and R6 are as defined in this invention.] It has the structure shown in [image / diagram].

[0012] In some embodiments of the present invention, the above pharmaceutically acceptable salt is formula (I-3) or (I-4) [ka] [In the formula, R2, R3, R4, R5, and R6 are as defined in this invention.] It has the structure shown in [image / diagram].

[0013] In some embodiments of the present invention, each of the above R1 is independently -OH or -OCH3, and the other variables are as defined in the present invention.

[0014] In some embodiments of the present invention, R1 is -OH or -OCH3, and the other variables are as defined in the present invention.

[0015] In some embodiments of the present invention, R2 and R3 are independently H or -CH3, and the other variables are as defined in the present invention.

[0016] In some embodiments of the present invention, R4 is H, F, Cl, -CH3, or -OCH2CH3, and the other variables are as defined in the present invention.

[0017] In some embodiments of the present invention, R5 is H, F, Cl, or -OCH3, and the other variables are as defined in the present invention.

[0018] In some embodiments of the present invention, each of the above R is independently F, Cl, Br, I, -CH3 or [ka] And among them, the -CH3 or [ka] Each of these consists of one, two, or three independent F, Cl, Br, I and [ka] The substituents may be substituted with substituents selected from the above, and the other variables are as defined in this invention.

[0019] In some embodiments of the present invention, each of the above R is independently F, Cl, Br, I, -CH3, [ka] The other variables are as defined in this invention.

[0020] In some aspects of the present invention, each of the above R a1 These are F, Cl, Br, I, -OCH3, independently. [ka] And among them, -OCH3, [ka] Each of these may be independently substituted by one, two, or three Rs, where R and the other variables are as defined in this invention.

[0021] In some aspects of the present invention, each of the above R a1 These are F, Cl, Br, I, -OCH3, independently. [ka] And R and the other variables are as defined in this invention.

[0022] In some aspects of the present invention, each of the above R a1 These are F, Cl, Br, I, -OCH3, independently. [ka] That is the case.

[0023] In some embodiments of the present invention, the above R a H, -CH3, -CH2CH3, [ka] Among them, -CH3, -CH2CH3, [ka] Each of these consists of 1, 2, or 3 R components, each independently. a1 It may also be substituted by R a1 And other variables are as defined in the present invention.

[0024] In some embodiments of the present invention, the above R a H, -CH3, [ka] And R a1 And other variables are as defined in the present invention.

[0025] In some embodiments of the present invention, the above R a H, -CH3, [ka] The other variables are as defined in this invention.

[0026] In some embodiments of the present invention, the above R a These are H, -CH3, or -CH2CH3, and among these, -CH3 and -CH2CH3 are 1, 2, or 3 independent F, Cl, Br, I and [ka] The substituents may be substituted with substituents selected from the above, and the other variables are as defined in this invention.

[0027] In some embodiments of the present invention, the above R a H, -CH3, -CF3, -CH2CH3 or [ka] The other variables are as defined in this invention.

[0028] In some embodiments of the present invention, R6 is H, F, Cl, Br, I, -OR a or -CH3, in which the -CH3 consists of 1, 2, or 3 independent F, Cl, Br , may be substituted with substituents selected from I, -OH and -OCH3, R a And other variables are as defined in the present invention.

[0029] In some embodiments of the present invention, the above R6 is H, F, Cl, Br, I, -OH, -OCH3, -OCH2CH3, -CH3, -CH2OH, -CH2OCH3, [ka] The other variables are as defined in this invention.

[0030] In some embodiments of the present invention, R6 is H, F, Cl, Br, I, -OH, -OCH3, -OCF3, -OCH2CH3, [ka] It is -CH3 or -CH2OH, and the other variables are as defined in this invention.

[0031] In some embodiments of the present invention, the above-mentioned constituent unit [ka] but, [ka] The other variables are as defined in this invention.

[0032] In some aspects of the present invention, each of the above R b H is independent of the other variables, and the other variables are as defined in this invention.

[0033] In some aspects of the present invention, each of the above R c1 The first variable is independently -OCH3, and the other variables are as defined in this invention.

[0034] In some embodiments of the present invention, the above R c H, -CH3, -CH2CH3, [ka] Among them, -CH3, -CH2CH3, [ka] Each of these consists of 1, 2, or 3 R components, each independently. c1 It may also be substituted by R c1 And other variables are as defined in the present invention.

[0035] In some embodiments of the present invention, R7 is H, [ka] The other variables are as defined in this invention.

[0036] Several other aspects of the present invention can be obtained by arbitrarily combining the above variables.

[0037] The present invention further provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof. [ka] [ka] [ka]

[0038] The present invention further provides a compound represented by the following formula. [ka] [ka] [ka] [ka] [ka]

[0039] In some embodiments of the present invention, the pharmaceutically acceptable salt is a sodium salt.

[0040] The present invention further provides a drug composition comprising the above compound or a pharmaceutically acceptable salt thereof, a β-lactam bacteriostatic agent, and a pharmaceutically acceptable carrier in a therapeutically effective amount.

[0041] In some aspects of the present invention, the above-mentioned β-lactam bacteriostatic agent is penicillin, cephalosporin These include rosporines, cephamycins, oxacepham, carbapenems, or monobactams.

[0042] In some aspects of the present invention, the above-mentioned β-lactam bacteriostatic agent is amoxicillin, piperacillin, ticarcillin, azurocillin, mezurocillin, cefazolin, cefradin, cephalothin, cefuroxime, cefaclor, cefotiam, cefprodil, cefotaxime, ceftriaxone, ceftazidime, cefoperazone, ceftizoxime, cefmenoxime, cefozidime, cefpodoximeproxetil, cefixime, ceftibuten, cefpirom, cefepime, cefoxitin, cefmetazole, panipenem, aztreonam, carmonam, cefoxitin, cefmetazole, latamoxef, flomoxef, imipenem, meropenem, ceftolozane, or cefiderocol. In some aspects of the present invention, the above-mentioned β-lactam bacteriostatic agent is meropenem.

[0043] The present invention further provides the use of the above compound, a pharmaceutically acceptable salt thereof, or the above drug composition in the manufacture of β-lactamase inhibitor drugs.

[0044] The present invention further provides the use of the above-mentioned compounds, pharmaceutically acceptable salts thereof, or drug compositions as drugs for treating bacterial infection-related diseases. In some embodiments, the bacterial infection-related disease is caused by bacteria expressing β-lactamase. In some embodiments, the bacterial infection-related disease is caused by Klebsiella pneumoniae or Escherichia coli. Technical Effects

[0045] This invention provides a novel boronic acid β-lactamase inhibitor that, when used in combination with antibiotics, exhibits strong bacteriostatic activity, particularly against various bacteria expressing β-lactamase. It has good water solubility, provides good exposure levels whether administered orally or intravenously, exhibits excellent pharmacokinetic properties, and is safe. When used in combination with antibiotics, it rapidly restores antibiotic activity and exhibits good efficacy, making it suitable for the treatment of diseases associated with bacterial infections.

[0046] Definition and Description Unless otherwise specified, the following terms used herein are intended to have the following meanings. Certain terms should not be considered ambiguous or unclear in the absence of a specific definition, but should be understood in their ordinary sense. Where a trade name is mentioned herein, it refers to the corresponding product or its active ingredient.

[0047] Here, the term “pharmaceutically acceptable” means that, within the bounds of reliable medical judgment, these compounds, materials, compositions, and / or dosage forms are suitable for use in contact with human and animal tissues, without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that the benefits / risks are commensurate with a reasonable ratio.

[0048] The term "pharmaceutically acceptable salt" refers to a salt of the compound of the present invention prepared by reacting a compound having a specific substituent discovered in the present invention with a relatively non-toxic acid or base. If the compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include salts of sodium, potassium, calcium, ammonium, organic amines or magnesium, or similar salts. If the compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of acid in a pure solution or a suitable inert solvent. Pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts. Examples of the inorganic acid salts include those of hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, bisulfate, hydroiodic acid, and phosphorous acid. As for the organic acid salts... Examples include salts of similar acids such as acetic acid, propionic acid, isobutyric 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, as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Some specific compounds of the present invention contain both basic and acidic functional groups and can therefore be converted into either a base addition salt or an acid addition salt.

[0049] The pharmaceutically acceptable salts of the present invention can be prepared from parent compounds containing acidic or basic moieties by conventional chemical methods. Generally, such salts are prepared by reacting these compounds as free acids or bases with stoichiometric amounts of appropriate bases or acids in water, an organic solvent, or a mixture thereof.

[0050] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention envisions all such compounds and includes cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures containing many enantiomers or non-enantiomers, all of which are within the scope of the present invention. Other chiral carbon atoms may be present in substituents such as alkyl groups. All of these isomers and mixtures thereof are within the scope of the present invention.

[0051] Unless otherwise specified, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0052] Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" refer to the inability of the double bond or the single bond of the ring-forming carbon atoms to rotate freely.

[0053] Unless otherwise specified, the term "diastereomer" refers to a stereoisomer in which a molecule has two or more chiral centers and the molecules are non-mirror images of each other.

[0054] Unless otherwise specified, "(+)" represents right-handed rotation, "(-)" represents left-handed rotation, and "(±)" represents racemic rotation.

[0055] Unless otherwise specified, wedge-shaped solid line connections [ka] and wedge-shaped dotted line connections [ka] The absolute arrangement of the center of a solid is connected by rod-shaped solid lines. [ka] and bar-shaped dotted line connections [ka] The relative arrangement of the center of a single solid is shown by the wavy line. [ka] wedge-shaped solid line connection [ka] or wedge-shaped dotted line joint [ka] or a wavy line [ka] Rod-shaped solid line connection [ka] and bar-shaped dotted line connections [ka] It represents.

[0056] Unless otherwise specified, the term "tautomer" or "tautomer form" means that isomers of different functional groups are in dynamic equilibrium at room temperature and can rapidly convert to each other. If tautomerism is possible (e.g., in solution), then chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversions via proton transfer, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via the recombination of some bonding electrons. An example of keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypento-3-en-2-one.

[0057] Unless otherwise specified, the terms "rich in one isomer," "rich in isomers," "rich in one enantiomer," or "rich in enantiomers" mean that the content of one isomer or enantiomer is less than 100%, and that isomer or enantiomer content is 60% or more. Or it means 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0058] Unless otherwise specified, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is present in 90% quantity and the other isomer or enantiomer is present in 10% quantity, the isomer or enantiomer excess (ee value) is 80%.

[0059] Optically active (R) and (S) isomers, and D and L isomers, are prepared by chiral synthesis, chiral reagents, or other prior art. If one enantiomer of a compound of the present invention is desired, the pure enantiomer of the desired type can be obtained by asymmetric synthesis or by induction with chiral auxiliaries, including separation of the resulting diastereomer mixture and cleavage of auxiliary groups. Alternatively, if the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), the compound is reacted with an appropriate optically active acid or base to form a salt of the diastereomer isomer, and then the diastereomer is separated by methods common in the art to recover the pure enantiomer. Furthermore, enantiomers and diastereoisomers are generally isolated by chromatography using a chiral stationary phase, optionally combined with chemical induction methods (e.g., generating carbamates from amines).

[0060] The compounds of the present invention may contain isotopes in unnatural proportions in one or more atoms constituting the compound. The compounds of the present invention may contain isotopic atoms in unnatural proportions in one or more atoms constituting the compound. For example, tritium ( 3 H), Iodine-125( 125 I) or C-14 ( 14Compounds labeled with radioactive isotopes, such as C), are used. As another example, hydrogen can be replaced with deuterium to form deuterated drugs. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared to non-deuterated drugs, deuterated drugs have advantages such as reduced toxic side effects, improved drug stability, enhanced efficacy, and extended biological half-life. All isotopic compositional variations of the compounds of the present invention, whether or not they are radioactive, are included within the scope of this disclosure.

[0061] The terms "optional" or "optional" mean that the subsequent matters or conditions may but are not necessarily to occur, including when the above matters or conditions occur and when they do not.

[0062] The terms “effective dose” or “therapeutic effective dose” in relation to pharmaceutically or pharmacologically active agents refer to a non-toxic but sufficient amount of the agent or agent to achieve the desired effect. For the oral dosage forms of the present invention, the “effective dose” of one active substance in the composition refers to the amount required to achieve the desired effect when used in combination with another active substance in the composition. Determining the effective dose varies from person to person, depending on age, the general state of receptors, and the specific active substance; however, the appropriate effective dose in a case can be determined by those skilled in the art based on usual experiments.

[0063] The term "substituted" refers to the substitution of one or more hydrogen atoms on a particular atom by a substituent, and may include deuterium and hydrogen variants, provided that the valence of the particular atom is normal and the substituted compound is stable. When the substituent is an oxo group (i.e., =O), it means that two hydrogen atoms are substituted. Positions on an aromatic ring cannot be substituted with an oxo group. "May be substituted" means that the atom is substituted by the substituent. This means that substitution is optional, and unless otherwise specified, the type and number of substituents may be arbitrary as long as it is chemically feasible.

[0064] If any of the variables (e.g., R) appear once or more in the composition or structure of a compound, the definitions for each case are independent. Therefore, for example, if a group is substituted with 0 to 2 R atoms, that group may be substituted with at most 2 R atoms, and the R atoms in each case are independent choices. Furthermore, combinations of substituents and / or their variants are permitted only if they result in a stable compound.

[0065] When the number of linking groups is 0, such as in -(CRR)0-, it means that the linking group is a single bond.

[0066] When one variable represents a single bond, it means that the two groups connected by that single bond are directly bonded. For example, if L in ALZ represents a single bond, the structure is essentially AZ.

[0067] If a substituent is empty, it means that the substituent is not present; for example, if X in AX is empty, the structure is essentially A. If it is not specified which atom the substituent is bonded to the group being substituted, such substituents may be bonded to any atom; for example, a pyridyl group as a substituent may be bonded to the group being substituted via any carbon atom of the pyridine ring.

[0068] If the direction of connection of the listed linking groups is not specified, the direction of connection is arbitrary. For example, [ka] If the linking group L in is -MW-, then -MW- links ring A and ring B in the same direction as the reading order from left to right. [ka] This is also acceptable, and ring A and ring B are connected in the reverse direction of the reading order from left to right. [ka] It may be. The combinations of the above-mentioned linking groups, substituents and / or their variants are allowed only when such combinations result in stable compounds.

[0069] Unless otherwise specified, when a group has one or more bondable sites, any one or more sites of the group can be bonded to other groups by chemical bonds. When the bonding mode of the chemical bond is delocalized and there are H atoms at the bondable sites, when the chemical bond is formed, the number of H atoms at the site decreases to a group with a corresponding valence according to the number of the formed chemical bonds. The chemical bond by which the site is bonded to other groups is a solid straight-line bond

Chemical Structure

Chemical Structure

Chemical Structure

Chemical Structure

[0070] Unless otherwise specified, "B" in the present invention represents boron.

[0071] Unless otherwise specified, "alkyl group of C 1-3 " refers to a straight-chain or branched-chain saturated hydrocarbon group containing 1 to 3 carbon atoms. The alkyl group of C 1-3 includes alkyl groups of C 1-2 and C 2-3 and may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methylene). Examples of the alkyl group of C 1-3 include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc. Unless otherwise specified, "alkenyl group of C 2~8 " represents a straight-chain or branched-chain hydrocarbon group of 2 to 8 carbon atoms containing at least one carbon-carbon double bond, and the carbon-carbon double bond may be located at any position in this group. The alkenyl group of C 2~8 includes alkenyl groups of C 2~6 、C 2~4 、C 2~3 、C4, C3, and C2 alkenyl groups, etc., and may be monovalent, divalent, or polyvalent. Examples of the alkenyl group of C 2~8 include, but are not limited to, vinyl group, propenyl group, butenyl group, pentenyl group, hexenyl group, butyldienyl group, pentyldienyl group, hexenyl group, etc.

[0072] Unless otherwise specified, the term "alkyl group of C 1-6 " refers to a straight-chain or branched-chain saturated hydrocarbon group containing 1 to 6 carbon atoms. The alkyl group of C 1-6 includes alkyl groups of C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C6 and C5 alkyl, which can be monovalent (e.g., methyl group), divalent (e.g., methylene group), or polyvalent (e.g., methine group). Examples of the alkyl group of C 1-6 include, but are not limited to, methyl group (Me), ethyl group (Et), propyl group (including n-propyl group and isopropyl group), butyl group (including n-butyl group, isobutyl group, s-butyl group, t-butyl group), pentyl group (including n-pentyl group, isopentyl group and neopentyl group), hexyl group, etc.

[0073] Unless otherwise specified, the term "alkoxy group of C 1-3 " refers to an alkyl group containing 1 to 3 carbon atoms bonded to the rest of the molecule through one oxygen atom. The alkoxy group of C 1-3 includes alkoxy groups of C 1-2 , C[[ID=3​​​​​​​​where p is 1 or 2), and includes a group having a partially unsaturated cyclic group and a partially cross-linked structure, and the non-aryl heterocyclic ring can form a condensed ring with an aryl group or a heteroaryl group. The 5- to 6-membered oxygen-containing non-aryl heterocyclic ring includes 5-membered and 6-membered oxygen-containing non-aryl heterocyclic rings and the like. The 5- to 6-membered oxygen-containing non-aryl heterocyclic ring includes a 5- to 6-membered heterocyclic alkenyl group. Examples of the 5- to 6-membered heterocyclic alkenyl group include [Chemical Formula] but are not limited thereto.

[0075] Unless otherwise specified, C n-n+m or C n -C n+m includes any case where the number of carbon atoms is from n to n + m. For example, C 1-12 is C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 and also includes any range from n to n + m. For example, C 1-12 is C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 and the like. Similarly, n-member to n + m-member represents that the number of atoms in the ring is from n to n + m. 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 from n to n + m. 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 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring and the like.

[0076] The term "leaving group" refers to a functional group or atom that has been substituted with another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction). For example, typical leaving groups include trifluoromethanesulfonic acid esters; chlorine, bromine, iodine; sulfonic acid esters such as methanesulfonic acid esters, toluenesulfonic acid esters, p-bromobenzenesulfonic acid esters, and p-toluenesulfonic acid esters; and acyl oxy groups such as acetyloxy and trifluoroacetyloxy.

[0077] The term "protecting group" includes, but is not limited to, "amino protecting groups," "hydroxy protecting groups," or "mercapto protecting groups." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group. Typical amino protecting groups include, but are not limited to, formyl; acyls such as alkanoyls (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyls such as t-butoxycarbonyl (Boc); arylmethoxycarbonyls such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyls such as benzyl (Bn), triphenylmethyl (Tr), and 1,1-bis(4'-methoxyphenyl)methyl; and silyls such as trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS). The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions of a hydroxyl group. Typical hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl, and t-butyl; acyl groups such as alkanoyl groups (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (DPM); and silyl groups such as trimethylsilyl (TMS) and t-butyldimethylsilyl (TBS).

[0078] The compounds of the present invention can be produced by various synthesis methods familiar to those skilled in the art, including, but not limited to, the specific embodiments listed below, embodiments combined therewith with other chemical synthesis methods, and equivalent alternative methods familiar to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

[0079] The structure of the compounds of the present invention can be confirmed by conventional methods familiar to those skilled in the art, and if the present invention relates to the absolute configuration of a compound, such absolute configuration can be confirmed by conventional means of the art. For example, in single-crystal X-ray diffraction (SXRD), diffraction intensity data is collected from a grown single crystal using a Bruker D8 venture diffractometer, the light source is CuKα radiation, and after collecting relevant data using the scanning mode: φ / ω scanning, the absolute configuration can be confirmed by further analyzing the crystal structure using a direct method (Shelxs97).

[0080] In this invention, the following abbreviations are used: aq represents water; eq represents equivalent; DCM represents dichloromethane; DMF represents N,N-dimethylformamide; DIPEA represents diisopropylethylamine; EA represents ethyl acetate; ₹ is , represents ethyl acetate. THF represents tetrahydrofuran. MeCN represents acetonitrile. NCS represents N-chlorosuccinimide. NBS represents N-bromosuccinimide. PE represents petroleum ether. TFA represents trifluoroacetic acid. TFAA represents trifluoroacetic anhydride. TEA represents triethylamine. HPLC represents high-performance liquid chromatography. Boc2O represents di-t-butyl dicarbonate. DMAP represents 4-dimethylaminopyridine. LDA represents diisopropylaminolithium. DIAD represents diisopropyl azodicarboxylic acid. SEM-Cl represents 2-(trimethylsilyl)ethoxymethyl chloride. CD3OD represents deuterated methanol. CDCl3 represents deuterated chloroform. D2O represents deuterated water. CFU represents colony-forming units. iv represents intravenous injection. ip represents intraperitoneal injection. PPh3 represents triphenylphosphine. Pd(Pph3)2Cl2.CH2Cl2 represents the 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex. Pd(Pph3)2Cl2 represents [1,1'-bis(diphenylphosphino)ferrocene]palladium. LiHMDS represents lithium hexamethyldisilazane. LiAlH4 represents lithium tetrahydroaluminate. [Examples]

[0081] The present invention will be described in detail below with reference to examples, but this does not mean to impose any limitations on the present invention. The compounds of the present invention can be produced by various synthesis methods familiar to those skilled in the art, including, but not limited to, the specific embodiments listed below, embodiments combined with other chemical synthesis methods, and equivalent alternative methods familiar to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention. Clearly, various modifications and improvements can be made to specific embodiments of the present invention, without departing from the spirit and scope of the present invention, for those skilled in the art.

[0082] Example 1 [ka]

[0083] Process 1: Production of Compound 1-2 To a solution of Compound 1-1 (100 g, 523.57 mmol, 1 eq) in DCM (1000 mL), DMAP (3.20 g, 26.18 mmol, 0.05 eq) and Boc2O (137.12 g, 628.28 mmol, 144.34 mL, 1.2 eq) were added. The mixed solution was stirred at 25 °C for 1 hour. The mixed solution was washed with 100 mL of dilute HCl aqueous solution (0.5 m ol / L). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain Compound 1-2.

[0084] Process 2: Production of Compound 1-3 At -70 °C, LDA (2 M, 329.77 mL, 1.2 eq) was added dropwise to a solution of Compound 1-2 in THF (1500 mL), and the mixture was stirred for 2 hours. This mixed solution was washed with HCl aqueous solution (2 mol / L, 500 mL) and extracted with EtOAc (100 mL×1). The organic phase was washed with brine (300 mL×l), then dried over anhydrous Na2SO4, and then filtered. The filtrate was concentrated under reduced pressure to obtain a crude product. This crude product was washed with petroleum ether / ethyl acetate = 3 / 1 (100 mL), filtered, and the filter cake was dried to obtain Product 1-3.

[0085] Process 3: Production of Compound 1-4 TFA (79.57 g, 697.81 mmol, 51.67 mL, 6.55 eq) was added dropwise to a solution of Compound 1-3 (31 g, 106.49 mmol, 1 eq) in DCM (50 mL). Then, the mixed solution was stirred at 20 °C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was washed with DCM (50 mL), filtered under reduced pressure, and the filter cake was dried to obtain Compound 1-4. 1 1H NMR (400 MHz, CD3OD) δ = 7.74 (dd, J = 5.5, 9.0 Hz, 1H), 6.67 (dd, J = 8.9, 10.5 Hz, 1H).

[0086] Process 4: Production of Compound 1-5 Compounds 1-4 (25 g, 106.38 mmol, 1 eq) were dissolved in a mixed solution of DMF (1.5 mL) and acetone (63.20 g, 1.09 mol, 80 mL, 10.23 eq). At 0°C, TFAA (151.00 g, 718.94 mmol, 100 mL, 6.76 eq) and TFA (10 mL) were added dropwise to the mixed solution. The mixed solution was heated to 100°C and stirred for 12 hours. The mixed solution was placed in saturated Na₂CO₃ (500 mL) and stirred for 10 minutes. Further extraction was performed with ethyl acetate (150 mL x 2). The combined organic phase was washed with saline solution (15 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. After purifying the residue by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 20 / 1), the crude product was washed with PE (40 mL), filtered, and the filter cake was dried under reduced pressure to obtain compounds 1-5. 1 H NMR (400MHz, CDCl3) δ=7.72-7.63(m,1H),6.78-6.65(m,1H),1.77-1.64(m,6H).

[0087] Step 5: Production of Compounds 1-6 Under nitrogen gas protection, compounds 1-5 (8.8 g, 31.99 mmol, 1 eq), bis(pinacolato)diborone (12.19 g, 47.99 mmol, 1.5 eq), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (5.23 g, 6.40 mmol, 0.2 eq), and potassium acetate (9.42 g, 95.98 mmol, 3 eq) were dissolved in dioxane (100 mL), replaced three times with N2, and the mixed solution was stirred at 65°C for 5 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to obtain compound 1-6.

[0088] Step 6: Production of Compounds 1-7 Compounds 1-6 (4.24 g, 13.16 mmol, 1 eq) were dissolved in a mixed solvent of tetrahydrofuran (40 mL) and water (20 mL). Sodium perborate tetrahydrate (5.06 g, 32.91 mmol, 2.5 eq) was added at 0°C, and the mixture was then stirred at 25°C for 1 hour under the protection of nitrogen gas. 20 mL of water was added to the reaction mixture, and ethyl acetate was added. The mixture was extracted with 20 mL x 2, washed with saline solution (40 mL x 1), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by washing with petroleum ether (10 mL), filtered, and the filtered cake was dried under vacuum to obtain compounds 1-7.

[0089] Step 7: Production of Compounds 1-8 Compound 1-7 (457 mg, 1.84 mmol, 1 eq) and compound 2-(2-bromopropan-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (389.49 mg, 1.84 mmol, 1 eq) were dissolved in DMF (5 mL). Potassium carbonate (279.08 mg, 2.02 mmol, 1.1 eq) was added to this mixture at 25°C, and the mixture was stirred at 25°C for 12 hours. 15 mL of water was added to the mixture, extracted with ethyl acetate (20 mL x 3), washed with saline solution (20 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 0 / 1 to 1 / 1) to obtain compound 1-8. LCMS (ESI) m / z: 381.2 (M+1).

[0090] Process 8: Manufacturing of Compound 1 Compounds 1-8 (37 mg, 97.31 μmol, 1 eq) were dissolved in isopropanol (1 mL), and NaOH (3 M, 64.88 μL, 2 eqs) was added at 0°C. The mixture was then stirred at 25°C for 2 hours. The reaction solution was filtered and purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 1% to 10%, 8 min) to obtain compound 1.1 H NMR (400MHz, CD3OD) δ = 6.75 (dd, J = 5.4, 8.8 Hz, 1H), 6.41 (dd, J = 8.9, 10.5 Hz, 1H), 1.14 (s, 6H); LCMS (ESI) m / z: 223.1 (M-18+1).

[0091] Example 2 [ka]

[0092] Step 1: Manufacturing of Compound 2 Compound 1-8 (100 mg, 263.01 μmol, 1 eq) was dissolved in MeOH (2 mL), and an aqueous sodium hydroxide solution (3 mol / L, 175.34 μL, 2 eqs) was added to this mixture at 0°C. The mixture was then stirred at 25°C for 2 hours. This reaction mixture was separated and purified by preparative high-performance liquid chromatography (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase 1% to 31%, 9 min) to obtain compound 2. 1 H NMR(400MHz,CD3OD)δ=6.66(dd,J=5.8,8.9Hz,1H),6.33(t,J=9.0Hz,1H),3.88(s,3H),1.13(s,6H);LCMS(ESI)m / z:255.1(M+1).

[0093] Example 3 [ka]

[0094] Process 1: Manufacturing of Compound 3-2 Compound 3-1 (5 g, 27.45 mmol, 1 eq) was dissolved in chloroform (100 mL), and liquid bromine (4.39 g, 27.45 mmol, 1.41 mL, 1 eq) was added to this mixture at 0°C. The mixture was then stirred at 25°C for 30 hours. This mixture was concentrated under vacuum, and the residue was washed with (petroleum ether / ethyl acetate = 5 / 1, 40 mL) to purify it and obtain compound 3-2. 1 H NMR (400MHz, CDCl3) δ = 12.87 (s, 1H), 7.62 (d, J = 8.9Hz, 1H), 6.40 (d, J = 8.9Hz, 1H), 4.02 (s, 3H).

[0095] Step 2: Production of Compound 3-3 Compound 3-2 (5.44 g, 22.02 mmol, 1 eq) was dissolved in DMF (0.2 mL) and acetone (13.43 g, 231.24 mmol, 17 mL, 10.50 eq). Anhydrous trifluoroacetic acid (31.71 g, 150.98 mmol, 21 mL, 6.86 eq) and trifluoroacetic acid (2 mL) were added to this mixture at 0°C, and the mixture was stirred at 100°C for 12 hours. The reaction solution was placed in saturated sodium carbonate aqueous solution (100 mL) and stirred for 10 minutes. It was extracted with ethyl acetate (50 mL x 2), washed with saline solution (15 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The solution was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 0 / 1 to 3 / 1) to obtain compound 3-3. 1 H NMR (400MHz, CDCl3) δ = 7.60 (d, J = 9.0 Hz, 1H), 6.51 (d, J = 9.0 Hz, 1H), 3.89 (s, 3H), 1.68 (s, 6H); LCMS (ESI) m / z: 286.9 (M + 1).

[0096] Step 3: Production of Compounds 3-4 Compound 3-3 (1.52 g, 5.29 mmol, 1 eq) and bis(pinacolato)diborone (3.36 g, 13.24 mmol, 2.5 eq) were mixed and dissolved in dioxane (15 mL). Potassium acetate (1.56 g, 15.88 mmol, 3 eq) and the 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex were added to this mixture, and the mixture was stirred at 65°C for 5 hours under the protection of nitrogen gas. Ethyl acetate (20 mL) was added to this mixture, and the mixture was filtered and concentrated under vacuum. 50 mL of water was added to the concentrate, and it was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saline solution (50 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 0 / 1 to 5 / 1) to obtain compound 3-4. LCMS(ESI)m / z:335.1(M+1).

[0097] Step 4: Production of Compounds 3-5 Compound 3-4 (1.45 g, 4.34 mmol, 1 eq) was dissolved in a mixed solution of tetrahydrofuran (20 mL) and water (10 mL), and sodium perborate tetrahydrate (1.67 g, 10.85 mmol, 2.09 mL, 2.5 eq) was added to this mixture at 0°C. This mixture was stirred at 25°C for 1 hour. 20 mL of water was added to the mixture, and it was extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saline solution (40 mL x 1), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to obtain compound 3-5. 1 H NMR (400MHz, CDCl3) δ = 7.08 (d, J = 9.0 Hz, 1H), 6.48 (d, J = 9.0 Hz, 1H), 3.84 (s, 3H), 1.68 (s, 6H); LCMS (ESI) m / z: 225.0 (M + 1).

[0098] Step 5: Production of Compounds 3-6 2-Iodomethyl-boronic acid pinacol ester (1.00 g, 3.75 mmol, 3 eq) and compound 3-5 (280 mg, 1.25 mmol, 1 eq) were dissolved in acetonitrile (5 mL), and K2CO3 (258.90 mg, 1.87 mmol, 1.5 eq) was added to this mixture at 25 °C. The mixture was then stirred at 65 °C for 4 hours under the protection of nitrogen gas. 10 mL of water was added to the mixture, and it was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saline solution (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound 3-6. LC-MS (ESI) m / z: 283.1 (M+1).

[0099] Step 6: Production of Compound 3 Compound 3-6 (355 mg, 1.26 mmol, 1 eq) was dissolved in isopropanol (2 mL), and an aqueous sodium hydroxide solution (1 M, 3.78 mL, 3 eqs) was added at 0°C. The mixture was then stirred at 25°C for 2 hours. After filtration, the filtrate was separated by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 1% to 6%, 5 min) to obtain compound 3. 1 H NMR (400MHz, CD3OD) δ = 6.50 (d, J = 8.7 Hz, 1H), 6.19 (d, J = 8.8 Hz, 1H), 3.72 (s, 3H), 3.39 (s, 2H); LCMS (ESI) m / z: 207.0 (M-18+1).

[0100] Example 4 [ka]

[0101] Process 1: Production of Compound 4-2 Compound 1-7 (1 g, 4.71 mmol, 1 eq) was dissolved in acetic acid (15 mL), NCS (755.21 mg, 5.66 mmol, 1.2 eq) was added, and the reaction mixture was stirred at 105°C for 12 hours under the protection of nitrogen gas. 20 mL of water was added to the mixture, and it was extracted with ethyl acetate (20 mL x 1). The combined organic phase was washed with saline solution (10 mL x 1), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was flushed with silica gel. The compound 4-2 was obtained by purification using column chromatography (petroleum ether / ethyl acetate = 10 / 0 to 8 / 1). 1 H NMR (400MHz, CD3OD) δ=7.06-6.97(m,1H),1.79(s,6H).

[0102] Step 2: Production of Compound 4-3 Compound 4-2 (250 mg, 1.01 mmol, 1 eq) was dissolved in acetonitrile (5 mL), and 2-iodomethyl-boronic acid pinacol ester (543.14 mg, 2.03 mmol, 2 eq) and potassium carbonate (210.16 mg, 1.52 mmol, 1.5 eq) were added. The reaction mixture was then stirred at 60°C for 3 hours under the protection of nitrogen gas. Water (20 mL) was added to the mixture and extracted with ethyl acetate (20 mL × 1). The combined organic phase was washed with saline solution (20 mL × 1), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. Separation was performed by preparative high-performance liquid chromatography (chromatographic column: Phenomenex luna C18 150 × 40 mm × 15 μm, mobile phase: pure aqueous solution containing 0.1% TFA and acetonitrile, acetonitrile content in mobile phase 25%~55%, 10 min) to obtain compound 4-3.

[0103] Step 3: Manufacturing of Compound 4 Compound 4-3 (200 mg, 656.89 μmol, 1 eq) was dissolved in isopropanol (2 mL), and under the protection of nitrogen gas, an aqueous NaOH solution (1 mol / L, 1.31 mL, 2 eqs) was gradually added at 0°C. The reaction mixture was then heated to 25°C under the protection of nitrogen gas and stirred for 1 hour. The mixture was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 1% to 6%, 4 min) to obtain compound 4. 1 H NMR (400MHz, CD3OD) δ=6.39 (d, J=8.8Hz, 1H), 3.46 (s, 2H); LCMS (ESI) m / z: 246.9 (M+1).

[0104] Example 5 [ka]

[0105] Process 1: Manufacturing of Compound 5-2 Compound 5-1 (3.7g, 17.84 mmol, 1 eq) was dissolved in DCM (40 mL), and Boc2O (4.67g, 21.40 mmol, 4.92 mL, 1.2 eq) and DMAP (108.95 mg, 891.77 μmol, 0.05 eq) were added to each solution. The reaction mixture was then stirred at 25°C for 16 hours under the protection of nitrogen gas. 20 mL of water was added to the mixture, and the pH was adjusted to 3-4 with 0.5 mol / L hydrochloric acid solution. The mixture was extracted with dichloromethane (50 mL x 2), washed with saline solution (100 mL x 2), dried over anhydrous Na₂SO₄, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 5-2. 1 H NMR (400MHz, CDCl3) δ=7.45(d,J=8.6Hz,1H),7.16(d,J=2.3Hz,1H),7.04(dd,J=2.3,8.6Hz,1H),1.49(s,9H).

[0106] Step 2: Production of Compound 5-3 Compound 5-2 (5.4 g, 17.56 mmol, 1 eq) was dissolved in THF (60 mL), and LDA (2 M, 10.53 mL, 1.2 eq) was gradually added at -78 °C under the protection of nitrogen gas. The reaction mixture was then stirred at -78 °C for 2 hours under the protection of nitrogen gas, and the reaction was quenched by adding NH4Cl (50 mL) to the mixture. The mixture was extracted with ethyl acetate (40 mL x 3), washed with saline solution (100 mL x 2), and the combined organic phase was dried over anhydrous Na2SO4. It was filtered and concentrated under vacuum, and the residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to obtain compound 5-3. 1 H NMR (400MHz, CDCl3) δ=11.61(s,1H),7.44(d,J=8.6Hz,1H),6.78(d,J=8.6Hz,1H),1.57(s,9H).

[0107] Step 3: Production of Compound 5-4 Compound 5-3 (1 g, 3.25 mmol, 1 eq) was dissolved in DCM (4 mL), and trifluoroacetic acid (6.16 g, 54.02 mmol, 4 mL, 16.62 eq) was gradually added at 0°C under the protection of nitrogen gas. The reaction mixture was then raised to 25°C under the protection of nitrogen gas and stirred for 12 hours, concentrated under vacuum, and further stirred with dichloromethane (5 mL) at room temperature. The mixture was filtered, the filter cake was washed with dichloromethane, and the filter cake was collected to obtain compound 5-4. 1 H NMR (400MHz, CD3OD) δ=7.59(d,J=8.6Hz,1H),6.93(d,J=8.6Hz,1H).

[0108] Step 4: Production of Compound 5-5 Compound 5-4 (3.3 g, 13.12 mmol, 1 eq) was dissolved in TFA (20 mL), and acetone (2.29 g, 39.37 mmol, 2.89 mL, 3 eq) was added. The reaction mixture was then added to TFAA (8.27 g, 39.37 mmol, 5.48 mL, 3 eq) and DMF (191.85 mg, 2.62 mmol, 201.94 μL, 0.2 eq) at 0°C under nitrogen gas protection, and the temperature was raised to 105°C and stirred for 32 hours. The mixture was concentrated under vacuum, saturated NaHCO3 (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The mixture was washed with saline solution (50 mL x 2), the organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to obtain compound 5-5. 1 H NMR (400MHz, CDCl3) δ = 7.59 (d, J = 8.6 Hz, 1H), 7.02 (d, J = 8.6 Hz, 1H), 1.71 (s, 6H); LCMS (ESI) m / z: 292.8 (M + 1).

[0109] Step 5: Production of Compounds 5-6 Compound 5-5 (1.4 g, 4.80 mmol, 1 eq), bis(pinacolato)diborone (1.83 g, 7.20 mmol, 1.5 eq), 1,1'-bis(diphenylphosphinos)ferrocene-palladium(II) dichloride-dichloromethane complex (784.35 mg, 960.47 μmol, 0.2 eq), and potassium acetate (1.41 g, 14.41 mmol, 3 eq) were dissolved in anhydrous dioxane (20 mL). The mixture was purged three times with nitrogen gas, heated to 65°C and stirred for 5 hours, and concentrated under vacuum. The residue was filamented in silica gel. The compounds were purified by sch column chromatography (petroleum ether / ethyl acetate = 10 / 0~0 / 1) to obtain compounds 5-6. LCMS (ESI) m / z: 339 (M+1).

[0110] Step 6: Production of Compounds 5-7 Compound 5-6 (2.9 g, 8.56 mmol, 1 eq) was dissolved in THF (18 mL) and H2O (9 mL), and sodium perborate tetrahydrate (2.64 g, 17.13 mmol, 3.29 mL, 2 eq) was added. The reaction mixture was then stirred at 25°C for 2 hours under the protection of nitrogen gas. H2O (10 mL) was added to the mixture, and it was extracted with ethyl acetate (20 mL x 3). The organic phase was washed with saline solution (50 mL x 2), dried over Na2SO4, filtered, concentrated under vacuum, and purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain compound 5-7. LCMS (ESI) m / z: 229 (M+1).

[0111] Step 7: Production of Compounds 5-8 Compound 5-7 (840 mg, 3.67 mmol, 1 eq) was dissolved in acetonitrile (10 mL), and 2-iodomethyl-boronic acid pinacol ester (1.97 g, 7.35 mmol, 2 eq) and K2CO3 (761.69 mg, 5.51 mmol, 1.5 eq) were added. The reaction mixture was then stirred at 60°C for 3 hours under the protection of nitrogen gas. Water (10 mL) was added to the mixture, and it was extracted with ethyl acetate (10 mL x 3). The organic phase was washed with saline solution (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The mixture was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain compound 5-8. LCMS (ESI) m / z: 287 (M+1).

[0112] Process 8: Manufacturing of Compound 5 Compound 5-8 (200 mg, 698.15 μmol, 1 eq) was dissolved in isopropanol (1 mL), and under the protection of nitrogen gas, an aqueous NaOH solution (1 mol / L, 1.40 mL, 2 eqs) was gradually added at 0°C. The reaction mixture was then stirred at 0-25°C for 1 hour under the protection of nitrogen gas. The mixture was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 1%-6%, 4 min) to obtain compound 5.1 H NMR (400MHz, CD3OD) δ=6.48 (s, 2H), 3.41 (s, 2H); LCMS (ESI) m / z: 229 (M+1); 211 (M-18+1).

[0113] Example 6 [ka]

[0114] Step 1: Preparation of Compound 6-2 Compound 6-1 (10 g, 47.85 mmol, 1 eq) was dissolved in DCM (100 mL), and Boc2O (12.53 g, 57.42 mmol, 13.19 mL, 1.2 eq) and DMAP (292.28 mg, 2.39 mmol, 0.05 eq) were added to each. The reaction mixture was then stirred at 25°C for 16 hours under the protection of nitrogen gas. 50 mL of water was added to the mixture, and it was extracted with dichloromethane (50 mL x 2). The combined organic phase was washed with saline solution (100 mL x 2), dried over Na2SO4, filtered, and concentrated under vacuum to obtain compound 6-2. 1 H NMR (400MHz, CDCl3) δ=7.37(dd,J=8.0,9.3Hz,1H),7.04(dd,J=7.3,10.1Hz,1H),1.50(s,9H).

[0115] Step 2: Production of Compound 6-3 Compound 6-2 (8.1 g, 26.20 mmol, 1 eq) was dissolved in THF (90 mL), and LDA (2 M, 19.65 mL, 1.5 eq) was gradually added at -78°C under the protection of nitrogen gas. The reaction mixture was then stirred at -78°C for 2 hours under the protection of nitrogen gas. Saturated NH4Cl aqueous solution (50 mL) was added to the mixture, and it was extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with saline solution (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to obtain compound 6-3. 1H NMR (400MHz, CDCl3) δ=11.77(s, 1H), 7.59-7.41(m, 1H), 1.56(s, 9H).

[0116] Step 3: Production of Compound 6-4 Compound 6-3 (5.1 g, 16.50 mmol, 1 eq) was dissolved in DCM (15 mL), and trifluoroacetic acid (23.10 g, 202.59 mmol, 15.00 mL, 12.28 eq) was gradually added at 0°C under the protection of nitrogen gas. The reaction mixture was then heated to 25°C under the protection of nitrogen gas and stirred for 2 hours. The mixture was concentrated under vacuum, and then washed with dichloromethane (25 mL) at room temperature. The mixture was filtered, and the filtered cake was collected to obtain compound 6-4. 1 H NMR (400MHz, CD3OD) δ=7.77 (dd, J=8.1, 9.9Hz, 1H).

[0117] Step 4: Production of Compounds 6-5 Compound 6-4 (2.5 g, 9.88 mmol, 1 eq) was dissolved in TFA (30 mL), and acetone (1.72 g, 29.64 mmol, 2.18 mL, 3 eq) was added. The reaction mixture was then added to TFAA (6.23 g, 29.64 mmol, 4.12 mL, 3 eq) and DMF (144.46 mg, 1.98 mmol, 152.06 μL, 0.2 eq) at 0°C under nitrogen gas protection, and the temperature was raised to 105°C and stirred for 32 hours. The mixture was concentrated under vacuum, saturated NaHCO3 aqueous solution (50 mL) was added, and extraction was performed with ethyl acetate (20 mL x 3). The organic phase was washed with saline solution (50 mL x 2), dried over anhydrous Na2SO4, filtered, concentrated under vacuum, and the residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to obtain compound 6-5. 1 H NMR (400MHz, CDCl3) δ=7.60 (dd, J=7.7, 9.3Hz, 1H), 1.71 (s, 6H); LCMS (ESI) m / z: 294 (M+1).

[0118] Step 5: Production of Compound 6-6 Compound 6-5 (900 mg, 3.07 mmol, 1 eq), bis(pinacolato)diborone (1.17 g, 4.61 mmol, 1.5 eq), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (501.58 mg, 614.21 μmol, 0.2 eq), and potassium acetate (904.19 mg, 9.21 mmol, 3 eq) were dissolved in anhydrous dioxane (10 mL). The mixture was purged three times with nitrogen gas, heated to 65°C and stirred for 5 hours, and concentrated under vacuum. The mixture was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 10 / 0~0 / 1) to obtain compound 6-6. LCMS (ESI) m / z: 341 (M+1).

[0119] Process 6: Production of Compounds 6-7 Compound 6-6 (680 mg, 2.00 mmol, 1 eq) was dissolved in a mixed solution of THF (6 mL) and H2O (3 mL), and sodium perborate tetrahydrate (922.82 mg, 6.00 mmol, 1.15 mL, 3 eq) was added. The reaction mixture was then stirred at 25°C for 2 hours under the protection of nitrogen gas. H2O (10 mL) was added to the mixture, and it was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saline solution (80 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain compound 6-7. LCMS (ESI) m / z: 231.4 (M+1).

[0120] Step 7: Production of Compounds 6-8 Compounds 6-7 (320 mg, 1.39 mmol, 1 eq) were dissolved in acetonitrile (5 mL), and 2-iodomethylboronic acid pinacol ester (744.93 mg, 2.78 mmol, 2 eq) and K2CO3 (384.30 mg, 2.78 mmol, 2 eq) were added. The reaction mixture was then stirred at 60°C for 3 hours under nitrogen gas protection. Water (10 mL) was added to the mixture, and it was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saline solution (80 mL x 2), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum. The residue was purified by preparative HPLC (column: Phenomenex luna). Compounds 6-8 were obtained by using a C18 substrate measuring 150 × 40 mm × 15 μm, with a mobile phase consisting of an aqueous solution containing 0.1% TFA and acetonitrile (acetonitrile content in the mobile phase was 20% to 50%, and the experiment was run for 10 minutes). 1 H NMR (400MHz, CDCl3) δ=7.01 (dd, J=7.1, 11.5Hz, 1H), 3.71 (s, 2H), 1.70 (s, 6H); LCMS (ESI) m / z: 288.9 (M+1).

[0121] Step 8: Production of Compound 6 Compound 6-8 (100 mg, 347.21 μmol, 1 eq) was dissolved in isopropanol (2 mL), and the mixture was heated at 0°C under the protection of nitrogen gas in NaOH (1 M, 694.42 μL). (2 eq) was gradually added, and the reaction mixture was then gradually heated to 25°C under the protection of nitrogen gas and stirred for 1 hour. The crude product was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase is 1% to 6%, 4 min) to obtain compound 6. 1 H NMR (400MHz, CD3OD) δ=6.40 (br dd, J=8.3, 11.8Hz, 1H), 3.40 (s, 2H); LCMS (ESI) m / z: 230.9 (M+1); 213 (M-18+1).

[0122] Example 7 [ka]

[0123] Process 1: Preparation of Compound 7-2 To a solution of compound 7-1 (10 g, 48.20 mmol, 1 eq) in DCM (100 mL), Boc2O (12.62 g, 57.84 mmol, 13.29 mL, 1.2 eq) and DMAP (294.45 mg, 2.41 mmol, 0.05 eq) were added, and the mixed solution was stirred at 25°C for 1 hour. H2O (50 mL) was added to the mixed solution, and it was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saline solution (100 mL x 2), dried over anhydrous Na2SO4, filtered, and the filtrate was concentrated under vacuum to obtain compound 7-2. 1 H NMR (400MHz, CDCl3) δ=7.39(dd,J=1.5,8.0Hz,1H),7.33-7.29(m,1H),7.14(dd,J=1.5,8.2Hz,1H),7.17-7.12(m,1H),1.59(s,9H).

[0124] Step 2: Production of Compound 7-3 To a solution of compound 7-2 (7g, 22.76 mmol, 1eq) in THF (100 mL), LDA (2M, 13.66 mL, 1.2 eq) was added. The mixture was stirred at -70°C for 2 hours. The mixed solution was completely quenched with H2O (20 mL) and extracted with siRNA (40 mL x 3). The combined organic phase was washed with aqueous NaCl solution (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0, 20 / 1) to obtain compound 7-3.

[0125] Step 3: Production of Compound 7-4 At 0°C, under the protection of nitrogen gas, TFA (38.50 g, 337.66 mmol, 25 mL, 20.36 eq) was added to a solution of compound 7-3 (5.1 g, 16.58 mmol, 1 eq) in DCM (25 mL), and the mixture was then stirred at 25°C for 12 hours. This compound was then analyzed. The compound was concentrated under open air. The crude product was washed with DCM (25 mL) at 25°C. Compound 7-4 was obtained.

[0126] Step 4: Production of Compound 7-5 At 0°C, compound 7-4 (3.0 g, 11.93 mmol, 1 eq) was dissolved in TFA (40 mL), and acetone (2.08 g, 35.79 mmol, 2.63 mL, 3 eq), TFAA (7.52 g, 35.79 mmol, 4.98 mL, 3 eq), and DMF (174.40 mg, 2.39 mmol, 183.58 μL, 0.2 eq) were added. The mixed solution was stirred at 20°C for 0.5 hours. Then, it was heated to 105°C and stirred for a further 32 hours. The solution was concentrated under vacuum, and then NaHCO3 solution (20 mL) was added and extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saline solution (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 50 / 1), and then washed with petroleum ether (40 mL) at 25°C to obtain compound 7-5. 1 H NMR (400MHz, CDCl3) δ = 7.68 (d, J = 8.7 Hz, 1H), 7.11 (d, J = 8.5 Hz, 1H), 1.80 (s, 6H); LCMS (ESI) m / z: 292.8 (M + 1).

[0127] Step 5: Production of Compounds 7-6 Under nitrogen gas protection, compound 7-5 (770 mg, 2.64 mmol, 1 eq), bis(pinacolato)diborone (1.01 g, 3.96 mmol, 1.5 eq), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (431.39 mg, 528.26 μmol, 0.2 eq), and potassium acetate (777.66 mg, 7.92 mmol, 3 eq) were added to 1,4-dioxane (3 mL), and the mixture was purged three times with nitrogen gas at 25 °C. The mixed solution was then stirred at 65 °C for 5 hours in an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 100 / 1, 10 / 1) to obtain compound 7-6. LCMS(ESI)m / z:339(M+1).

[0128] Step 6: Production of Compound 7-7 To a mixed solution of compound 7-6 (1.3 g, 3.84 mmol, 1 eq) in THF (20 mL) and H2O (10 mL), sodium perborate tetrahydrate (1.77 g, 11.52 mmol, 2.22 mL, 3 eq) was added, and the mixture was stirred at 25°C for 16 hours. H2O (10 mL) was added to the solution, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saline solution (80 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1, 5 / 1) to obtain compound 7-7. LCMS (ESI) m / z: 229 (M+1).

[0129] Process 7: Production of Compounds 7-8 At 25°C, compound 7-7 (100 mg, 437.39 μmol, 1 eq) was dissolved in acetonitrile (3 mL) and 2-iodomethyl-boronic acid pinacol ester (234.35 mg, 874.78 μmol, 2 eq) and K2CO3 (120.90 mg, 874.78 μmol, 2 eq) were added. The mixture was then stirred at 60°C for 3 hours. H2O (5 mL) was added to the solution, and the aqueous phase was adjusted to pH 3-4 with 0.5 mol / L HCl. The solution was then extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saline solution (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. Compound 7-8 was obtained. LCMS (ESI) m / z: 287 (M+1).

[0130] Process 8: Production of Compound 7 At 0°C, a solution of compound 7-8 (140 mg, 488.70 μmol, 1 eq) in isopropanol (1 mL) was mixed with NaOH aqueous solution (1 M, 977.40 μL, 2 eqs), and the mixture was stirred at 25°C for 1 hour. This solution was then purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 1% to 6%, 4 min) to obtain compound 7. 1 H NMR (400MHz, CD3OD) δ = 6. 49 (s, 2H), 3.41 (s, 2H); LCMS (ESI) m / z: 229 (M+1); 211 (M-18+1).

[0131] Example 8 [ka]

[0132] Step 1: Preparation of Compound 8-2 (1S,2S,6R,8S)-4-(bromomethyl)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0 2,6To a solution of decane (1.85 g, 6.79 mmol, 1.2 eq) in DMF (15 mL), K2CO3 (1.02 g, 7.35 mmol, 1.3 eq) and compound 1-7 (1.2 g, 5.66 mmol, 1 eq) were added. The mixed solution was stirred at 20°C for 12 hours. The reaction mixture was diluted with 50 mL of H2O and extracted with siRNA (100 mL x 2). The combined organic layer was washed with aqueous NaCl solution (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to obtain compound 8-2.

[0133] Step 2: Preparation of Compound 8-3 To a solution of compound 8-2 (900 mg, 2.23 mmol, 1 eq) in DMF (10 mL), K2CO3 (769.26 mg, 5.57 mmol, 2.5 eq) and CH3I (948.04 mg, 6.68 mmol, 415.81 μL, 3 eq) were added. The mixed solution was stirred at 20°C for 12 hours, and H2O (30 mL) was added to the reaction mixture. The solution was filtered under reduced pressure, and the filtered cake was dried under reduced pressure to obtain a portion of compound 8-3. The filtrate was extracted with siRNA (30 mL x 2), and the combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the remaining compound 8-3. 1 H NMR (400MHz, DMSO-d6) δ=8.21-7.93(m,2H),7.29-7.17(m,1H),7.03-6.91(m,1H),3.77-3.61(m,2H),1.71(s,6H).

[0134] Step 3: Production of Compound 8 At 0°C, a solution of compound 8-3 (220 mg, 814.76 μmol, 1 eq) in i-PrOH (i.e., isopropanol, 2.5 mL) is prepared by adding NaOH (2 M, 814.76 μL, 2 Compound 8 was obtained by adding compound eq) and stirring for 1 hour, then concentrating the reaction mixture under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (column: Waters Xbridge 150×25mm×5μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile ratio 1%~6%, 4 min) to obtain compound 8. 1 H NMR (400MHz, CD3OD) δ=6.49 (dd, J=5.8, 8.7Hz, 1H), 6.29-6.18 (m, 1H), 3.43-3.38 (m, 2H); LCMS (ESI) m / z: 213.1 (M+1).

[0135] Example 9 [ka]

[0136] Process 1: Manufacturing of Compound 9 At 0°C, a solution of compound 8-3 (300 mg, 1.11 mmol, 1 eq) in MeOH (2.5 mL) was mixed dropwise with an aqueous NaOH solution (2 M, 1.11 mL, 2 eqs) and stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 1% to 26%, 9 min) to obtain compound 9. 1 H NMR (400MHz, CD3OD) δ = 6.69-6.58 (m, 1H), 6.31-6.20 (m, 1H), 3.86 (s, 3H), 3.38 (s, 2H); LCMS (ESI) m / z: 227.1 (M+1).

[0137] Example 10 [ka]

[0138] Step 1: Preparation of Compound 10-2 At 25℃, compound 10-1 (10g, 64.06 mmol, 1eq) and NBS (12 0.54 g, 70.46 mmol, 1.1 eq) was added to AcOH (50 mL), and the mixed solution was stirred at 80°C for 24 hours. At 0°C, the mixed solution was added to water (115 mL). Then, it was filtered, and the filtered cake was dried to obtain compound 10-2. 1 H NMR (400 MHz, CD3OD) δ=7.61 (ddd, J=3.1, 8.1, 11.2 Hz, 2H); LCMS (ESI) m / z: 234.9 (M+1).

[0139] Step 2: Preparation of Compound 10-3 At 0°C, compound 10-2 (12.74 g, 54.21 mmol, 1 eq) was dissolved in TFA (100 mL), and acetone (9.45 g, 162.63 mmol, 11.96 mL, 3 eq), TFAA (34.16 g, 162.63 mmol, 22.62 mL, 3 eq), and DMF (792.50 mg, 10.84 mmol, 834.21 μL, 0.2 eq) were added. The mixture was then stirred at 25°C for 1 hour. Subsequently, the temperature was raised to 100°C and the mixture was stirred for a further 35 hours. The mixed solution was concentrated under reduced pressure to obtain the residue, and then at 0°C, aqueous NaHCO3 solution (500 mL) was added to the residue, followed by extraction with EA (200 mL). The organic layer was washed with 100 mL of saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 0 / 1 to 10 / 1) to obtain compound 10-3. LCMS (ESI) m / z: 274.8 (M+1).

[0140] Step 3: Preparation of Compound 10-4 Under nitrogen gas protection, compound 10-3 (1.78 g, 6.47 mmol, 1 eq), bis(pinacolato)diborone (2.46 g, 9.71 mmol, 1.5 eq), bis(triphenylphosphine)palladium dichloride (454.20 mg, 647.11 μmol, 0.1 eq), di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (549.58 mg, 1.29 mmol, 0.2 eq), and potassium acetate (1.91 g, 19.41 mmol, 3 eq) were added to dioxane (40 mL), replaced three times with N2, and the mixed solution was stirred at 55°C for 5 hours under nitrogen gas protection. EA (20 mL) was added to the mixed solution, filtered, and concentrated under reduced pressure to obtain the residue. The reaction mixture was quenched by adding 50 mL of H2O to the residue, and then extracted with EA (20 mL x 2). The organic layer was washed with 50 mL of saline solution, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain compound 10-4.

[0141] Step 4: Production of Compound 10-5 At 0°C, compound 10-4 (2.03 g, 6.30 mmol, 1 eq) was dissolved in a mixed solution of THF (20 mL) and water (10 mL), and sodium perborate tetrahydrate (2.91 g, 18.91 mmol, 3.64 mL, 3 eq) was added. The mixed solution was stirred at 25°C for 1 hour. Water (20 mL) was added to the reaction mixture, and the mixture was extracted with EA (20 mL x 2). The combined organic layer was washed with saline solution (40 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to obtain compound 10-5. LCMS (ESI) m / z: 213.1 (M+1).

[0142] Step 5: Production of compound 10-6 At 25°C, 2-iodomethyl-boronic acid pinacol ester (631.32 mg, 2.36 mmol, 2 eq) and compound 10-5 (250 mg, 1.18 mmol, 1 eq) were dissolved in acetonitrile (5 mL), and K2CO3 (244.27 mg, 1.77 mmol, 1.5 eq) was added to this solution. The mixture was then stirred at 65°C for 4 hours. Water (10 mL) was added to the mixed solution, and it was extracted with EA (10 mL x 3). The combined organic layer was then salted. The solution was washed with water (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative HPLC (column: 3-Phenomenex Luna C18 75 × 30 mm × 3 μm, mobile phase: aqueous solution containing 0.1% TFA and acetonitrile, acetonitrile content in mobile phase: 26%~56%, 10 min) to obtain compound 10-6. LCMS (ESI) m / z: 270.9 (M+1).

[0143] Step 6: Production of Compound 10 At 0°C, NaOH (1M, 740.69 μL, 2 eqs) was added dropwise to a solution of compound 10-6 (100 mg, 370.35 μmol, 1 eq) in isopropanol (1 mL). The mixed solution was then stirred at 25°C for 2 hours. The crude product was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 1% to 6%, 4 min) to obtain compound 10. 1 H NMR(400MHz,D2O)δ=6.63(dd,J=3.3,8.8Hz,1H),6.56(dd,J=3.1,9.9Hz,1H),3.34(s,2H);LCMS(ESI)m / z:212.8(M+1).

[0144] Example 11 [ka]

[0145] Step 1: Preparation of Compound 11-2 At 0°C, compound 11-1 (10 g, 54.89 mmol, 1 eq) was dissolved in chloroform (200 mL), and then liquid bromine (8.77 g, 54.89 mmol, 2.83 mL, 1 eq) was added. The mixture was stirred at 25°C for 30 hours. The mixture was concentrated under reduced pressure to obtain the residue. The crude product was washed with petroleum ether / ethyl acetate (150 mL, 5 / 1) for 30 minutes at 25°C. The mixture was filtered to obtain compound 11-2. LC-MS (ESI) m / z: 247.0 (M+1).

[0146] Step 2: Preparation of Compound 11-3 To a solution of compound 11-2 (12.39 g, 50.15 mmol, 1 eq) in trifluoroacetic acid (100 mL), acetone (8.74 g, 150.46 mmol, 11.06 mL, 3 eqs) was added. At 0°C, anhydrous trifluoroacetic acid (31.60 g, 150.46 mmol, 20.93 mL, 3 eqs) and DMF (733.14 mg, 10.03 mmol, 771.73 μL, 0.2 eqs) were added. The mixture was then stirred at 25°C for 1 hour, and then heated to 100°C and stirred for 47 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue, which was quenched by adding it to an aqueous sodium bicarbonate solution (500 mL) at 0°C, and then extracted with ethyl acetate (200 mL x 1). The organic layer was washed with saline solution (100 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to obtain compound 11-3. 1 H NMR (400MHz, CDCl3) δ = 7.60 (d, J = 9.0 Hz, 1H), 6.51 (d, J = 9.0 Hz, 1H), 3.89 (s, 3H), 1.68 (s, 6H); LCMS (ESI) m / z: 288.9 (M + 1).

[0147] Step 3: Preparation of Compound 11-4 Compound 11-3 (3 g, 10.45 mmol, 1 eq), bis(pinacolato)diborone (3.98 g, 15.67 mmol, 1.5 eq), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride-dichloromethane complex (1.71 g, 2.09 mmol, 0.2 eq), and potassium acetate (3.08 g, 31.35 mmol, 3 eq) were mixed in dioxane (40 mL), purged three times with nitrogen gas, and then the mixture was stirred in a nitrogen atmosphere at 65°C for 12 hours. Ethyl acetate (50 mL) was added to the mixture, filtered, and concentrated under reduced pressure to obtain the residue. Water (50 mL) was added to the mixture, and then extracted with ethyl acetate (20 mL x 2). The organic layer was washed with 50 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product of compound 11-4 was obtained by purification using silica gel flash column chromatography (petroleum ether / ethyl acetate = 0 / 1 to 5 / 1). LCMS (ESI) m / z: 335.1 (M+1).

[0148] Step 4: Production of Compound 11-5 Compound 11-4 (1.23 g, 3.68 mmol, 1 eq) was added to tetrahydrofuran (12 mL) and water (6 mL), and sodium perborate tetrahydrate (1.70 g, 11.04 mmol, 2.12 mL, 3 eq) was added at 0°C. The mixture was then stirred at 25°C for 1 hour. Water (20 mL) was added to the reaction mixture, and it was extracted with ethyl acetate (20 mL × 2). The combined organic layer was washed with brine (40 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 20 / 1~0 / 1) to obtain the crude product of compound 11-5. LCMS (ESI) m / z: 225.0 (M+1).

[0149] Step 5: Production of Compound 11-6 Compound 11-5 (365 mg, 1.63 mmol, 1 eq) and NCS (416.96 mg, 2.12 mmol, 1.3 eq) were mixed in tetrahydrofuran (10 mL) and stirred at 50°C for 5 hours. Water (20 mL) was added to the mixture, and it was extracted with ethyl acetate (20 mL x 2). The combined organic layer was then washed with saline solution (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a mixture of compound 11-6 and compound 12-1, which was used directly in the next reaction. LCMS (ESI) m / z: 258.9 (M+1).

[0150] Step 6: Production of Compound 11-7 2-Iodomethyl-boronic acid pinacol ester (1.69 g, 6.32 mmol, 2 eq) and crude products of compounds 11-6 and 12-1 (818 mg, 3.16 mmol) Compound 11-7 (LCMS(ESI) m / z: 317.0 (M+1)) was mixed in acetonitrile (10 mL) and potassium carbonate (655.64 mg, 4.74 mmol, 1.5 eq) was added at 25°C. The mixture was then stirred at 65°C for 4 hours. Water (10 mL) was added to the mixture and extracted with ethyl acetate (10 mL × 3). The combined organic layer was washed with saline solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (column: Phenomenex luna C18 150 × 40 mm × 15 μm, mobile phase: aqueous solution containing 0.1% TFA and acetonitrile, acetonitrile content in mobile phase 23%~53%, 8 min) to obtain compound 11-7 (LCMS(ESI) m / z: 317.0 (M+1)) and compound 12-2 (LCMS(ESI) m / z: 351.1 (M+1)).

[0151] Step 7: Manufacturing of Compound 11 Compound 11-7 (100 mg, 315.96 μmol, 1 eq) was dissolved in isopropanol (1 mL), and an aqueous sodium hydroxide solution (1 M, 631.91 μL, 2 eqs) was added at 0°C. The mixture was then stirred at 25°C for 2 hours. The crude product was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 1% to 6%, 4 min) to obtain compound 11. 1 H NMR (400MHz, D2O) δ = 6.64 (s, 1H), 3.69 (s, 3H), 3.22 (s, 2H); LCMS (ESI) m / z: 240.9 (M-18+1).

[0152] Example 12 [ka]

[0153] Process 1: Production of Compound 12 Compound 12-2 (100 mg, 284.95 μmol, 1 eq) was dissolved in isopropanol (1 mL), and aqueous sodium hydroxide solution (1 M, 569.89 μL, 2 eqs) was added at 0°C. The mixture was then stirred at 25°C for 2 hours. The crude product was purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 1% to 6%, 4 min) to obtain compound 12. 1 H NMR (400MHz, D2O) δ = 3.71 (s, 3H), 3.31 (s, 2H); LCMS (ESI) m / z: 274.9 (M-18+1).

[0154] Example 13 [ka]

[0155] Step 1: Preparation of Compound 13-2 Compound 13-1 (10 g, 70.36 mmol, 1 eq) was dissolved in dichloromethane (100 mL), and Boc2O (16.89 g, 77.40 mmol, 17.78 mL, 1.1 eq) and DMAP (429.79 mg, 3.52 mmol, 0.05 eq) were added. The mixture was stirred at 25°C for 16 hours. Water (50 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saline solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to obtain compound 13-2. 1 H NMR (400MHz, CDCl3) δ=6.98(dd,J=8.9,10.8Hz,1H),6.73(dd,J=2.8,7.2Hz,1H),6.67-6.60(m,1H),3.81(s,3H),1.49(s,9H).

[0156] Step 2: Preparation of Compound 13-3 Compound 13-2 (16.9 g, 69.76 mmol, 1 eq) was dissolved in tetrahydrofuran solution (170 mL), and diisopropylaminolithium (2 M, 41.86 mL, 1.2 eq) was added dropwise under nitrogen gas at -70°C, and the mixture was stirred at -70°C for 2 hours. The reaction mixture was diluted with 1 N dilute hydrochloric acid (20 mL) and extracted with ethyl acetate (40 mL x 3). The combined organic layer was washed with saline solution (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to obtain compound 13-3. 1 H NMR (400MHz, CDCl3) δ=7.17(dd,J=9.2,10.5Hz,1H),6.67(dd,J=4.1,9.3Hz,1H),3.91(d,J=1.0Hz,3H),1.66(s,9H).

[0157] Step 3: Preparation of Compound 13-4 To a solution of compound 13-3 (12.25 g, 50.57 mmol, 1 eq) in dichloromethane (35 mL) at 0°C, trifluoroacetic acid (53.90 g, 472.71 mmol, 35 mL, 9.35 eq) was added and the mixture was stirred at 25°C for 16 hours. This solution was concentrated under reduced pressure, and the resulting crude product was stirred with petroleum ether (70 mL) at 25°C, filtered, and the filtered cake was dried to obtain compound 13-4. 1 H NMR(400MHz, CDCl3)δ=11.67(s,1H),11.63-11.49(m,1H),7.30-7.28(m,1H),6.79(dd,J=3.9,9.4Hz,1H),4.26(d,J=2.9Hz,3H).

[0158] Step 4: Preparation of Compound 13-5 At 0°C, NBS (9.29 g, 52.18 mmol, 1.05 eq) was added in multiple portions to a solution of compound 13-4 (9.25 g, 49.69 mmol, 1 eq) in dichloromethane (100 mL), and the mixture was then stirred at 25°C for 12 hours. This solution was concentrated under vacuum. The crude product was mixed with water (100 mL) and stirred at room temperature for 30 minutes. The mixture was filtered to obtain compound 13-5. 1 H NMR (400MHz, CD3OD) δ = 7.63 (d, J = 10.6 Hz, 1H), 3.95 (d, J = 1.3 Hz, 3H); LCMS (ESI) m / z: 265 (M + 1).

[0159] Step 5: Production of Compound 13-6 At 0°C, compound 13-5 (12.38 g, 46.71 mmol, 1 eq) was dissolved in trifluoroacetic acid (130 mL) and then acetone (8.14 g, 140.13 mmol, 10.30 mL, 3 eqs), anhydrous trifluoroacetic acid (29.43 g, 140.13 mmol, 19.49 mL, 3 eqs), and DMF (682.82 mg, 9.34 mmol, 718.76 μL, 0.2 eq) were added. The mixture was stirred at 105°C for 48 hours. This solution was concentrated under vacuum, then sodium bicarbonate solution (20 mL) was added, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saline solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 500 / 1 to 50 / 1), and then the compound was stirred with petroleum ether (100 mL) at 0°C for 1 hour. It was filtered to obtain compound 13-6. 1 H NMR (400MHz, CDCl3) δ = 7.57 (d, J = 10.6 Hz, 1H), 4.08 (d, J = 2.2 Hz, 3H), 1.77 (s, 6H); LCMS (ESI) m / z: 305 (M + 1).

[0160] Step 6: Production of Compound 13-7 At 25°C, compound 13-6 (2.7 g, 8.85 mmol, 1 eq), bis(pinacolato)diborone (8.99 g, 35.40 mmol, 4 eq), bis(triphenylphosphine)palladium dichloride (621.15 mg, 884.97 μmol, 0.1 eq), potassium acetate (3.47 g, 35.40 mmol, 4 eq), and di-tert-butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphine (751.58 mg, 1.77 mmol, 0.2 eq) were mixed in 30 mL of dioxane, degassed, and purged three times with nitrogen gas. The mixture was then stirred at 65°C for 5 hours in a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 50 / 1 to 0 / 1) to obtain crude product 13-7. LC-MS (ESI) m / z: 353 (M+1).

[0161] Step 7: Preparation of Compound 13-8 Compound 13-7 (1 g, 2.84 mmol, 1 eq) was dissolved in a mixed solution of tetrahydrofuran (10 mL) and water (5 mL), and sodium perborate tetrahydrate (1.31 g, 8.52 mmol, 1.64 mL, 3 eq) was added. The mixture was stirred at 25°C for 16 hours. Water (30 mL) was added to the solution, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saline solution (150 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to obtain compound 13-8. 1 H NMR (400MHz, CDCl3) δ = 7.02 (d, J = 11.6 Hz, 1H), 3.98 (d, J = 0.9 Hz, 3H), 1.77 (s, 6H); LCMS (ESI) m / z: 242.9 (M + 1).

[0162] Process 8: Production of Compound 13-9 Compound 13-8 (1.7 g, 1.75 mmol, 25% purity, 1 eq) was dissolved in acetonitrile (20 mL), and 2-iodomethylboronic acid pinacol ester (470.10 mg, 1.75 mmol, 1 eq) and potassium carbonate (363.79 mg, 2.63 mmol, 1.5 eq) were added at 20 °C. The mixture was then stirred at 60 °C for 3 hours. Water (5 mL) was added to the solution, and the aqueous phase was adjusted to pH 3-4 with 0.5 N dilute hydrochloric acid. The solution was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saline solution (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (column: Zhongpu RD-C18 150×25mm×3μm, mobile phase: aqueous solution containing 0.1% TFA and acetonitrile, acetonitrile content in mobile phase 17%~47%, 10 min) to obtain compound 13-9. LCMS(ESI) m / z: 300.9 (M+1).

[0163] Step 9: Production of Compound 13 Compound 13-9 (60 mg, 199.97 μmol, 1 eq) was dissolved in isopropanol (0.5 mL), and sodium hydroxide aqueous solution (1 M, 399.94 μL, 2 eqs) was added at 0°C. The mixture was then stirred at 25°C for 1 hour. Acetone was added to the solution, and it was filtered and vacuum-dried to obtain compound 13. 1 H NMR (400MHz, CD3OD) δ = 6.30 (d, J = 12.4 Hz, 1H), 3.83 (s, 3H), 3.39 (s, 2H); LCMS (ESI) m / z: 242.9 (M + 1); 224.9 (M-18 + 1).

[0164] Example 14 [ka]

[0165] Step 1: Preparation of Compound 14-2 At 20°C, compound 14-1 (30g, 197.18 mmol, 25.42 mL, 1 eq) and triethyl orthoformate (160.72g, 1.08 mol, 180.38 mL, 5.5 eq) were mixed, to which HClO4 (23.67g, 164.93 mmol, 14.26 mL, 70% purity, 8.36 e-1 eq) was added dropwise. The temperature was controlled to below 40°C, and the mixture was stirred at 20°C for 1.5 hours. Then, methyl tert-butyl ether (600 mL) was added, followed by filtration. The filtration cake was collected, dissolved in H2O (200 mL), stirred at 80°C for 2 hours, extracted with 400 mL of ethyl acetate (200 mL x 2), washed with 300 mL of saturated brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 14-2. 1 H NMR(400MHz,DMSO-d6)δ=10.78(s,1H),8.15(d,J=6.00Hz,1H),7.87(s,1H),6.92(dd, J=8.76,2.25Hz,1H),6.85(d,J=2.13Hz,1H),6.22(d,J=6.00Hz,1H).

[0166] Step 2: Preparation of Compound 14-3 Compound 14-2 (23.89 g, 147.34 mmol, 1 eq) was dissolved in EtOH (240 mL), and Pd / C (4.78 g, 10% purity) was added in N2 at 20°C. After several substitutions with hydrogen gas, the reaction mixture was stirred in H2 (50 psi) at 55°C for 24 hours. Pd / C was removed by filtration, and the filtrate was distilled under reduced pressure to obtain the crude product. The product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 8 / 1) to obtain compound 14-3. 1 H NMR(400MHz,DMSO-d6)δ=9.16-9.10(m,1H),6.89-6.81(m,1H),6.32-6.27(m,1 H),6.20-6.15(m,1H),4.13-4.06(m,2H),2.70-2.61(m,2H),1.95-1.85(m,2H).

[0167] Step 3: Preparation of Compound 14-4 Compound 14-3 (14.23 g, 94.76 mmol, 1 eq) was dissolved in DCM (150 mL), and DMAP (578.82 mg, 4.74 mmol, 0.05 eq) was added at room temperature. Subsequently, Boc2O (24.82 g, 113.71 mmol, 26.12 mL, 1.2 eq) was gradually added. This mixture was stirred at 20°C for 4 hours. The reaction mixture was quenched with HCl (0.2 M, 50 mL) at 20°C, extracted with DCM (150 mL), washed with saturated saline (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 14-4, which was then used in the next step. 1 H NMR(400MHz, CDCl3)δ=6.92(d,J=8.25Hz,1H),6.56(s,1H),6.59-6.55(m,1H ),4.11-4.06(m,2H),2.68(t,J=6.50Hz,2H),1.95-1.86(m,2H),1.47(s,9H).

[0168] Step 4: Preparation of Compound 14-5 Compound 14-4 (24.47 g, 97.77 mmol, 1 eq) was dissolved in THF (240 mL), and LDA (2 M, 58.66 mL, 1.2 eq) was gradually added dropwise in N2. The mixture was stirred at -20°C for 1.5 hours. The reaction mixture was quenched with NH4Cl (300 mL) at -78°C, extracted with 400 mL of ethyl acetate, washed with saturated saline (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0) to obtain compound 14-5. LCMS (ESI) m / z: 195.2 (M-55).

[0169] Step 5: Production of Compound 14-6 Compound 14-5 (16.55 g, 66.12 mmol, 1 eq) was dissolved in DCM (50 mL), and TFA (76.46 g, 670.59 mmol, 49.65 mL, 10.14 eq) was added at room temperature. This mixture was stirred at 20°C for 1 hour. The mixture was concentrated under reduced pressure to obtain the crude product, which was stirred at room temperature in PE:EA=20:1 (126 mL) for 10 min, filtered, and the filtered cake was dried to obtain compound 14-6. 1 H NMR (400MHz, CDCl3) δ=7.16(d,J=8.56Hz,1H),6.63(d,J=8.56Hz,1H),4.51-4.41(m,2H),2.78(t,J=6.48Hz,2H),2.16-2.07(m,2H).

[0170] Step 6: Preparation of Compound 14-7 Compound 14-6 (15.22 g, 78.38 mmol, 1 eq) was dissolved in DCM (150 mL), and then NBS (12.55 g, 70.54 mmol, 0.9 eq) was added at room temperature. The mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with 100 mL of H2O, extracted with 100 mL of DCM, and washed with 200 mL of saline solution (100 mL x 2). The product was dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was stirred at 20°C with petroleum ether:ethyl acetate = 20:1 (126 mL) for 30 minutes, filtered, and the filtered cake was dried to obtain compound 14-7.1 H NMR (400MHz, CDCl3)δ=12.77-12.69(m,1H),11.53-11.36(m,1H),7.51-7.42(m,1H),4.51-4.45(m,2H),2.82-2.76(m,2H),2.19-2.08(m,2H).

[0171] Step 7: Production of Compound 14-8 Compound 14-7 (13.82 g, 50.61 mmol, 1 eq) was dissolved in TFA (56 mL), acetone (29.39 g, 506.08 mmol, 37.21 mL, 10 eq) was added at 0°C, and TFAA (31.89 g, 151.82 mmol, 21.12 mL, 3 eq) was added dropwise. After several substitutions with nitrogen gas, the reaction mixture was stirred in N2 at 100°C for 48 hours. The mixture was concentrated under reduced pressure to remove the solvent, diluted in 200 mL of saturated NaHCO3 solution, and extracted with 300 mL of EA (100 mL x 3). The mixture was washed with saturated saline (150 mL x 1), dried over Na2SO4, filtered, concentrated under reduced pressure to obtain the residue, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~5 / 1) to obtain compound 14-8. LCMS(ESI)m / z:315.0(M+3).

[0172] Process 8: Production of Compound 14-9 Compound 14-8 (1 g, 1.60 mmol, 50% purity, 1 eq) was dissolved in dioxane (20 mL), and then pinacol borate (1.01 g, 3.99 mmol, 2.5 eq), potassium acetate (470.10 mg, 4.79 mmol, 3 eq), and Pd(dppf)Cl2 (233.67 mg, 319.34 μmol, 0.2 eq) were added under a nitrogen gas flow. The mixture was stirred at 70°C for 12 hours under nitrogen gas protection. The reaction mixture was filtered, then diluted with 40 mL of water, extracted with 60 mL of ethyl acetate (30 mL x 2), washed with saturated saline solution (60 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 1 / 1) to obtain compound 14-9. LCMS(ESI)m / z:361.2(M+1).

[0173] Process 9: Production of Compound 14-10 Compound 14-9 (1.74 g, 4.82 mmol, 1 eq) was dissolved in a mixed solution of THF (10 mL) and H2O (10 mL). Sodium perborate tetrahydrate (1.48 g, 9.64 mmol, 2 eq) was added at 20°C, and the mixture was stirred at 20°C for 1 hour. The reaction solution was diluted with 20 mL of water, then extracted with 80 mL of ethyl acetate (40 mL x 2), washed with saturated brine (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to obtain compound 14-10. LCMS (ESI) m / z: 251.1 (M+1).

[0174] Step 10: Production of Compound 14-11 Compound 14-10 (214 mg, 855.16 μmol, 1 eq) was dissolved in acetonitrile (2 mL), and 2-iodomethyl pinacolborate (274.91 mg, 1.03 mmol, 1.2 eq) and K2CO3 (141.83 mg, 1.03 mmol, 1.2 eq) were added sequentially at room temperature. After the additions were complete, the mixture was purged three times with nitrogen gas, and then stirred in N2 at 60°C for 6 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent acetonitrile. The residue was diluted with 20 mL of H2O and extracted with 100 mL of ethyl acetate (20 mL x 5). The combined organic layer was washed with 30 mL of saline solution (30 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 14-11. LCMS (ESI) m / z: 309.1 (M+1).

[0175] Step 11: Preparation of Compound 14 Compound 14-11 (318 mg, 1.03 mmol, 1 eq) was dissolved in i-PrOH (1 mL), and NaOH (2 M, 1.03 mL, 2 eq) was added dropwise at room temperature. The mixture was reacted at 20°C with stirring for 2 hours. The reaction mixture was diluted with 1 mL of H2O and purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: water containing 10 mM NH4HCO3 and acetonitrile, acetonitrile content in mobile phase 1%~6%, 4 min) to obtain compound 14. LCMS(ESI) m / z: 251.0 (M+1); 1 H NMR(400MHz,D2O)δ=6.34(s,1H),4.02-3.95(m,2H),3.20(s,2H),2.55(t,J=6.48Hz,2H),1.88-1.79(m,2H).

[0176] Example 15 [ka]

[0177] Step 1: Preparation of Compound 15-2 LiHMDS (1M THF solution, 363.82 mL, 3 eq) was dissolved in toluene (150 mL) solution, cooled to -70°C, and within 3 minutes, compound 15-1 (17 g, 121.27 mmol, 17.65 mL, 1 eq) in toluene (20 mL) solution was added, and the mixture was stirred for 0.5 hours. Then, within 0.5 hours, 4-methylbenzenesulfonyl bromide (59.87 g, 254.67 mmol, 2.1 eq) in tetrahydrofuran (50 mL) solution was added, followed by the addition of LiHMDS (1M, 121.27 mL, 1 eq). After the addition was complete, the temperature was gradually raised to 20°C and the mixture was stirred for 0.5 hours. THF (50 mL) was added to the solution and the mixture was stirred for a further 0.5 hours at 25°C. The reaction mixture was placed in NH4Cl (100 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (100 mL x 2). The combined organic phase was washed with saline solution (200 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 1 / 0 to 100 / 1) to obtain compound 15-2.1 H NMR (400MHz, CDCl3) δ=7.32(d,J=8.9Hz,1H),6.64-6.59(m,1H),6.43(dd,J=2.8,8.9Hz,1H),5.53(s,1H),4.00(q,J=7.0Hz,2H),1.42(t,J=7.0Hz,3H).

[0178] Step 2: Preparation of Compound 15-3 Compound 15-2 (6.4 g, 29.48 mmol, 1 eq) was dissolved in dichloromethane (70 mL), and Boc2O (7.08 g, 32.43 mmol, 7.45 mL, 1.1 eq) and DMAP (180.11 mg, 1.47 mmol, 0.05 eq) were added. The mixture was stirred at 25°C for 16 hours. H2O (50 mL) was added to the reaction solution, and the aqueous phase was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saline solution (100 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound 15-3 without purification. 1 H NMR(400MHz,CDCl3)δ=7.37(d,J=8.9Hz,1H),6.69(d,J=2.8Hz,1H),6.61(dd, J=2.9,8.9Hz,1H),3.93(q,J=7.0Hz,2H),1.50(s,9H),1.33(t,J=7.0Hz,3H).

[0179] Step 3: Preparation of Compound 15-4 Compound 15-3 (9 g, 28.38 mmol, 1 eq) was dissolved in tetrahydrofuran solution (90 mL), LDA (1 M, 34.05 mL, 1.2 eq) was added, and the mixture was stirred at -70°C for 2 hours under nitrogen gas. The reaction mixture was diluted with NH4Cl (50 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layer was washed with aqueous NaCl solution (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was stirred in petroleum ether at 25°C for 1 hour, filtered, and the filtered cake was dried to obtain compound 15-4. 1H NMR (400MHz, CDCl3) δ=12.29(br s,1H),7.44(d,J=8.9Hz,1H),6.24(d,J=8.9Hz,1H),3.94(q,J=6.9Hz,2H),1.53(s,9H),1.38(t,J=7.0Hz,3H).

[0180] Step 4: Production of Compound 15-5 Compound 15-4 (5.15 g, 16.24 mmol, 1 eq) was dissolved in a solution of dichloromethane (20 mL), and trifluoroacetic acid (31.41 g, 275.47 mmol, 20.40 mL, 16.97 eq) was added. The mixture was heated from 0°C to 25°C in nitrogen gas and stirred for 2 hours. This compound was concentrated under vacuum. The crude product was stirred with petroleum ether (20 mL) at 25°C for 2 hours, filtered, and the filtered cake was dried to obtain compound 15-5. 1 H NMR (400MHz, CDCl3) δ=12.87(s,1H),7.60(d,J=8.8Hz,1H),6.37(d,J=8.9Hz,1H),4.26(q,J=7.1Hz,2H),1.51(s,3H).

[0181] Step 5: Production of Compound 15-6 Compound 15-5 (4.2 g, 16.09 mmol, 1 eq) was dissolved in TFA (10 mL) solution, acetone (2.80 g, 48.26 mmol, 3.55 mL, 3 eq) was added, and anhydrous trifluoroacetic acid (10.14 g, 48.26 mmol, 6.71 mL, 3 eq) and dimethylformamide (235.17 mg, 3.22 mmol, 247.55 μL, 0.2 eq) were added at 0°C. The mixture was stirred at 20°C for 0.5 hours. Then, it was heated to 105°C and stirred for a further 32 hours. The solution was concentrated under vacuum, then NaHCO3 solution (30 mL) was added, and it was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 0, 10 / 1) to obtain compound 15-6. LCMS: 302.9 (M+3); 1H NMR (400MHz, CDCl3) δ=7.56(d,J=9.1Hz,1H),6.48(d,J=9.1Hz,1H),4.09(q,J=7.0Hz,2H),1.68(s,6H),1.45(t,J=7.0Hz,3H).

[0182] Step 6: Production of Compound 15-7 Compound 15-6 (2.1 g, 6.97 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (2.66 g, 10.46 mmol, 1.5 eq), Pd(dppf)Cl2.CH2Cl2 (1.14 g, 1.39 mmol, 0.2 eq), and potassium acetate (2.05 g, 20.92 mmol, 3 eq) were dissolved in dioxane (20 mL), purged three times with nitrogen gas, and the mixture was stirred at 65°C for 5 hours under nitrogen gas protection. The reaction mixture was filtered to remove the solvent and concentrated under reduced pressure. The crude product was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 500 / 1~10 / 1) to obtain compound 15-7. LCMS: 349.0 (M+1).

[0183] Step 7: Production of Compound 15-8 Compound 15-7 (3.6 g, 10.34 mmol, 1 eq) was dissolved in a mixed solution of tetrahydrofuran (30 mL) and water (15 mL). Sodium perborate tetrahydrate (4.77 g, 31.02 mmol, 5.97 mL, 3 eq) was added, and the mixture was stirred at 25°C for 2 hours. Water (10 mL) was added to the solution, and the pH was adjusted to 3-4 with 0.5 N HCl. The aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saline solution (80 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 1-5 / 1) to obtain compound 15-8. LCMS: 239.0 (M+1); 1H NMR (400MHz, CDCl3) δ=7.04(d,J=9.0Hz,1H),6.47(d,J=9.2Hz,1H),4.04(q,J=7.0Hz,2H),1.68(s,6H),1.42(t,J=7.0Hz,3H).

[0184] Process 8: Production of Compound 15-9 Compound 15-8 (1.2 g, 5.04 mmol, 1 eq) was dissolved in acetonitrile solution (3 mL), and 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (2.70 g, 10.07 mmol, 2 eq) and K2CO3 (1.39 g, 10.07 mmol, 2 eq) were added. The mixture was stirred at 25°C, and then at 60°C for 3 hours. H2O (5 mL) was added to the solution, and the aqueous phase was adjusted to pH=3-4 with 0.5 N HCl. The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saline solution (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (chromatographic column: Phenomenex luna C18 (250 × 70 mm × 15 μm), mobile phase: water (containing 0.1% TFA) and acetonitrile, acetonitrile content in mobile phase: 15%~45%, 12 min) to obtain compound 15-9. LCMS(ESI) m / z: 297.1 (M+1); 1 H NMR (400MHz, CDCl3) δ=7.07(d,J=9.1Hz,1H),6.47(d,J=9.1Hz,1H),4.08-4.03(m,2H),3.70(s,2H),1.67(s,6H),1.43(t,J=6.9Hz,3H).

[0185] Process 9: Manufacturing of Compound 15 Compound 15-9 (100 mg, 337.75 μmol, 1 eq) was dissolved in isopropanol (1.5 mL), and NaOH (1 M, 675.49 μL, 2 eqs) was added at 0°C. The mixture was then stirred at 25°C for 1 hour. Acetone was added to the solution, and the mixture was filtered and concentrated under vacuum to obtain compound 15. LC-MS (ESI) m / z: 239.1 (M+1), 221 (M-18+1); 1H NMR (400MHz, CD3OD) δ=6.46(d,J=8.6Hz,1H),6.16(d,J=8.6Hz,1H),3.96(q,J=7.0Hz,2H),3.38(s,2H),1.33(t,J=7.0Hz,3H).

[0186] Example 16 [ka]

[0187] Step 1: Preparation of Compound 16-2 Compound 16-1 (15 g, 105.54 mmol, 1 eq) was dissolved in dichloromethane (300 mL), and liquid bromine (18.55 g, 116.09 mmol, 5.98 mL, 1.1 eq) was added. The mixture was stirred at -15°C for 1 hour. The mixture was then stirred at 10°C for 1 hour. The reaction mixture was quenched by adding sodium sulfite (5 mL) at 0-5°C. The mixture was extracted with ethyl acetate (10 mL). The organic layer was washed with saline solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 16-2. 1 H NMR (400MHz, CDCl3) δ=6.98(d,J=8.7Hz,1H),6.76(d,J=11.9Hz,1H),3.77(s,3H).

[0188] Step 2: Preparation of Compound 16-3 To a solution of compound 16-2 (23.2 g, 104.97 mmol, 1 eq) in dichloromethane (200 mL), DMAP (641.18 mg, 5.25 mmol, 0.05 eq) and Boc2O (25.20 g, 115.46 mmol, 26.53 mL, 1.1 eq) were added. The mixture was stirred at 25°C for 12 hours. The reaction mixture was quenched by adding aqueous hydrochloric acid (1 mL, 0.5 N) at 0-5°C. The separated organic layer was washed with 30 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 16-3.

[0189] Step 3: Preparation of Compound 16-4 At -78°C, diisopropylaminolithium (1M, 100.89mL, 1.2eq) was added to a solution of compound 16-3 (27g, 84.08 mmol, 1eq) in tetrahydrofuran (200mL). The mixture was stirred at -78°C for 2 hours. The reaction mixture was quenched by adding 100mL of aqueous ammonium chloride at -78°C, and then extracted with 250mL of ethyl acetate. The organic layer was washed with 150mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) to obtain compound 16-4.

[0190] Step 4: Preparation of Compound 16-5 At 0-5°C, trifluoroacetic acid (154.00 g, 1.35 mol, 100 mL, 18.86 eq) was added to a solution of compound 16-4 (23 g, 71.62 mmol, 1 eq) in dichloromethane (100 mL), and the mixture was stirred at 20°C for 1 hour. The reaction mixture was then prepared under reduced pressure. The mixture was concentrated to obtain the residue. The crude product was stirred with dichloromethane (20 mL), filtered, and the filter cake was dried to obtain compound 16-5. LC-MS (ESI) m / z: 265.1 / 266.9 (M+1 / M+3); 1 H NMR (400MHz, CDCl3) δ=7.38(d,J=8.6Hz,1H),3.80(s,3H).

[0191] Step 5: Preparation of Compound 16-6 At 0-5°C, to a solution of compound 16-5 (8 g, 30.18 mmol, 1 eq) in trifluoroacetic acid (190 mL), anhydrous trifluoroacetic acid (25.36 g, 120.74 mmol, 16.79 mL, 4 eq), acetone (7.01 g, 120.74 mmol, 8.88 mL, 4 eq), and N,N-dimethylformamide (441.27 mg, 6.04 mmol, 464.49 μL, 0.2 eq) were added, and the mixture was stirred at 105°C for 32 hours. The reaction mixture was concentrated, the residue was diluted with water (100 mL), and extracted with ethyl acetate (50 mL x 2). The combined organic layer was washed with saline solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to obtain compound 16-6. LCMS(ESI)m / z:304.9(M+1). 1 H NMR (400MHz, CDCl3) δ=7.34(d,J=8.2Hz,1H),3.83(s,3H),1.69(s,6H).

[0192] Step 6: Preparation of Compound 16-7 Compound 16-6 (1.1 g, 3.61 mmol, 1 eq), bis(pinacotato)diboronic acid (2.75 g, 10.82 mmol, 3 eq), potassium acetate (1.06 g, 10.82 mmol, 3 eq), and tetrakis(triphenylphosphine)palladium (208.31 mg, 180.27 μmol, 0.05 eq) were mixed in 30 mL of dioxane, replaced three times with N2, and then stirred at 65°C in a nitrogen atmosphere for 17 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 50 mL of water and extracted with 50 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to obtain compound 16-7. LCMS(ESI)m / z:270.9(M+1).

[0193] Step 7: Preparation of Compound 16-8 Compound 16-7 (1 g, 3.70 mmol, 1 eq) was dissolved in a mixed solution of tetrahydrofuran (10 mL) and water (10 mL), and sodium perborate tetrahydrate (1.71 g, 11.11 mmol, 2.14 mL, 3 eq) was added. The mixture was stirred at 20°C for 5 hours. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The organic layer was washed with 20 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 20 / 1~2 / 1) to obtain compound 16-8. LCMS (ESI) m / z: 243.0 (M+1).

[0194] Step 8: Preparation of Compound 16-9 Compound 16-8 (340 mg, 1.40 mmol, 1 eq), 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (564.11 mg, 2.11 mmol, 1.5 eq), and potassium carbonate (291.03 mg, 2.11 mmol, 1.5 eq) were mixed in acetonitrile (5 mL), degassed, purged three times with nitrogen gas, and the mixture was stirred at 60°C for 1 hour. 20 mL of water was added to quench the reaction mixture, and then it was extracted with 20 mL of ethyl acetate. The organic layer was washed with 5 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by thin-layer chromatography (ethyl acetate) to obtain compound 16-9. 1 1H NMR (400MHz) , CDCl3)δ=6.85(d,J=7.7Hz,1H),3.89(s,2H),3.80(s,3H),1.69(s,6H);LCMS(ESI)m / z:300.8(M+1).

[0195] Step 9: Production of Compound 16 At 20°C, a solution of compound 16-9 (140 mg, 466.60 μmol, 1 eq) in isopropanol (1.6 mL) was mixed with sodium hydroxide solution (2 M, 466.60 μL, 2 eqs). The mixture was stirred at 20°C for 0.5 hours, filtered, and the filtered cake was purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 1% to 6%, 4 min) to obtain compound 16. 1 H NMR (400MHz, D2O) δ=6.43(d,J=8.9Hz,1H),3.72(s,3H),3.24(s,2H). LCMS(ESI)m / z:243.0(M+1).

[0196] Example 17 [ka]

[0197] Step 1: Preparation of Compound 17-2 Compound 17-1 (40 g, 546.92 mmol, 57.47 mL, 1 eq) and a 4 Å molecular sieve (40 g) were dissolved in pentane (400 mL). Then, buta-2-ene (38.33 g, 546.92 mmol, 5.66 mL, 1 eq) was added to this mixture at 25°C, and the mixture was stirred at 25°C for 12 hours. The mixture was filtered and concentrated under reduced pressure to obtain compound 17-2.

[0198] Step 2: Preparation of Compound 17-3 Compound 17-2 (63.26 g, 505.23 mmol, 1 eq) and 3-oxobutanoate were dissolved in toluene (500 mL), then p-toluenesulfonic acid monohydrate (1.92 g, 10.10 mmol, 0.02 eq) was added at 25°C, and the mixture was stirred at 25°C for 72 hours. Water (500 mL) was added to the mixture, the organic layer was washed with saline solution (200 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The substance was obtained. Compound 17-3 was obtained by distillation of the residue at 80-95°C. LC-MS (ESI) m / z: 169.1 (M+1).

[0199] Step 3: Preparation of Compound 17-4 Compound 17-3 (20.87 g, 124.09 mmol, 1 eq) was dissolved in acetic acid (150 mL), and then liquid bromine (39.66 g, 248.17 mmol, 12.79 mL, 2 eq) was added to this mixture at 25°C. The mixture was then stirred at 100°C for 24 hours. This mixture was added to water (300 mL), stirred at 25°C for 15 minutes, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 1 / 1) to obtain compound 17-4. LCMS (ESI) m / z: 245.0 / 247.0 (M+1 / M+3).

[0200] Step 4: Preparation of Compound 17-5 Compound 17-4 (10.52 g, 42.93 mmol, 1 eq) was dissolved in a mixed solvent of ethanol (80 mL) and water (38 mL). Then, sodium hydroxide (5.15 g, 128.78 mmol, 710.00 μL, 3 eq) was added to this mixture at 0°C, and the mixture was stirred at 80°C for 12 hours. The mixture was concentrated under reduced pressure, and HCl (0.5 N) was added to adjust the pH to 2-3. Extraction was performed with ethyl acetate (100 mL x 3), the combined organic layer was washed with saline solution (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain compound 17-5. LCMS (ESI) m / z: 213.0 (M-18+1).

[0201] Step 5: Production of Compound 17-6 Compound 17-5 (12.22 g, 52.89 mmol, 1 eq) was dissolved in trifluoroacetic acid (120 mL). Then, at 0°C, acetone (18.43 g, 317.34 mmol, 23.33 mL, 6 eq), anhydrous trifluoroacetic acid (33.33 g, 158.67 mmol, 22.07 mL, 3 eq), and DMF (773.19 mg, 10.58 mmol, 813.89 μL, 0.2 eq) were added to this mixture. The mixture was then heated to 105°C and stirred for 48 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. At 0°C, 300 mL of aqueous sodium bicarbonate solution was added, and the mixture was extracted with 200 mL of ethyl acetate. The combined organic layer was washed with 200 mL of saline solution, dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain compound 17-6. LCMS (ESI) m / z: 271.0 (M+1).

[0202] Step 6: Production of Compound 17-7 Compound 17-6 (1.23 g, 4.54 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.73 g, 6.81 mmol, 1.5 eq), bis(triphenylphosphine)palladium dichloride (318.45 mg, 453.70 μmol, 0.1 eq), and potassium acetate (1.34 g, 13.61 mmol, 3 eq) were dissolved in anhydrous dioxane (20 mL). This mixture was purged three times with nitrogen gas, and then stirred at 65°C for 5 hours. The mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 0 / 1) to obtain compound 17-7. LCMS(ESI)m / z:319.1(M+1).

[0203] Step 7: Production of Compound 17-8 Compound 17-7 (1.02 g, 3.21 mmol, 1 eq) is dissolved in a mixed solvent of tetrahydrofuran (14 mL) and water (7 mL), and sodium perborate tetrahydrate is dissolved at 0°C. 1.48 g, 9.62 mmol, 1.85 mL, 3 eq) was added, and the mixture was stirred at 15°C for 1 hour under the protection of nitrogen gas. 10 mL of water was added to the reaction mixture, extracted with ethyl acetate (20 mL x 3), washed with saline solution (30 mL x 1), dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to obtain compound 17-8. LCMS (ESI) m / z: 209.2 (M+1).

[0204] Process 8: Production of Compound 17-9 Compound 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (468.35 mg, 1.75 mmol, 2 eqs) and compound 17-8 (182 mg, 874.12 μmol, 1 eq) were dissolved in acetonitrile (5 mL). Potassium carbonate (181.21 mg, 1.31 mmol, 1.5 eqs) was added to this mixture at 25 °C, and the mixture was stirred at 65 °C for 4 hours. 10 mL of water was added to the mixture, extracted with ethyl acetate (20 mL x 3), washed with saline solution (30 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain compound 17-9. 1 H NMR(400MHz,CD3OD)δ=7.19(d,J=8.4Hz,1H),6.92(dd,J=0.7,8.4Hz,1H),3.88(brs,2H),2.55(s,3H),1.72(s,6H);LCMS(ESI)m / z:267.1(M+1).

[0205] Process 9: Production of Compound 17 Compound 17-9 (64 mg, 240.55 μmol, 1 eq) was dissolved in isopropanol (0.5 mL), sodium hydroxide (1 M, 601.38 μL, 2.5 eq) was added at 0°C, and the mixture was then stirred at 25°C for 3 hours. The crude product was purified by washing with acetone (2 mL), filtered, and the filter cake was dried under vacuum to obtain compound 17. 1 H NMR(400MHz,D2O)δ=6.51(d,J=8.1Hz,1H),6.41(dd,J=0.6,8.1Hz,1H),3.24(s,2H),2.06(s,3H);LCMS(ESI)m / z:209.1(M+1),191.1(M-18+1).

[0206] Example 18 [ka]

[0207] Step 1: Preparation of Compound 18-2 Compound 18-1 (3 g, 8.40 mmol, 1 eq) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (957.85 mg, 8.40 mmol, 621.98 μL, 1 eq) was added. The mixture was stirred at 0-5°C and then at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The crude product was stirred with dichloromethane (10 mL), filtered, and the filtered cake was dried to obtain product 18-2.

[0208] Step 2: Preparation of Compound 18-3 Compound 18-2 (5.6 g, 18.60 mmol, 1 eq) was dissolved in trifluoroacetic acid (60 mL), and acetone (3.24 g, 55.81 mmol, 4.10 mL, 3 eq) was added. The mixture was cooled to 0-5°C, and anhydrous trifluoroacetic acid (11.72 g, 55.81 mmol, 7.76 mL, 3 eq) and N,N-dimethylformamide (271.95 mg, 3.72 mmol, 286.26 μL, 0.2 eq) were added. The mixture was stirred at 105°C for 16 hours. The reaction mixture was concentrated. The residue was diluted with sodium bicarbonate (30 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with saline solution (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) to obtain compound 18-3. 1 H NMR (400MHz, CDCl3) δ=7.82(d,J=8.8Hz,1H),7.16-6.79(m,1H),1.86-1.75(m,6H).

[0209] Step 3: Preparation of Compound 18-4 A mixture of compound 18-3 (3.4 g, 9.97 mmol, 1 eq), bis(pinacotato)diboronic acid (10.13 g, 39.87 mmol, 4 eq), and potassium acetate (2.93 g, 29.91 mmol, 2 eq) was mixed with dioxane (40 mL), and then Pd(dppf)Cl2 (575.95 mg, 498.42 μmol, 0.05 eq) was added. The mixture was degassed and purged three times with nitrogen gas. The mixture was then heated to 40°C in a nitrogen atmosphere and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 40 mL of water and extracted with 30 mL of ethyl acetate. The combined organic layer was washed with 30 mL of saline, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 18-4. LCMS(ESI) m / z: 389.1 (M+1).

[0210] Step 4: Preparation of Compound 18-5 Compound 18-4 (3 g, 7.73 mmol, 1 eq) was first added to a mixed solution of tetrahydrofuran (30 mL) and water (30 mL), followed by sodium perborate tetrahydrate (3.57 g, 23.19 mmol, 4.46 mL, 3 eq). The mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~5 / 1) to obtain compound 18-5. LCMS(ESI) m / z: 279.0 (M+1); 1 H NMR (400MHz, CDCl3) δ=7.19(d,J=8.9Hz,1H),7.02-6.89(m,1H),5.26(brs,1H),1.86-1.75(m,6H).

[0211] Step 5: Preparation of Compound 18-6 Compound 18-5 (800 mg, 2.88 mmol, 1 eq) was dissolved in acetonitrile (10 mL), and then 2-iodomethylboronic acid pinacol ester (1.54 g, 5.75 mmol, 2 eqs) was added to the solution, followed by potassium carbonate (596.18 mg, 4.31 mmol, 1.5 eq). The mixture was stirred at 65°C for 4 hours. The reaction mixture was diluted with 15 mL of water and extracted with 15 mL of ethyl acetate. The combined organic layer was washed with 15 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative HPLC (chromatographic column: Phenomenex luna C18 250 × 50 mm × 10 μm, mobile phase: water containing 0.1% TFA and acetonitrile, acetonitrile content 30%~55%, 17 min) to obtain compound 18-6. LCMS(ESI)m / z:337.0(M+1); 1 H NMR(400MHz,CDCl3)δ=6.99(d,J=9.1Hz,1H),6.86(dd,J=1.3,9.0Hz,1H),5.19(br s,1H),3.94- 3.88 (m, 2H), 1.70 (s, 6H).

[0212] Step 6: Production of Compound 18 Compound 18-6 (100 mg, 297.60 μmol, 1 eq) was dissolved in isopropanol (1 mL), and sodium hydroxide (1 M, 595.19 μL, 2 eqs) was added. The mixture was stirred at 0°C for 1 hour. The solution was filtered, washed with acetone, and concentrated under vacuum. Compound 18 (30 mg) was obtained without purification. LC-MS (ESI) m / z: 279.0 (M+1); 1 H NMR (400MHz, D2O) δ = 6.65-6.59 (m, 1H), 6.55 (d, J = 1.5Hz, 1H), 3.27 (s, 2H).

[0213] Example 19 [ka]

[0214] Step 1: Preparation of Compound 19-2 Compound 19-1 (1 g, 4.08 mmol, 1 eq) was dissolved in dimethylformamide (10 mL) solution, and potassium phosphate (866.30 mg, 4.08 mmol, 1 eq) and 1-bromo-2-fluoroethane (777.19 mg, 6.12 mmol, 1.5 eq) were added. The mixture was stirred at 25°C, then at 65°C for 16 hours. The residue was added to water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with saline solution (30 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20 / 1 to 3 / 1) to obtain compound 19-2. LCMS: 291(M+1); 1 H NMR(400MHz,CDCl3)δ=7.64-7.59(m,1H),6.58(d,J=9.1Hz,1H),5.58(s,2H) ,4.85-4.81(m,1H),4.72-4.70(m,1H),4.33-4.30(m,1H),4.27-4.23(m,1H).

[0215] Step 2: Preparation of Compound 19-3 Compound 19-2 (500 mg, 1.72 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.74 g, 6.87 mmol, 4 eq), bis(triphenylphosphine)palladium dichloride (120.57 mg, 171.78 μmol, 0.1 eq), and potassium acetate (674.34 mg, 6.87 mmol, 4 eq) were dissolved in dioxane (10 mL), the mixture was purged with nitrogen gas, and the mixture was stirred at 65°C for 16 hours in an N2 atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain compound 19-3. LCMS: 339.1 (M+1).

[0216] Step 3: Preparation of Compound 19-4 Compound 19-3 (600 mg, 1.77 mmol, 1 eq) was dissolved in a solution of tetrahydrofuran (10 mL) and H2O (5 mL). Sodium perborate tetrahydrate (273.02 mg, 1.77 mmol, 341.27 μL, 1 eq) was added, and the mixture was stirred at 25°C for 0.5 hours. Water (10 mL) was added to the solution, and the pH was adjusted to 3-4 with 0.5 N HCl. The aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saline solution (80 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1-0 / 1) to obtain compound 19-4. LCMS: 229.1 (M+1).

[0217] Step 4: Preparation of Compound 19-5 Compound 19-4 (20 mg, 87.65 μmol, 1 eq) was dissolved in acetonitrile (2 mL) solution, and 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (46.96 mg, 175.30 μmol, 2 eq) and K2CO3 (24.23 mg, 175.30 μmol, 2 eq) were added. The mixture was stirred at 25°C, then at 65°C for 2 hours. H2O (5 mL) was added to the solution, and the aqueous phase was adjusted to pH=3-4 with 0.5 N HCl. The solution was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saline solution (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound 19-5. LCMS (ESI) m / z: 287.1 (M+1).

[0218] Step 5: Manufacturing of Compound 19 Compound 19-5 (30 mg, 104.89 μmol, 1 eq) was dissolved in isopropanol (0.5 mL) solution, and NaOH (2 M, 104.89 μL, 2 eqs) was added. The mixture was stirred at 0°C, then at 25°C for 1 hour. The solution was filtered, and the filtered crude product was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content 1%~6%, 4 min) to obtain compound 19. LC-MS (ESI) m / z: 257 / 239 (M+1 / M-18+1); 1 H NMR(400MHz,D2O)δ=6.55(d,J=8.7Hz,1H),6.28(d,J=8.8Hz,1H),4.66-4.59(m,2H),4.20-4.15(m,1H),4.13-4.07(m,1H),3.22(s,2H).

[0219] Example 20 [ka]

[0220] Step 1: Synthesis of compound 20-2 Compound 19-1 (600 mg, 2.45 mmol, 1 eq) was dissolved in DMF (6 mL). The mixture was dissolved, and potassium phosphate (1.30 g, 6.12 mmol, 2.5 eq) and bromomethylcyclopropane (495.87 mg, 3.67 mmol, 351.68 μL, 1.5 eq) were added. The mixture was stirred at 25°C for 8 hours. The residue was diluted with 10 mL of EA and extracted with H2O (4 mL x 2). The organic layer was washed with 8 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 10 / 1) to obtain compound 20-2. 1 H NMR(400MHz,CDCl3)δ=7.66(d,J=9.0Hz,1H),6.62(d,J=9.0Hz,1H),5.66(s,2H),3.99(d,J =6.7Hz,2H),1.37(dddd,J=1.4,3.3,4.9,6.5Hz,1H),0.73-0.66(m,2H),0.49-0.43(m,2H).

[0221] Step 2: Synthesis of Compound 20-3 Compound 20-2 (150 mg, 501.48 μmol, 1 eq) was mixed with bis(pinacotato)diboronic acid (509.37 mg, 2.01 mmol, 2.5 eq) and potassium acetate (147.65 mg, 1.50 mmol, 3 eq). Dioxane (4 mL) was added to this mixture, followed by the addition of Pd(dppf)Cl2 (81.90 mg, 100.30 μmol, 0.2 eq). The mixture was degassed and purged three times with nitrogen gas. The mixture was then stirred at 65°C in a nitrogen atmosphere for 8 hours. Crude product 20-3 was used in the next step without further purification. LCMS(ESI) m / z: 347.1 (M+1).

[0222] Step 3: Synthesis of Compound 20-4 Compound 20-3 (250 mg, 722.16 μmol, 1 eq) was added to a mixed solution of THF (4 mL) and H2O (4 mL), and then sodium perborate tetrahydrate (222.22 mg, 1.44 mmol, 277.78 μL, 2 eq) was added. The mixture was stirred at 0-5°C for 1 hour. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0-5 / 1) to obtain compound 20-4. LC-MS (ESI) m / z: 237.0 (M+1).

[0223] Step 4: Synthesis of Compound 20-5 Compound 20-4 (20 mg, 84.67 μmol, 1 eq) was dissolved in acetonitrile (1 mL), and 2-iodomethylboronic acid pinacol ester (45.36 mg, 169.33 μmol, 2 eqs) was added, followed by potassium carbonate (17.55 mg, 127.00 μmol, 1.5 eqs). The mixture was stirred at 65°C for 4 hours. The reaction mixture was diluted with 15 mL of water and extracted with 15 mL of ethyl acetate. The combined organic layer was washed with 15 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. Compound 20-5 was obtained without purification.

[0224] Step 5: Synthesis of Compound 20 Compound 20-5 (24 mg, 81.61 μmol, 1 eq) was dissolved in isopropanol (0.5 mL), and sodium hydroxide (2 M, 81.61 μL, 2 eqs) was added. The mixture was stirred at 0°C for 1 hour. The solution was filtered, washed with acetone, and concentrated under vacuum. The crude product was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content 1%~6%, 4 min) to obtain compound 20. LC-MS (ESI) m / z: 265 (M+1); 1H NMR(400MHz,CD3OD)δ=6.50(br dd,J=2.4,6.9Hz,1H),6.18(br d,J=8.3Hz,1H),3.76(d,J=6.6Hz,2H),3.39 (br s,2H),1.97(d,J=7.2Hz,1H),1.29-1.15(m,2H),0.53(br d,J=6.7Hz,2H),0.33(br d,J=4.5Hz,2H).

[0225] Example 21 [ka]

[0226] Step 1: Synthesis of Compound 21-2 Compound 21-1 (600 mg, 2.45 mmol, 1 eq) was dissolved in N,N-dimethylformamide (6 mL), and potassium phosphate (1.30 g, 6.12 mmol, 2.5 eq) and 1-iodobutane (675.91 mg, 3.67 mmol, 417.23 μL, 1.5 eq) were added. The mixture was stirred at 25°C for 8 hours. The residue was diluted with 10 mL of water and extracted with 20 mL of ethyl acetate (10 mL x 2). The combined organic layer was washed with 10 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. Compound 21-2 was obtained without purification. 1 H NMR(400MHz,CDCl3)δ=7.66(d,J=9.0Hz,1H),6.63(d,J=9.0Hz,1H),5.65(s,2H),4 .10(t,J=6.5Hz,2H),1.93-1.82(m,2H),1.62-1.56(m,2H),1.00(t,J=7.4Hz,3H).

[0227] Step 2: Synthesis of Compound 21-3 A mixture of compound 21-2 (490 mg, 1.63 mmol, 1 eq), bis(pinacotato)diboronic acid (1.65 g, 6.51 mmol, 4 eq), and potassium acetate (479.08 mg, 4.88 mmol, 3 eq) was mixed with dioxane (2 mL), and then Pd(dppf)Cl2 (265.76 mg, 325.44 μmol, 0.2 eq) was added. The mixture was then degassed and purged three times with nitrogen gas, and the mixture was stirred at 65°C for 8 hours in a nitrogen atmosphere. The residue was diluted with 10 mL of water and extracted with 20 mL of ethyl acetate (10 mL x 2). The combined organic layer was washed with 10 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to obtain compound 21-3. LCMS(ESI)m / z:349.1(M+1).

[0228] Step 3: Synthesis of Compound 21-4 Compound 21-3 (1.4 g, 4.02 mmol, 1 eq) was dissolved in a mixed solution of THF (4 mL) and H2O (4 mL), and sodium perborate tetrahydrate (1.24 g, 8.04 mmol, 1.55 mL, 2 eq) was added. The mixture was stirred at 0-5°C for 1 hour. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of EA. Combined organic The layer was washed with 20 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to obtain compound 21-4.

[0229] Step 4: Synthesis of Compound 21-5 Compound 21-4 (300 mg, 1.26 mmol, 1 eq) was dissolved in acetonitrile (1.5 mL), and 2-iodomethylboronic acid pinacol ester (674.71 mg, 2.52 mmol, 2 eqs) was added, followed by potassium carbonate (261.06 mg, 1.89 mmol, 1.5 eq). The mixture was stirred at 25°C for 4 hours. The reaction mixture was diluted with 15 mL of water and extracted with 15 mL of ethyl acetate. The combined organic layer was washed with 15 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was stirred in petroleum ether at 25°C, filtered, and the filtered cake was dried to obtain compound 21-5.

[0230] Step 5: Synthesis of Compound 21 Compound 21-5 (80 mg, 270.20 μmol, 1 eq) was dissolved in isopropanol (1 mL), and sodium hydroxide (2 M, 270.20 μL, 2 eq) was added. The mixture was stirred at 0-5°C for 1 hour. The solution was filtered, washed with acetone, and concentrated under vacuum to obtain compound 21. LC-MS (ESI) m / z: 249.1 (M-18+1); 1 H NMR(400MHz,CD3OD)δ=6.45(d,J=8.7Hz,1H),6.15(d,J=8.8Hz,1H),3.90(t,J= 6.5Hz, 2H), 3.38 (s, 2H), 1.71 (s, 2H), 1.57-1.45 (m, 2H), 0.96 (t, J=7.4Hz, 3H).

[0231] Example 22 [ka]

[0232] Step 1: Synthesis of Compound 22-2 Compound 22-1 (3 g, 10.99 mmol, 1 eq) was dissolved in tetrahydrofuran (30 mL), and 3-hydroxyazetidine-1-carboxylic acid tert-butyl (2.00 g, 11.54 mmol, 1.05 eq) was added, followed by triphenylphosphine (4.32 g, 16.48 mmol, 1.5 eq). After the addition was complete, DIAD (3.33 g, 16.48 mmol, 3.20 ml, 1.5 eq) was added dropwise at 20°C. The resulting mixture was stirred at 50°C for 12 hours. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to obtain compound 22-2.

[0233] Step 2: Synthesis of Compound 22-3 Compound 22-2 (4.5g, 10.51 mmol, 1 eq) and bis(pinacotato)di A mixture of boronic acid (4.00 g, 15.76 mol, 1.5 eq) and potassium acetate (4.12 g, 42.03 mmol, 4 eq) was dissolved in dioxane (50 mL). Finally, Pd(dppf)Cl2 (858.07 mg, 1.05 mmol, 0.1 eq) was added, the mixture was degassed, and the atmosphere was purged three times with nitrogen gas. The mixture was then stirred at 80°C for 12 hours in a nitrogen atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to obtain compound 22-3. LCMS (ESI) m / z: 420.1 (M-56+1).

[0234] Step 3: Synthesis of Compound 22-4 Compound 22-3 (7 g, 5.89 mmol, 40% purity, 1 eq) was dissolved in a mixed solvent of tetrahydrofuran (20 mL) and water (10 mL), and sodium perborate tetrahydrate (2.27 g, 14.73 mmol, 2.5 eq) was added. The mixture was stirred at 20°C for 1 hour. The mixture was filtered and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 4 / 1~1 / 1) to obtain compound 22-4. LCMS (ESI) m / z: 310.0 (M-56+1).

[0235] Step 4: Synthesis of Compound 22-5 Compound 22-4 (650 mg, 1.78 mmol, 1 eq) was dissolved in acetonitrile (5 ml), and potassium carbonate (368.80 mg, 2.67 mmol, 1.5 eq) and 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (953.18 mg, 3.56 mmol, 2 eq) were added. The mixture was stirred at 60°C for 3 hours. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saturated brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150 × 40 mm × 15 μm, mobile phase: water containing 0.1% TFA and acetonitrile, acetonitrile content 26%~56%, 10 min) to obtain compound 22-5. LCMS(ESI)m / z:368.1(M-56+1); 1 H NMR(400MHz,CDCl3)δ=7.12(d,J=9.2Hz,1H),6.31-6.14(m,1H),4.99-4.87(m,1H),4.37-4.31(m,2H),4.15(br dd,J=3.9,9.7Hz,2H),3.81-3.77(m,2H),1.77(s,6H),1.50-1.44(m,9H).

[0236] Step 5: Synthesis of Compound 22 Compound 22-5 (50 mg, 118.14 μmol, 1 eq) was dissolved in isopropanol (1 mL), and sodium hydroxide (2 M, 118.14 μL, 2 eqs) was added. The mixture was stirred at 0-5°C for 1 hour. The solution was filtered to obtain compound 22. LC-MS (ESI) m / z: 310.1 (M-56+1); 1 H NMR(400MHz,D2O)δ=6.51(d,J=8.8Hz,1H),6.02-5.84(m,1H),4.84-4.79(m,1H),4.27-4.14(m,2H),4.02-3.84(m,3H),1.44-1.27(m,10H).

[0237] Example 23 [ka]

[0238] Step 1: Preparation of Compound 23-2 Compound 22-1 (1 g, 3.66 mmol, 1 eq) was dissolved in dimethylformamide (10 mL) solution, and K2CO3 (1.01 g, 7.32 mmol, 2 eq) and 3-iodooxetane (1.01 g, 5.49 mmol, 1.5 eq) were added. The mixture was stirred at 25°C, and then stirred at 100°C for 36 hours. The mixture was placed in ice water (15 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (20 mL x 2). The mixture was washed with brine (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 30 / 1, 10 / 1) to obtain compound 23-2. LCMS: 329 / 331 (M+1 / M+3); 1 H NMR (400MHz, CDCl3) δ=7.54(d,J=8.9Hz,1H),5.99(d,J=9.0Hz,1H),5.19(quin,J=5.8Hz,1H),4.96-4.89(m,2H),4.85-4.77(m,2H),1.70(s,6H).

[0239] Step 2: Preparation of Compound 23-3 Compound 23-2 (600 mg, 1.82 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.39 g, 5.47 mmol, 3 eq), Pd(dppf)Cl2.CH2Cl2 (297.73 mg, 364.58 μmol, 0.2 eq), and potassium acetate (536.70 mg, 5.47 mmol, 3 eq) were dissolved in dioxane (3 mL), purged three times with nitrogen gas, and stirred at 25°C. The mixture was then heated to 65°C in N2 and stirred for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 30 / 1 to 10 / 1) to obtain compound 23-3.

[0240] Step 3: Preparation of Compound 23-4 Compound 23-3 (500 mg, 1.33 mmol, 1 eq) was dissolved in tetrahydrofuran (10 mL) and H2O (5 mL), and sodium perborate tetrahydrate (408.98 mg, 2.66 mmol, 511.22 μL, 2 eq) was added. The mixture was stirred at 25°C for 0.5 hours. H2O (5 mL) was added to the solution, and the pH was adjusted to 3-4 with 0.5 N HCl. The aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saline solution (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1-0 / 1) to obtain compound 23-4. LCMS: 267 (M+1).

[0241] Step 4: Preparation of Compound 23-5 Compound 23-4 (30 mg, 1.24 mmol, 1 eq) was dissolved in acetonitrile (5 mL) solution, and 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (664.10 mg, 2.48 mmol, 2 eq) and potassium carbonate (342.61 mg, 2.48 mmol, 2 eq) were added at 25 °C, followed by stirring at 65 °C for 5 hours. H₂O (5 mL) was added to the solution, and the aqueous phase was adjusted to pH 3-4 with 0.5 N HCl, and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saline solution (30 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (column: Phenomenex luna). A 150×40mm×15μm C18 substrate was used, with the mobile phase consisting of water and acetonitrile containing 0.1% TFA (acetonitrile content 9%~39%), and the mixture was tested for 10 minutes to obtain compound 23-5. LC-MS (ESI) m / z: 325 (M+1); 1 H NMR(400MHz,CDCl3)δ=7.11(d,J=9.0Hz,1H),6.10(d,J=9.0Hz,1H),5.27-5 .21(m,1H),5.02-4.96(m,2H),4.93-4.87(m,2H),3.79(s,2H),1.78(s,6H).

[0242] Step 5: Production of Compound 23 Compound 23-5 (110 mg, 339.41 μmol, 1 eq) was dissolved in isopropanol (1 mL) solution, and NaOH (2 M, 339.41 μL, 2 eq) was added at 0°C. The mixture was then stirred at 25°C for 1 hour. Acetone (10 mL) was added to the mixture and stirred for 30 minutes. The mixture was filtered to obtain compound 23. LC-MS (ESI) m / z: 267.2 (M+1); 1 H NMR (400MHz, D2O) δ=6.49(d,J=8.8Hz,1H),5.87(d,J=8.8Hz,1H),5.17-5.01(m,1H),4.98-4.81(m,4H),3.22(s,2H).

[0243] Example 24 [ka]

[0244] Step 1: Synthesis of compound 24-2 Compound 22-1 (500 mg, 1.83 mmol, 1 eq) was dissolved in N,N-dimethylformamide (4 mL), and potassium phosphate (971.63 mg, 4.58 mmol, 2.5 eq) and 2-iodopropane (466.87 mg, 2.75 mmol, 274.63 μL, 1.5 eq) were added. The mixture was stirred at 50°C for 8 hours. The residue was diluted with 10 mL of water and extracted with ethyl acetate (4 mL x 2). The combined organic layer was washed with 8 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. Column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~10) was performed. The residue was purified by (1) to obtain compound 24-2. LC-MS (ESI) m / z: 315.1 (M+1); 1 H NMR (400MHz, CDCl3) δ=7.54(d,J=9.2Hz,1H),6.54-6.46(m,1H),4.62-4.49(m,1H),1.67(s,6H),1.39-1.33(m,6H).

[0245] Step 2: Synthesis of Compound 24-3 A mixture of compound 24-2 (790 mg, 2.51 mmol, 1 eq), potassium acetate (738.03 mg, 7.52 mmol, 3 eq), and bis(pinacotato)diboronic acid (2.55 g, 10.03 mmol, 4 eq) was mixed with dioxane (4 mL), and then Pd(dppf)Cl2 (409.41 mg, 501.33 μmol, 0.2 eq) was added, and the mixture was purged three times with nitrogen gas. The mixture was stirred at 65°C for 8 hours. The residue was diluted with 15 mL of water and extracted with 20 mL of ethyl acetate (10 mL x 2). The combined organic layer was washed with 10 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain compound 24-3. LCMS(ESI)m / z:363.1(M+1).

[0246] Step 3: Synthesis of Compound 24-4 Compound 24-3 (1.6 g, 4.42 mmol, 1 eq) was dissolved in a mixed solvent of tetrahydrofuran (2 mL) and water (2 mL), and sodium perborate tetrahydrate (1.36 g, 8.83 mmol, 2 eq) was added. The mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~5 / 1) to obtain compound 24-4. LCMS(ESI) m / z: 253.1 (M+1); 1 H NMR (400MHz, CDCl3) δ=7.11(d,J=9.0Hz,1H),6.61-6.51(m,1H),4.61-4.45(m,1H),1.42-1.38(m,6H),1.28(s,7H),1.25(s,12H).

[0247] Step 4: Synthesis of Compounds 24-5 Compound 24-4 (400 mg, 1.59 mmol, 1 eq) was dissolved in acetonitrile (1 mL), and 2-iodomethylboronic acid pinacol ester (849.59 mg, 3.17 mmol, 2 eq) and potassium carbonate (328.73 mg, 2.38 mmol, 1.5 eq) were added. The mixture was stirred at 65°C for 4 hours. The reaction mixture was diluted with 15 mL of water and extracted with 15 mL of ethyl acetate. The combined organic layer was washed with 15 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative HPLC (chromatographic column: Phenomenex luna C18 150 × 40 mm × 15 μm, mobile phase: water containing 0.1% TFA and acetonitrile, acetonitrile content 20%~50%, 10 min) to obtain compound 24-5. LCMS(ESI)m / z:311.1(M+1); 1H NMR (400MHz, CDCl3) δ=7.15(d,J=9.1Hz,1H),6.67-6.48(m,1H),4.65-4.45(m,1H),3.85-3.76(m,2H),1.75(s,6H),1.46-1.38(m,6H).

[0248] Step 5: Synthesis of Compound 24 Compound 24-5 (180 mg, 580.45 μmol, 1 eq) was dissolved in isopropanol (1 mL), and sodium hydroxide (2 M, 580.45 μL, 2 eqs) was added. The mixture was stirred at 0-5°C for 1 hour. The solution was filtered, washed with acetone, and concentrated under vacuum. The crude product was purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: 10 mmol / L ammonium bicarbonate). Compound 24 was obtained by dissolving a monoium aqueous solution in acetonitrile (acetonitrile content 1%-6%, 5 min). LC-MS (ESI) m / z: 253.1 (M+1); 1 H NMR (400MHz, D2O) δ=6.49(d,J=8.7Hz,1H),6.25(d,J=8.7Hz,1H),4.26(t,J=6.1Hz,1H),3.18(s,2H),1.13(d,J=6.1Hz,6H).

[0249] Example 25 [ka]

[0250] Step 1: Synthesis of Compound 25-2 Compound 22-1 (800 mg, 2.93 mmol, 1 eq) was dissolved in N,N-dimethylformamide (7 mL), and potassium phosphate (1.55 g, 7.32 mmol, 2.5 eq) and 2-bromo-1,1-difluoroethane (636.94 mg, 4.39 mmol, 1.5 eq) were added. The mixture was stirred at 100°C for 8 hours. The reaction mixture was diluted with 15 mL of water and extracted with 15 mL of ethyl acetate. The combined organic layer was washed with 15 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~5 / 1) to obtain compound 25-2. LCMS(ESI) m / z: 339.1 (M+3); 1 H NMR (400MHz, CDCl3) δ=7.62(d,J=9.0Hz,1H),6.51(d,J=9.0Hz,1H),6.33-5.94(m,1H),4.21(dt,J=4.2,12.7Hz,2H),1.73-1.67(m,6H).

[0251] Step 2: Synthesis of Compound 25-3 Compound 25-2 (1 g, 2.97 mmol, 1 eq), potassium acetate (873.36 mg, 8.90 mmol, 3 eq), and bis(pinacotato)diboronic acid (3.01 g, 11.87 mmol, 4 eq) were dissolved in dioxane (10 mL). Pd(dppf)Cl2 (484.49 mg, 593.27 μmol, 0.2 eq) was then added, and the mixture was purged three times with nitrogen gas. The mixture was stirred at 65°C for 8 hours. The reaction mixture was diluted with 15 mL of water and extracted with 15 mL of ethyl acetate. The combined organic layer was washed with 15 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 20 / 1~5 / 1) to obtain compound 25-3. LCMS(ESI) m / z: 385.1 (M+1); 1H NMR(400MHz,CDCl3)δ=7.77(d,J=8.4Hz,1H),6.55-6.52(m,1H),6.37-5.99(m,1H),4.29-4.17(m,2H),1.64(d,J=0.9Hz,6H),1.31-1.13 (m,12H).

[0252] Step 3: Synthesis of Compound 25-4 Compound 25-3 (700 mg, 1.82 mmol, 1 eq) was dissolved in a mixed solvent of THF (4 mL) and H2O (4 mL), and sodium perborate tetrahydrate (560.69 mg, 3.64 mmol, 700.86 μL, 2 eqs) was added. The mixture was stirred at 0-5°C for 1 hour. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0-5 / 1) to obtain compound 25-4. LC-MS (ESI) m / z: 275.1 (M+1); 1 H NMR (400MHz, CDCl3) δ=7.07(d,J=9.0Hz,1H),6.56-6.50(m,1H),6.30-5.94(m,1H),4.21-4.11(m,2H),1.71-1.67(m,6H).

[0253] Step 4: Synthesis of Compound 25-5 Compound 25-4 (190 mg, 692.88 μmol, 1 eq) was dissolved in acetonitrile (5 mL), and 2-iodomethylboronic acid pinacol ester (371.25 mg, 1.39 mmol, 2 eqs) was added, followed by potassium carbonate (143.64 mg, 1.04 mmol, 1.5 eq). The mixture was stirred at 65°C for 4 hours. The reaction mixture was diluted with 15 mL of water and extracted with 15 mL of ethyl acetate. The combined organic layer was washed with 15 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative HPLC (chromatographic column: Phenomenex). A 75×30mm×3μm Luna C18 substrate was used, with the mobile phase consisting of water and acetonitrile containing 0.1% TFA (acetonitrile content 24%~54%), and the mixture was prepared for 7 minutes to obtain compound 25-5. LC-MS (ESI) m / z: 333.1 (M+1); 1 H NMR (400MHz, CDCl3) δ=7.16(d,J=9.1Hz,1H),6.63(d,J=9.1Hz,1H),6.44-6.02(m,1H),4.26(d,J=4.3Hz,2H),3.90-3.75(m,2H),1.83-1.73(m,6H).

[0254] Step 5: Synthesis of Compound 25 Compound 25-5 (170 mg, 511.95 μmol, 1 eq) was dissolved in isopropanol (1.5 mL), and sodium hydroxide (2 M, 511.95 μL, 2 eqs) was added. The mixture was stirred at 25°C for 1 hour. The solution was filtered to obtain compound 25. LC-MS (ESI) m / z: 257.0 (M-18+1); 1 H NMR(400MHz,D2O)δ=6.54(d,J=8.8Hz,1H),6.27(d,J=8.9Hz,1H),6.07(s,1H),4.12(d,J=3.8Hz,2H),3.21(s,2H).

[0255] Example 26 [ka]

[0256] Step 1: Preparation of Compound 26-2 Compound 22-1 (1 g, 3.66 mmol, 1 eq) and 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (1.70 g, 7.32 mmol, 32.33 μL, 2 eq) were dissolved in NN-dimethylformamide (10 mL), potassium carbonate (759.15 mg, 5.49 mmol, 1.5 eq) was added, the mixture was degassed, and the mixture was purged three times with nitrogen gas. The mixture was then stirred at 95°C for 2 hours. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The organic layer was washed with 10 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 30 / 1) to obtain compound 26-2. 1 H NMR (400MHz, CDCl3) δ=7.63(d,J=8.9Hz,1H),6.57(d,J=9.0Hz,1H),4.39(d,J=8.1Hz,2H),1.70(s,6H).

[0257] Step 2: Preparation of Compound 26-3 Compound 26-2 (650 mg, 1.83 mmol, 1 eq), bis(pinacotato)diboronic acid (929.64 mg, 3.66 mmol, 2 eqs), potassium acetate (538.92 mg, 5.49 mmol, 3 eqs), and Pd(dppf)Cl2.CH2Cl2 (149.48 mg, 183.04 μmol, 0.1 eq) were dissolved in dioxane (10 mL), degassed, and purged three times with nitrogen gas. The mixture was then stirred and reacted at 70°C for 12 hours in a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 50 mL of water and extracted with 50 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 5 / 1) to obtain compound 26-3.

[0258] Step 3: Preparation of Compound 26-4 Compound 26-3 (900 mg, 2.81 mmol, 1 eq) was dissolved in a mixed solution of tetrahydrofuran (10 mL) and water (10 mL), and sodium perborate tetrahydrate (865.39 mg, 5.62 mmol, 2 eqs) was added. The mixture was stirred at 20°C for 0.5 hours. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The organic layer was washed with 20 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 20 / 1~2 / 1) to obtain compound 26-4. LCMS (ESI) m / z: 293.0 (M+1).

[0259] Step 4: Preparation of Compound 26-5 Compound 26-4 (400 mg, 1.37 mmol, 1 eq) and 2-(iodomethyl) -4,4,5,5-tetramethyl-1,3,2-dioxaborolane (733.45 mg, 2.74 mmol, 2 eq) and potassium carbonate (283.79 mg, 2.05 mmol, 1.5 eq) were mixed in acetonitrile (5 mL), purged three times with nitrogen gas, and then the mixture was stirred at 60°C for 3 hours in a nitrogen atmosphere. The reaction mixture was quenched by adding 20 mL of water, and then extracted with 20 mL of ethyl acetate. The organic layer was washed with 5 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was stirred with petroleum ether (10 mL), filtered, and the filter cake was dried to obtain compound 26-5. 1 H NMR(400MHz, CDCl3)δ=7.10(d,J=9.0Hz,1H),6.69(d,J=9.0Hz,1H),4.43(q,J=8.4Hz,2H),3.96(s,2H),1.78(s,6H);LCMS(ESI)m / z:351.0(M+1).

[0260] Step 5: Production of Compound 26 Compound 26-5 (100 mg, 285.67 μmol, 1 eq) was dissolved in isopropanol (1 mL), and sodium hydroxide solution (2 M, 285.67 μL, 2 eqs) was added. The mixture was stirred at 20°C for 1 hour. Acetone (5 mL) was added, and the mixture was stirred for 1 hour. Then, it was concentrated under reduced pressure, and the resulting residue was purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 1% to 6%, 4 min) to obtain compound 26. 1 H NMR(400MHz,D2O)δ=6.58(d,J=8.8Hz,1H),6.31(d,J=8.8Hz,1H),4.37(q,J=8.7Hz,2H),3.24(s,2H). LCMS (ESI) m / z: 292.9 (M+1).

[0261] Example 27 [ka]

[0262] Step 1: Preparation of Compound 27-2 Compound 22-1 (2 g, 7.32 mmol, 1 eq), Compound 27-1 (2.09 g, 10.99 mmol, 32.33 μL, 1.5 eq), and potassium carbonate (1.52 g, 10.99 mmol, 1.5 eq) were mixed in N,N-dimethylformamide (10 mL), purged three times with nitrogen gas, and the reaction mixture was stirred at 75°C for 12 hours. The reaction mixture was diluted with water (20 mL), extracted with ethyl acetate (20 mL), the organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was subjected to silica gel flash column chromatography (petroleum ether / ethyl acetate = The compound 27-2 was obtained by purification using LC-MS (ESI) with a ratio of 312.9 / 314.9 (M+1 / M+3). 1H NMR (400MHz, CDCl3) δ=7.60(d,J=9.0Hz,1H),6.92(d,J=9.0Hz,1H),3.78-3.68(m,1H),1.67(s,6H),0.92-0.73(m,4H).

[0263] Step 2: Preparation of Compound 27-3 Compound 27-2 (340 mg, 1.09 mmol, 1 eq) was dissolved in dioxane (5 mL), potassium acetate (319.67 mg, 3.26 mol, 3 eq) and bis(pinacotato)diboronic acid (1.10 g, 4.34 mmol, 4 eq) were added, and finally, Pd(dppf)Cl2 (177.34 mg, 217.15 μmol, 0.2 eq) was added. The mixture was stirred at 70°C for 8 hours. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain compound 27-3, which was used in the next step without further purification. LCMS (ESI) m / z: 361.1 (M+1).

[0264] Step 3: Preparation of Compound 27-4 Compound 27-3 (1 g, 2.78 mmol, 1 eq) was dissolved in a mixed solvent of THF (4 mL) and H2O (4 mL), and sodium perborate tetrahydrate (854.28 mg, 5.55 mmol, 1.07 mL, 2 eqs) was added. The mixture was stirred at 0-5°C for 1 hour. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0-5 / 1) to obtain compound 27-4. LCMS(ESI) m / z: 251.1 (M+1); 1H NMR (400MHz, CDCl3) δ=7.16(d,J=9.2Hz,1H),6.99-6.89(m,1H),3.87-3.73(m,1H),1.75(s,6H),0.95-0.79(m,4H).

[0265] Step 4: Preparation of Compound 27-5 Compound 27-4 (100 mg, 399.61 μmol, 1 eq) was dissolved in MeCN (3 mL), and potassium carbonate (82.84 mg, 599.41 μmol, 1.5 eq) and 2-iodomethylboronic acid pinacol ester (214.11 mg, 799.21 μmol, 2 eq) were added. The mixture was stirred at 65°C for 4 hours. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative HPLC (chromatographic column: Phenomenex Luna C18 75 × 30 mm × 3 μm, mobile phase: water containing 0.1% TFA and acetonitrile, acetonitrile content 24%~54%, 7 min) to obtain compound 27-5. LCMS(ESI)m / z:309.1(M+1).

[0266] Step 5: Production of Compound 27 Compound 27-4 (40 mg, 129.83 μmol, 1 eq) was dissolved in isopropanol (1 mL), and sodium hydroxide (2 M, 129.83 μL, 2 eqs) was added. The mixture was stirred at 0°C for 30 minutes. The mixture was filtered to obtain compound 27. LC-MS (ESI) m / z: 251.1 (M+1); 1 H NMR(400MHz,D2O)δ=6.52(d,J=2.6Hz,2H),3.73-3.60(m,1H),3.18(s,2H),0.61-0.52(m,4H).

[0267] Example 28 [ka]

[0268] Step 1: Synthesis of Compound 28-2 Compound 22-1 (850 mg, 3.11 mmol, 1 eq) was dissolved in N,N-dimethylformamide (5 mL), and potassium phosphate (1.65 g, 7.78 mmol, 2.5 eq) and 1-bromopentane (705.22 mg, 4.67 mmol, 582.83 μL, 1.5 eq) were added. The mixture was stirred at 70°C for 4 hours. The reaction mixture was diluted with 15 mL of water and extracted with 15 mL of ethyl acetate. The combined organic layer was washed with 15 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 5 / 1) to obtain compound 28-2. 1 H NMR(400MHz,CDCl3)δ=7.55(d,J=9.1Hz,1H),6.48(d,J=9.0Hz,1H),3.99(t,J=6.8Hz ,2H),1.87-1.78(m,2H),1.71-1.65(m,6H),1.48-1.27(m,4H),0.86(t,J=7.2Hz,3H).

[0269] Step 2: Synthesis of Compound 28-3 Compound 28-2 (950 mg, 2.77 mmol, 1 eq) was dissolved in dioxane (7 mL), potassium acetate (814.94 mg, 8.30 mmol, 3 eq) and bis(pinacotato)diboronic acid (2.81 g, 11.07 mmol, 4 eq) were added, and finally, Pd(dppf)Cl2 (452.08 mg, 553.59 μmol, 0.2 eq) was added. The mixture was stirred at 80°C for 6 hours. The reaction mixture was diluted with 15 mL of water and extracted with 15 mL of ethyl acetate. The combined organic layer was washed with 15 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~5 / 1) to obtain product 28-3. LCMS(ESI) m / z: 391.1 (M+1).

[0270] Step 3: Synthesis of Compound 28-4 Compound 28-3 (1.5 g, 3.84 mmol, 1 eq) was dissolved in a mixed solution of tetrahydrofuran (4 mL) and water (4 mL), and sodium perborate tetrahydrate (1.18 g, 7.69 mmol, 1.48 mL, 2 eqs) was added. The mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0~5 / 1) to obtain compound 28-4. LCMS(ESI)m / z:281.1(M+1).

[0271] Step 4: Synthesis of Compound 28-5 Compound 28-4 (350 mg, 1.25 mmol, 1 eq) was dissolved in acetonitrile (2 mL), and 2-iodomethylboronic acid pinacol ester (668.99 mg, 2.50 mmol, 2 eq) and potassium carbonate (258.85 mg, 1.87 mmol, 1.5 eq) were added. The mixture was stirred at 65°C for 4 hours. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was stirred in PE at 25°C for 20 minutes to obtain compound 28-5. LCMS(ESI)m / z:339.1(M+1); 1 H NMR(400MHz,CDCl3)δ=7.15-7.09(m,1H),6.58-6.47(m,1H),4.03(s,2H),3.92(s,2H),1.92-1.86(m,2H),1.76(s,6H),1.53-1.46(m,2H),1.40(br d,J=6.9Hz,2H),0.97-0.93(m,3H).

[0272] Step 5: Synthesis of Compound 28 Compound 28-5 (110 mg, 325.29 μmol, 1 eq) was dissolved in isopropanol (1.5 mL), and sodium hydroxide (2 M, 325.29 μL, 2 eqs) was added. The mixture was stirred at 0-5°C for 1 hour. The solution was filtered to obtain compound 28. LC-MS (ESI) m / z: 263.1 (M-18+1); 1 H NMR(400MHz,D2O)δ=6.53(d,J=8.8Hz,1H),6.26(br d,J=8.8Hz,1H),3.87(br t,J=6.6Hz,2H),3.21(s,2H),1.66-1.51(m,2H),1.36-1.17(m,4H),0.86-0.75(m,3H).

[0273] Example 29 [ka]

[0274] Step 1: Preparation of Compound 29-2 Compound 22-1 (1 g, 3.66 mmol, 1 eq) was dissolved in dimethylformamide (10 mL) solution, and K2CO3 (1.01 g, 7.32 mmol, 2 eqs) and 1-iodopropane (933.75 mg, 5.49 mmol, 536.64 μL, 1.5 eqs) were added. The mixture was stirred at 25°C, and then stirred at 50°C for 2 hours. The residue was added to water (10 mL). The aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with saline solution (30 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 30 / 1 to 10 / 1) to obtain compound 29-2. LCMS: 317(M+3); 1 H NM R(400MHz, CDCl3)δ=7.55(d,J=9.1Hz,1H),6.48(d,J=9.1Hz,1H),3.96(t,J=6.6Hz,2H),1.84(sxt,J=7.1Hz,2H),1.68(s,6H),1.02(t,J=7.4Hz,3H).

[0275] Step 2: Preparation of Compound 29-3 Compound 29-2 (1.1 g, 3.49 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.33 g, 5.24 mmol, 1.5 eq), and Pd(dppf)Cl2,CH2Cl2, potassium acetate (1.03 g, 10.47 mmol, 3 eq) were dissolved in dioxane (3 mL), purged three times with nitrogen gas at 25 °C, and then the mixture was stirred in N2 at 75 °C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was placed in ice water (15 mL) and stirred for 10 minutes. The aqueous phase was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saline solution (50 mL x 2) and dried over Na2SO4. The mixture was filtered with anhydrous Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1, 0 / 1) to obtain compound 29-3. LCMS: 363.2 (M+1).

[0276] Step 3: Preparation of Compound 29-4 Compound 29-3 was dissolved in tetrahydrofuran (20 mL) and H2O (10 mL), sodium perborate tetrahydrate (220.88 mg, 1.44 mmol, 276.10 μL, 2 eq) was added, the mixture was stirred, and left at 25°C for 1 hour. H2O (10 mL) was added to the solution, and the pH was adjusted to 3-4 with 0.5 N HCl. The aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saline solution (50 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1-5 / 1) to obtain compound 29-4. LCMS (ESI) m / z: 253.1 (M+1).

[0277] Step 4: Preparation of Compound 29-5 Compound 29-4 (300 mg, 1.19 mmol, 1 eq) was dissolved in acetonitrile (5 mL) solution, and 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (637.19 mg, 2.38 mmol, 2 eq) and K2CO3 (328.73 mg, 2.38 mmol, 2 eq) were added at 25°C, and the mixture was stirred at 65°C for 5 hours. H2O (5 mL) was added to the solution, and the pH of the aqueous phase was adjusted with 0.5 N HCl to pH=3-4, and the mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saline solution (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was stirred with petroleum ether (10 mL) at 25°C for 30 minutes, filtered, and the filter cake was dried to obtain compound 29-5. LCMS(ESI)m / z:311(M+1); 1 H NMR(400MHz,CDCl3)δ=7.12(d,J=9.1Hz,1H),6.51(d,J=9.3Hz,1H),4.00(t,J=6. 6Hz, 2H), 3.92 (s, 2H), 1.91 (s, J = 7.1Hz, 2H), 1.77 (s, 6H), 1.09 (t, J = 7.4Hz, 3H).

[0278] Step 5: Manufacturing of Compound 29 Compound 29-5 (220 mg, 709.43 μmol, 1 eq) was dissolved in isopropanol (2 mL) solution, and NaOH (2 M, 709.43 μL, 2 eq) was added at 0°C. The mixture was then stirred at 25°C for 1 hour. Acetone (10 mL) was added to the mixture and stirred for 30 minutes. The mixture was filtered to obtain compound 29. LC-MS (ESI) m / z: 253 (M+1); 235 (M-18+1); 1 H NMR(400MHz,D2O)δ=6.53(d,J=8.6Hz,1H),6.27(d,J=8.8Hz,1H),3.83( t,J=6.6Hz,2H),3.22(s,2H),1.61(qd,J=7.2,14.0Hz,2H),0.87(t,J=7.4Hz,3H).

[0279] Example 30 [ka]

[0280] Step 1: Synthesis of compound 30-2 Compound 22-1 (2.24 g, 8.20 mmol, 1 eq) was dissolved in dichloromethane (20 mL), stirred, and a 4 Å molecular sieve (2.24 g) was added to the solution. Phenylboronic acid (2 g, 16.40 mmol, 2 eq), copper acetate (3.35 g, 18.45 mmol, 2.25 eq), and pyridine (2.59 g, 32.81 mmol, 2.65 mL, 4 eq) were added sequentially. The mixture was stirred at 25°C for 72 hours. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 60 / 1 to 40 / 1) to obtain compound 30-2. LCMS (ESI) m / z: 349.1 (M+1).

[0281] Step 2: Synthesis of compound 30-3 Compound 30-2 (430 mg, 1.23 mmol, 1 eq) was dissolved in dioxane (6 mL), potassium acetate (362.57 mg, 3.69 mmol, 3 eq) and bis(pinacotato)diboronic acid (1.25 g, 4.93 mmol, 4 eq) were added, and finally Pd(dppf)Cl2 (201.13 mg, 246.29 μmol, 0.2 eq) was added. The mixture was purged three times with nitrogen gas and stirred at 70°C for 8 hours. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain compound 30-3. LCMS (ESI) m / z: 397.1 (M+1).

[0282] Step 3: Synthesis of Compound 30-4 Compound 30-3 (800 mg, 2.02 mmol, 1 eq) was dissolved in a mixed solution of THF (5 mL) and water (5 mL), and sodium perborate tetrahydrate (621.28 mg, 4.04 mol, 776.60 μL, 2 eq) was added. The mixture was stirred at 0°C for 1 hour. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1~3 / 1) to obtain compound 30-4.

[0283] Step 4: Synthesis of compound 30-5 Compound 30-4 (100 mg, 349.31 μmol, 1 eq) was dissolved in acetonitrile (3 mL), and potassium carbonate (72.42 mg, 523.96 μmol, 1.5 eq) and 2-iodomethylboronic acid pinacol ester (187.16 mg, 698.62 μmol, 2 eq) were added. The mixture was stirred at 65°C for 4 hours. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative HPLC (chromatographic column: Phenomenex Synergi C18 150 × 25 mm × 10 μm, mobile phase: water and acetonitrile containing 0.1% TFA, acetonitrile content 38%~68%, 10 min) to obtain compound 30-5. LCMS(ESI)m / z:345.1(M+1).

[0284] Step 5: Synthesis of compound 30 Compound 30-5 (30 mg, 87.18 μmol, 1 eq) was dissolved in isopropanol (1 mL) solution, and sodium hydroxide (2 M, 87.18 μL, 2 eqs) was added. The mixture was stirred at 0-5°C for 30 minutes. The solution was filtered to obtain compound 30. LC-MS (ESI) m / z: 287.1 (M+1); 1H NMR(400MHz,D2O)δ=7.33-7.21(m,2H),7.05-6.87(m,3H),6.59(d,J=8.8Hz,1H),6.21(d,J=8.6Hz,1H),3.27(s,2H).

[0285] Example 31 [ka]

[0286] Step 1: Preparation of Compound 31-2 Compound 22-1 (100 mg, 366.19 μmol, 1 eq) was dissolved in DMF (2 mL), and then benzyl bromide (75.16 mg, 439.43 μmol, 52.19 μL, 1.2 eq) and K2CO3 (75.92 mg, 549.29 μmol, 1.5 eq) were added sequentially at room temperature. The mixture was stirred at 50°C for 24 hours. The reaction mixture was diluted with 5 mL of H2O, extracted with 10 mL of RINKAN, washed with saturated NaCl aqueous solution (10 mL x 3), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 31-2. LCMS(ESI) m / z: 362.9 (M+1); 1 H NMR (400MHz, CDCl3) δ=7.54(d,J=9.1Hz,1H),7.48-7.42(m,2H),7.36-7.28(m,2H),7.28-7.21(m,1H),6.54(s,1H),5.19(s,2H),1.69(s,6H).

[0287] Step 2: Preparation of Compound 31-3 Compound 31-2 (1.34 g, 3.68 mmol, 1 eq), bis(pinacolato)dibo 1.87 g, 7.37 mmol, 2 eqs of ron and potassium acetate (1.08 g, 11.05 mmol, 3 eqs) were dissolved in 12 mL of dioxane. Pd(dppf)Cl2 (269.55 mg, 368.39 μmol, 0.1 eq) was then added, the mixture was degassed, purged three times with N2, and then stirred at 70°C for 12 hours under N2 protection. The reaction mixture was diluted with 30 mL of H2O and extracted with 40 mL of EA (20 mL x 2). The combined organic layer was washed with 30 mL of saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain compound 31-3. LCMS(ESI) m / z: 411.3 (M+1)

[0288] Step 3: Preparation of Compound 31-4 Compound 31-3 (1.57 g, 3.83 mmol, 1 eq) was dissolved in a mixed solvent of THF (7 mL) and H2O (7 mL), and then sodium perborate tetrahydrate (1.18 g, 7.65 mmol, 1.47 mL, 2 eq) was added. The mixture was stirred at 20°C for 30 min. The solution was adjusted to pH 7-8 with 1 N HCl, and then extracted with EA (20 mL x 2). The combined organic phase was washed with saline solution (20 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1-5 / 1) to obtain compound 31-4. 1 H NMR(400MHz, CDCl3)δ=7.54(d,J=7.46Hz,2H),7.40(t,J=7.46Hz,2H),7.33(d,J=7. 34Hz, 1H), 7.11 (d, J=9.05Hz, 1H), 6.60 (d, J=9.05Hz, 1H), 5.22 (s, 2H), 1.78 (s, 6H).

[0289] Step 4: Preparation of Compound 31-5 Compound 31-4 (467 mg, 1.56 mmol, 1 eq) was dissolved in acetonitrile (5 mL), and 2-iodomethyl pinacolborate (833.21 mg, 3.11 mmol, 2 eqs) and K2CO3 (322.39 mg, 2.33 mmol, 1.5 eqs) were added sequentially. The mixture was then stirred in N2 at 60°C for 3 hours. The reaction mixture was diluted with 20 mL of H2O, extracted with 60 mL of EA (20 mL x 3), washed with 30 mL of saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was stirred with petroleum ether at 25°C for 30 min, filtered, and the filtered cake was dried to obtain compound 31-5. 1 H NMR(400MHz,CDCl3)δ=7.60-7.51(m,2H),7.43-7.35(m,2H),7.32(br d,J=7.21Hz,1H),7.08(d,J=9.05Hz,1H),6.56(d,J=9.05Hz,1H),5.21(s,2H),3.92(s,2H),1.77(s,6H).

[0290] Step 5: Production of Compound 31 Compound 31-5 (535 mg, 1.49 mmol, 1 eq) was dissolved in i-PrOH (2 mL), and NaOH (2 M, 1.64 mL, 2.2 eq) was added at room temperature. The mixture was stirred at room temperature for 1 hour. The solution was filtered to obtain compound 31. LC-MS (ESI) m / z: 301.1 (M+1). 1 H NMR(400MHz,D2O)δ=7.44-7.40(m,1H),7.44-7.39(m,1H),7.41-7.39(m,1H),7.36(t,J=7.47Hz,2H),7.30(br d,J=7.03Hz,1H),6.49(d,J=8.78Hz,1H),6.26(d,J=8.78Hz,1H),4.99(s,2H),3.22(s,2H).

[0291] Example 32 [ka]

[0292] Step 1: Preparation of Compound 32-2 At -100°C to -90°C, n-butyllithium (2.5M, 16.90mL, 1.2eq) was added dropwise to a solution of dichloromethane (4.49g, 52.82 mmol, 3.40mL, 1.5eq) in tetrahydrofuran (50mL), and the mixture was stirred at -100°C to -90°C for 30 minutes. Then, at -100°C to -90°C, a solution of 2,4,4,5,5-pentamethyl-1,3,2-dioxaborolane (5g, 35.21 mmol, 1eq) in tetrahydrofuran (10mL) was added dropwise, followed by the addition of zinc dichloride (1M, 28.17mL, 0.8eq). The mixture was then heated to 25°C and stirred for a further 12 hours. The reaction mixture was quenched by adding 50mL of aqueous ammonium chloride at 0°C, and then diluted with 50mL of saline solution and extracted with 100mL of ethyl acetate. The organic layer was washed with 50 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 32-2. 1 H NMR (400MHz, CDCl3) δ = 3.44 (m, 1H), 1.56-1.41 (m, 3H), 1.33-1.14 (m, 12H).

[0293] Step 2: Preparation of compound 32-4 To a solution of compound 15-8 (200 mg, 839.50 μmol, 1 eq) in acetonitrile (2 mL), potassium carbonate (232.06 mg, 1.68 mmol, 2 eqs), potassium iodide (278.72 mg, 1.68 mmol, 2 eqs), and compound 32-2 (319.81 mg, 1.68 mmol, 2 eqs) were added. The mixture was stirred at 65°C for 3 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 10 mL of water and extracted with 20 mL of ethyl acetate (10 mL x 2). The combined organic layer was washed with 10 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 32-4.

[0294] Step 3: Production of Compound 32 Compound 32-4 (260 mg, 838.42 μmol, 1 eq) was dissolved in isopropanol (2.6 mL) solution, and sodium hydroxide (2 M, 838.42 μL, 2 eqs) was added. The mixture was stirred at 20°C for 1 hour, then sodium hydroxide (2 M, 838.42 μL, 2 eqs) was added, and the mixture was stirred again at 20°C for another 1 hour. The mixture was filtered to obtain the filtrate. The residue was purified by preparative HPLC (chromatographic column: Waters A 150×50mm×10μm Xbridge C18 substrate was used, and the mobile phase consisted of water and acetonitrile containing 10 mmol / L ammonium bicarbonate (acetonitrile content in the mobile phase was 1% to 12%, 10 min), yielding compound 32. 1 H NMR(400MHz,D2O)δ=6.52(br d,J=8.6Hz,1H),6.27(br d,J=8.6Hz,1H),3.92(q,J=6.7Hz,2H),3.30(br d,J=7.1Hz,1H),1.32-1.06(m,6H). LCMS (ESI) m / z: 252.9 (M+1).

[0295] Example 33 [ka]

[0296] Step 1: Preparation of Compound 33-2 At a temperature of 0-5°C, sodium hydride (2.04 g, 50.98 mmol, 60% purity, 2.3 eq) was added to a solution of compound 33-1 (4.5 g, 22.16 mmol, 1 eq) in tetrahydrofuran (45 mL), and the mixture was stirred at 0-5°C for 0.5 hours. Then, iodomethane (3.46 g, 24.38 mmol, 1.52 mL, 1.1 eq) was added. The mixture was stirred for a further 0.5 hours at 0-5°C, then heated to 25°C and stirred for a further 11 hours. The reaction mixture was quenched by adding 50 mL of aqueous ammonium chloride at 0-5°C, and then extracted with 50 mL of ethyl acetate. The organic layer was washed with 20 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. Compound 33-2 was obtained by purification using silica gel flash column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 20 / 1). 1 H NMR (400MHz, CDCl3) δ=7.35(d,J=8.2Hz,1H),6.94(d,J=2.0Hz,1H),6.72(dd,J=2.0,8.2Hz,1H),5.43(s,1H),4.32(s,2H),3.31(s,3H).

[0297] Step 2: Preparation of Compound 33-3 Compound 33-2 (4 g, 18.43 mmol, 1 eq) was dissolved in a 40 mL solution of dichloromethane, DMAP (112.57 mg, 921.41 μmol, 0.05 eq) was added, followed by Boc2O (4.83 g, 22.11 mmol, 5.08 mL, 1.2 eq). The mixture was stirred at 20°C for 12 hours. The reaction mixture was quenched by adding an aqueous hydrochloric acid solution (0.2 N, 10 mL), and the separated organic layer was washed with 10 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 33-3.

[0298] Step 3: Preparation of Compound 33-4 At -70 to -60°C, n-butyllithium (2.5M, 9.51mL, 1.3eq) was added dropwise to a solution of diisopropylamine (2.41g, 23.77 mmol, 3.36mL, 1.3eq) in tetrahydrofuran (10mL), and the mixture was then stirred at 0°C for 15 minutes to obtain a diisopropylaminolithium solution. The above diisopropylaminolithium solution was gradually added to a solution of compound 33-3 (5.8g, 18.29 mmol, 1eq) in tetrahydrofuran (58mL) at -70 to -60°C. The mixture was stirred at -70 to -60°C for 1 hour. The mixture was stirred. The reaction mixture was quenched by adding 50 mL of aqueous ammonium chloride solution at -78°C, then extracted with 50 mL of ethyl acetate, washed the organic layer with 50 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 33-4.

[0299] Step 4: Preparation of Compound 33-5 Compound 33-4 (5.8 g, 18.29 mmol, 1 eq) was dissolved in a 25 mL solution of dichloromethane, and trifluoroacetic acid (38.50 g, 337.66 mmol, 25 mL, 18.47 eq) was added. The mixture was stirred at 20°C for 20 minutes. The mixture was concentrated to obtain the residue. The residue was purified by preparative HPLC (column: Phenomenex luna C18 250 × 50 mm × 10 μm, mobile phase: water containing 1% trifluoroacetic acid and acetonitrile, acetonitrile content in mobile phase: 30%~60%, 20~22 min) to obtain compound 33-5. 1 H NMR (400MHz, CDCl3) δ=7.73(d,J=8.0Hz,1H),6.82(d,J=8.0Hz,1H),4.70(s,2H),3.53(s,3H).

[0300] Step 5: Production of compound 33-6 Compound 33-5 (1.4 g, 5.36 mmol, 1 eq), dichloromethane (6.60 g, 77.71 mmol, 5 mL, 14.49 eq), and potassium phosphate (2.50 g, 11.80 mmol, 2.2 eq) were mixed in N,N-dimethylformamide (20 mL), degassed, and purged three times with nitrogen gas. The mixture was then stirred at 100°C for 48 hours in a nitrogen atmosphere. The reaction mixture was concentrated, then 30 mL of water quench was added, and the mixture was extracted with 30 mL of ethyl acetate. The organic layer was washed with 20 mL of saline solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 50 / 1 to 20 / 1) to obtain compound 33-6. 1 H NMR (400MHz, CDCl3) δ=7.71(d,J=8.4Hz,1H),7.30(d,J=8.4Hz,1H),5.61(s,2H),4.79(s,2H),3.44(s,3H).

[0301] Step 6: Preparation of Compound 33-7 Compound 33-6 (800 mg, 2.93 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.49 g, 5.86 mmol, 2 eqs), potassium acetate (862.52 mg, 8.79 mmol, 3 eqs), and Pd(dppf)Cl2.CH2Cl2 (239.24 mg, 292.95 μmol, 0.1 eq) were mixed in 10 mL of dioxane, degassed, and purged three times with nitrogen gas. The mixture was then stirred at 70°C for 12 hours in a nitrogen atmosphere. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain compound 33-7. LC-MS (ESI) m / z: 239.2 (M+1).

[0302] Step 7: Preparation of Compound 33-8 Compound 33-7 (1.1 g, 4.62 mmol, 1 eq) was dissolved in a solution of tetrahydrofuran (10 mL) and water (10 mL). Sodium perborate tetrahydrate (1.42 g, 9.24 mmol, 1.78 mL, 2 eq) was added. The mixture was stirred at 20°C for 0.5 hours. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The organic layer was washed with 20 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. Silica gel flash column chromatography (petroleum ether / The residue was purified with ethyl acetate (10 / 1 to 3 / 1) to obtain compound 33-8. 1 H NMR(400MHz,CDCl3)δ=7.26-7.20(d,J=8.4Hz,1H),7.15-7.09(d,J=8.4Hz,1H),5 .61(s,2H),5.37(s,1H),4.76(s,2H),3.42(s,3H);LCMS(ESI)m / z:233.0(M+23).

[0303] Process 8: Production of Compound 33-9 Compound 33-8 (100 mg, 475.78 μmol, 1 eq), 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (165.70 mg, 618.51 μmol, 1.3 eq), and potassium carbonate (85.48 mg, 618.51 μmol, 1.3 eq) were mixed in acetonitrile (1 mL), degassed, and purged three times with nitrogen gas. The mixture was then stirred and reacted at 60°C for 4 hours in a nitrogen atmosphere. The reaction mixture was diluted with 10 mL of water and extracted with 10 mL of ethyl acetate. The organic layer was washed with 10 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 33-9. The crude product was used in the next step without purification.

[0304] Process 9: Production of Compound 33 Compound 33-9 (127 mg, 473.83 μmol, 1 eq) was dissolved in isopropanol (1 mL), sodium hydroxide (2 M, 521.22 μL, 2.2 eqs) was added, and the mixture was stirred at 20°C for 1 hour. The mixture was filtered to obtain the filtrate. The residue was purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: water containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase is 1% to 6%, 4 min) to obtain compound 33. 1 H NMR(400MHz,D2O)δ=6.64-6.52(m,2H),4.29(s,2H),3.26(s,2H),3.23(s,3H).

[0305] Example 34 [ka]

[0306] Step 1: Preparation of Compound 34-2 Compound 22-1 (2 g, 7.32 mmol, 1 eq) and 2-methoxyethanol (668.76 mg, 8.79 mmol, 1.2 eq) were dissolved in tetrahydrofuran (20 mL), and triphenylphosphine (2.31 g, 8.79 mmol, 1.2 eq) and diisopropyl azodicarboxylate (1.78 g, 8.79 mmol, 1.71 mL, 1.2 eq) were added. The mixture was stirred at 20 °C for 0.5 hours. The reaction mixture was quenched by adding 0.1 ml of water, and then concentrated under reduced pressure to obtain the residue. Silica gel flash column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 6 / 1) was performed. Compound 34-2 was obtained by purification using the method described below.

[0307] Step 2: Preparation of Compound 34-3 Compound 34-2 (4g, 7.25 mmol, 60% purity, 1 eq), bis(pinacotato)diboronic acid (3.68g, 14.49 mmol, 2 eq), potassium acetate (2.13g, 21.74 mmol, 3 eq), and (Pd(dppf)Cl2.CH2Cl2 (591.84mg, 724.73 μmol, 0.1 eq)) were mixed in dioxane (50 mL), degassed, and purged three times with nitrogen gas. The mixture was then stirred and subjected to a nitrogen gas atmosphere. The reaction was carried out in air at 70°C for 12 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 50 mL of water and extracted with 50 mL of ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. Compound 34-3 was obtained by silica gel flash column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 1 / 1). LC-MS (ESI) m / z: 297.0 (M+1).

[0308] Step 3: Preparation of Compound 34-4 Compound 34-3 (3.5 g, 11.82 mmol, 1 eq) was dissolved in tetrahydrofuran (20 mL) and water (20 mL), and sodium perborate tetrahydrate (3.64 g, 23.64 mmol, 4.55 mL, 2 eq) was added. The mixture was stirred at 20°C for 0.5 hours. The reaction mixture was diluted with 50 mL of water and extracted with 50 mL of ethyl acetate. The organic layer was washed with 20 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 34-4. LCMS(ESI) m / z: 269.0 (M+1); 1 H NMR (400MHz, CDCl3) δ=7.14(d,J=9.0Hz,1H),6.61(d,J=9.0Hz,1H),4.24-4.17(m,2H),3.90-3.79(m,2H),3.55-3.47(m,3H),1.77(s,6H).

[0309] Step 4: Preparation of Compound 34-5 Compound 34-4 (300 mg, 1.12 mmol, 1 eq), 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (389.47 mg, 1.45 mmol, 1.3 eq), and potassium carbonate (200.93 mg, 1.45 mmol, 1.3 eq) were mixed in acetonitrile (3 mL), degassed, purged three times with nitrogen gas, and then stirred at 60°C for 4 hours in a nitrogen atmosphere. The reaction mixture was diluted with 10 mL of water and extracted with 10 mL of ethyl acetate. The aqueous layer was then adjusted to pH < 3 with aqueous hydrochloric acid (1 N), extracted with 10 mL of ethyl acetate, washed with 10 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 34-5. LCMS (ESI) m / z: 326.9 (M+1).

[0310] Step 5: Manufacturing of Compound 34 Compound 34-5 (350 mg, 1.07 mmol, 1 eq) was dissolved in isopropanol (3 mL), and aqueous sodium hydroxide solution (3 M, 787.07 μL, 2.2 eq) was added. The mixture was stirred at 20°C for 1 hour. The mixture was filtered to obtain the filtrate. The residue was purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 1% to 6%, 4 min) to obtain compound 34. 1 H NMR(400MHz,D2O)δ=6.55(d,J=8.7Hz,1H),6.25(d,J=8.8Hz,1H),4.05-3.96(m,2H),3.75-3.65(m,2H),3.35(s,3H),3.22(s,2H). LCMS(ESI)m / z:269.0(M+1).

[0311] Example 35 [ka]

[0312] Step 1: Preparation of Compound 35-2 Compound 35-1 (4 g, 28.54 mmol, 1 eq) was dissolved in tetrahydrofuran solution (40 mL), and NaH (1.71 g, 42.81 mmol, 60% purity, 1.5 eq) was added at 0°C. The mixture was then stirred for 30 minutes, and SEM-Cl (7.14 g, 42.81 mmol, 7.58 mL, 1.5 eq) was gradually added. The mixture was heated to 25°C and stirred for 3 hours. This solution was added to water (60 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saline solution (100 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain compound 35-2. LC-MS (ESI) m / z: 271.2 (M+1).

[0313] Step 2: Preparation of Compound 35-3 LiAlH4 (1.50 g, 39.52 mmol, 1.39 eq) was suspended in tetrahydrofuran (70 mL) solution. While stirring at 10-20°C, tetrahydrofuran (30 mL) solution of 1-(2-trimethylsilylethoxymethyl)pyrazole-4-carboxylate ethyl (i.e., compound 35-2, 7.7 g, 28.48 mmol, 1 eq) was added dropwise, and the mixture was stirred at 20°C for 13 hours. H2O (1.5 mL) was gradually added dropwise to the solution at 0°C, followed by the addition of 15% NaOH (1.5 mL) solution, then H2O (4.5 mL). The mixture was stirred for 10 minutes, filtered, and the filtrate was concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1, 0 / 1) to obtain compound 35-3. LCMS (ESI) m / z: 229.2 (M+1); 1 H NMR(400MHz,CDCl3)δ=7.56(d,J=13.8Hz,2H),5.41(s,1H),4.62(s,1H),3.58(dd,J=7.7,8.8Hz,2H),2.28(br s,1H),1.01-0.86(m,2H),0.01-0.02(m,9H).

[0314] Step 3: Production of Compound 35-5 Compound 22-1 (3g, 10.99 mmol, 1eq) is dissolved in THF (30 mL) solution to prepare [1-(2-trimethylsilylethoxymethyl)pyrazole-4-yl]meth Nol (i.e., compound 35-3, 3.01 g, 13.18 mmol, 1.2 eq) and PPh3 (5.76 g, 21.97 mmol, 2 eq) were added, and DIAD (4.44 g, 21.97 mmol, 4.27 ml, 2 eq) was gradually added at 0°C. The mixture was heated to 25°C and stirred for 16 hours. H2O (30 mL) was added to the solution, and it was extracted with ethyl acetate (40 mL × 1). The combined organic phase was washed with saline solution (40 mL × 1), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain compound 35-5. LCMS: 483.2 (M+1).

[0315] Step 4: Preparation of Compound 35-6 Compound 35-5 (3.9 g, 8.07 mmol, 1 eq) was added to 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (3.07 g, 12.10 mmol, 1.5 eq), Pd(dppf)Cl2.CH2Cl2 (329.41 mg, 403.37 μmol, 0.05 eq), and potassium acetate (2.38 g, 24.20 mmol, 3 eq). The mixture was dissolved in 40 mL of dioxane and stirred at 25°C, then at 70°C for 12 hours. 50 mL of H2O was added to the solution, and it was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saline solution (100 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain compound 35-6. LCMS: 531.2 (M+1).

[0316] Step 5: Production of compound 35-7 Compound 35-6 was dissolved in tetrahydrofuran (30 mL) and H2O (15 mL), and the mixture was stirred for 2 hours with sodium perborate tetrahydrate (2.20 g, 14.33 mmol, 2.76 mL, 2 eq). H2O (40 mL) was added to the solution and extracted with ethyl acetate (40 mL x 2). The combined organic phase was washed with saline solution (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to obtain compound 35-7. LCMS (ESI) m / z: 421.2 (M+1).

[0317] Step 6: Preparation of Compound 35-8 Compound 35-7 (460.00 mg, 1.09 mmol) was dissolved in acetonitrile (5 mL) and, with stirring, 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (351.65 mg, 1.31 mmol, 1.2 eq) and K2CO3 (196.54 mg, 1.42 mmol, 1.3 eq) were chlorided at 25°C, and the mixture was stirred at 60°C for 2 hours. H2O (5 mL) was added to the solution, and the aqueous phase was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saline solution (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative HPLC (column: Phenomenex luna C18 150×40mm×15μm, mobile phase: water containing 0.225% formic acid and acetonitrile, acetonitrile content 37%~67%, 10 minutes) to obtain compound 35-8. LCMS(ESI) m / z: 479.2 (M+1).

[0318] Step 7: Production of compound 35 Compound 35-8 (100 mg, 209.04 μmol, 1 eq) was dissolved in isopropanol (1 mL), and NaOH (3 M, 139.36 μL, 2 eqs) was added. The mixture was stirred at 0°C, and then at 25°C for 1 hour. The mixture was filtered to obtain compound 35-9. LC-MS (ESI) m / z: 421 (M+1); 1H NMR(400MHz,D2O)δ=7.92(s,1H),7.75(s,1H),6.62(d,J=8.7Hz,1H), 6.35(d,J=8.8Hz,1H),5.49(s,2H),5.02(s,2H),3.72-3.60(m,2H),3.34(s,2H),0.99-0.88(m,2H),0.00(s,9H).

[0319] Example 36 [ka]

[0320] Step 1: Preparation of Compound 36-2 Compound 35-1 (3 g, 21.41 mmol, 1 eq) was dissolved in dimethylformamide (75 mL) solution, and Cs2CO3 (17.44 g, 53.53 mmol, 2.5 eq) and iodomethane (3.04 g, 21.41 mmol, 1.33 mL, 1 eq) were added. The mixture was stirred at 25°C for 12 hours. This solution was concentrated under vacuum, H2O (20 mL) was added, and the solution was extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saline solution (50 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound 36-2. LCMS (ESI) m / z: 155.3 (M+1).

[0321] Step 2: Preparation of Compound 36-3 LiAlH4 (1.3 g, 34.26 mmol, 1.60 eq) was dissolved in THF (30 mL) solution, and a THF (10 mL) solution of ethyl 1-methylpyrazole-4-carboxylate (i.e., compound 36-2, 3.3 g, 21.41 mmol, 1 eq) was gradually added dropwise, and the mixture was stirred at 10-20°C and 20°C for 1 hour. H2O (1.3 mL) was gradually added dropwise to the solution at 0°C, a 15% NaOH (1.3 mL) solution was added, and H2O (3.9 mL) was added, the mixture was stirred for 10 minutes, filtered, and the filtrate was concentrated under vacuum to obtain compound 36-3.

[0322] Step 3: Preparation of Compound 36-5 Compound 22-1 (1.7 g, 6.23 mmol, 1 eq) was dissolved in tetrahydrofuran solution (30 mL), and compounds 36-3 (698.04 mg, 6.23 mmol, 1 eq) and PPh3 (3.27 g, 12.45 mmol, 2 eq) were added. DIAD (2.52 g, 12.45 mmol, 2.42 mL, 2 eq) was then gradually added dropwise at 0°C, and subsequently... The mixture was stirred at 20°C for 1 hour. H2O (10 mL) was added to the solution and extracted with ethyl acetate (20 mL x 1). The combined organic phase was washed with saline solution (20 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The compound was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5 / 1~0 / 1) to obtain compound 36-5. LCMS: 367 / 369.0 (M+1 / M+3).

[0323] Step 4: Preparation of Compound 36-6 Compound 36-5 (1.3 g, 4.27 mmol, 1.0 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.63 g, 6.41 mmol, 1.5 eq), potassium acetate (1.26 g, 12.82 mmol, 3 eq), and Pd(dppf)Cl2.CH2Cl2 (348.88 mg, 427.21 μmol, 0.1 eq) were mixed in dioxane (15 mL) at 25 °C, and then stirred at 75 °C for 12 hours. H2O (15 mL) was added to the solution, and the aqueous phase was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saline solution (50 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5 / 1~1 / 2) to obtain compound 36-6. LCMS: 415.3 (M+1).

[0324] Step 5: Production of compound 36-7 Compound 36-6 (1.3 g, 3.14 mmol, 1 eq) was dissolved in tetrahydrofuran (16 mL) and H2O (8 mL). Sodium perborate tetrahydrate (482.83 mg, 3.14 mmol, 603.54 μL, 1 eq) was added, and the mixture was stirred for 2 hours. H2O (40 mL) was added to the solution, and it was extracted with ethyl acetate (40 mL x 2). The combined organic phase was washed with saline solution (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to obtain compound 36-7. LCMS (ESI) m / z: 305.1 (M+1); 1 H NMR (400MHz, CDCl3) δ=7.52(s,1H),7.45(s,1H),7.05(d,J=9.0Hz,1H),6.55(d,J=9.0Hz,1H),4.98(s,2H),3.82(s,3H),1.67(s,6H).

[0325] Step 6: Preparation of Compound 36-8 Compound 36-7 (250 mg, 821.57 μmol, 1 eq) was dissolved in acetonitrile (4 mL) solution, and 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (264.12 mg, 985.88 μmol, 1.2 eq) and K2CO3 (147.61 mg, 1.07 mmol, 1.3 eq) were added. The mixture was stirred at 25°C, then at 60°C for 7 hours. Water (5 mL) was added to the solution, and the pH was adjusted to 3-4 with 1 N HCl. The mixture was then extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saline solution (30 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound 36-8. LCMS (ESI) m / z: 363.2 (M+1).

[0326] Step 7: Production of Compound 36 Compound 36-8 (250 mg, 690.34 μmol, 1 eq) was dissolved in i-PrOH (2 mL), and NaOH (3 M, 460.23 μL, 2 eqs) was added at 0°C. The mixture was then stirred at 25°C for 1 hour. The solution was filtered, and the filtrate was purified as is. The crude product was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content 1%~6%, 4 min) to obtain compound 36. LCM S(ESI)m / z: 305 (M+1), 327 (M+23); 1 H NMR(400MHz,D2O)δ=7.59(s,1H),7.50(s,1H),6.55(d,J=8.8Hz,1H),6.30(d,J=8.7Hz,1H),4.86(s,2H),3.77(s,3H),3.23(s,2H).

[0327] Example 37 [ka]

[0328] Step 1: Preparation of Compound 37-2 Compound 22-1 (2 g, 7.32 mmol, 1 eq) and oxetane-3-ylmethanol (774.32 mg, 8.79 mmol, 1.2 eq) were dissolved in tetrahydrofuran solution (30 mL), and PPh3 (2.88 g, 10.99 mmol, 1.5 eq) and DIAD (2.22 g, 10.99 mmol, 2.14 mL, 1.5 eq) were added. The mixture was stirred at 20°C for 5 hours. The reaction mixture was diluted with 100 mL of H2O and extracted with 200 mL of EA (100 mL x 2). The combined organic layer was washed with 100 mL of saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to obtain compound 37-2.

[0329] Step 2: Preparation of Compound 37-3 Compound 37-2 (1.39 g, 4.05 mmol, 1 eq), bis(pinacolato)diborone (2.57 g, 10.12 mmol, 2.5 eq), Pd(dppf)Cl2 (592.33 mg, 809.51 μmol, 0.2 eq), and potassium acetate (1.19 g, 12.14 mmol, 3 eq) were dissolved in dioxane (26 mL), and the mixture was stirred in N2 at 70°C for 12 hours. The reaction mixture was diluted with 20 mL of H2O, extracted with 60 mL of EA, washed with 60 mL of saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 37-3. LCMS (ESI) m / z: 391.2 (M+1).

[0330] Step 3: Preparation of Compound 37-4 Compound 37-3 (3.8 g, 9.74 mmol, 1 eq) was dissolved in a mixed solvent of THF (38 mL) and H2O (38 mL). Sodium perborate tetrahydrate (2.25 g, 14.61 mmol, 1.5 eq) was added at room temperature, the mixture was degassed, and the mixture was replaced three times with N2. The mixture was then stirred in N2 at 20°C for 1.5 hours. The reaction mixture was filtered, then diluted with 20 mL of H2O, and extracted with 40 mL of EA (20 mL x 2). The combined organic layer was washed with 40 mL of saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure. Compound 37-4 was obtained by purification by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 2 / 1). LCMS (ESI) m / z: 281.2 (M+1).

[0331] Step 4: Preparation of Compound 37-5 Compound 37-4 (140 mg, 499.51 μmol, 1 eq) was dissolved in acetonitrile (2 mL), and 2-iodomethyl pinacolborate (200.73 mg, 749.27 μmol, 1.5 eq) and Na2CO3 (79.42 mg, 749.27 μmol, 1.5 eq) were added at room temperature. The mixture was degassed and replaced three times with N2, and then stirred in N2 at 60°C for 6 hours. The reaction mixture was diluted with 30 mL of H2O, the pH was adjusted with citric acid to 4, and then extracted with EA (20 mL x 5), washed with 40 mL of saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 37-5. LCMS (ESI) m / z: 339.2 (M+1).

[0332] Step 5: Production of compound 37 Compound 37-5 (90 mg, 266.18 μmol, 1 eq) was dissolved in i-PrOH (1 mL), and NaOH (2 M, 266.18 μL, 2 eq) was added. The mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with 1 mL of H2O. The mixture was purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: water containing 10 mM NH4HCO3 and acetonitrile, acetonitrile content in mobile phase 1% to 6%, 4 min) to obtain compound 37. LC-MS (ESI) m / z: 281.1 (M+1). 1 H NMR(400MHz,D2O)δ=6.55(d,J=8.8Hz,1H),6.29(d,J=8.8Hz,1H),4.79(dd,J=6.4,8.1Hz,2 H),4.53(t,J=6.3Hz,2H),4.08(d,J=6.4Hz,2H),3.32(tt,J=6.3,8.0Hz,1H),3.22(s,2H).

[0333] Example 38 [ka]

[0334] Compound 38-1 (100 mg, 333.36 μmol, 1 eq), Compound 15 (72.35 mg, 666.71 μmol, 2 eq), K2CO3 (92.15 mg, 666.71 μmol, 2 eq), and potassium iodide (110.67 mg, 666.71 μmol, 2 eq) were dissolved in DMF (2 mL), purged three times with nitrogen gas, and the mixture was stirred in N2 at 50°C for 12 hours. The reaction mixture was diluted with 1 mL of H2O and 1 mL of acetonitrile and purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: containing 10 mmol / L aqueous solution of ammonium bicarbonate and acetonitrile, with acetonitrile content in the mobile phase being 13% to 43%, 10 min) to obtain Compound 38. LCMS (ESI) m / z: 620.1 (2M); 1 H NMR(400MHz,CD3OD)δ=6.66(d,J=8.7Hz,1H),6.25(br d,J=8.8Hz,1H),5.90(s,2H),3.95(q,J=7.0H z,2H),3.41(s,2H),2.13(s,3H),1.31(t,J=7.0Hz,3H).

[0335] Example 39 [ka]

[0336] Process 1: Production of Compound 142 Compound 15 (100 mg, 333.36 μmol, 1 eq), chloromethyl 2-methylpropionate (91.06 mg, 666.71 μmol, 2 eqs), potassium iodide (166.01 mg, 1.00 mmol, 3 eqs), and potassium carbonate (46.07 mg, 333.36 μmol, 1 eq) were mixed in N,N-dimethylformamide (1 mL), degassed, and purged three times with nitrogen gas. The mixture was then stirred at 50°C for 12 hours in a nitrogen gas atmosphere. The reaction mixture was quenched by adding 0.5 mL of water, and the filtrate was obtained by filtration. The residue was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 7% to 40%, 9 min) to obtain compound 39. 1 H NMR(400MHz,CD3OD)δ=6.64(d,J=8.8Hz,1H),6.22(d,J=8.8Hz,1H),5.91(s,2H),4.00- 3.90(m,2H),3.39(s,2H),2.70-2.59(m,1H),1.30(t,J=7.0Hz,3H),1.23-1.19(m,6H).

[0337] Example 40 [ka]

[0338] Step 1: Synthesis of compound 40-2 Compound 13-6 (2.6 g, 8.52 mmol, 1 eq) was dissolved in dichloromethane (30 mL), and boron trichloride (1 M, 17.04 mL, 2 eq) was added. The mixture was stirred at -40°C for 1 hour. Sodium bicarbonate (30 mL) was added to the mixture, and then the reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The organic layer was washed with 10 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 50 / 1 to 20 / 1) to obtain compound 40-2. LCMS (ESI) m / z: 291.0 (M+1).

[0339] Step 2: Synthesis of compound 40-3 Compound 40-2 (1.5 g, 5.15 mmol, 1 eq) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (1.07 g, 7.73 mmol, 1.5 eq) and 2,2,2-trifluoroethyl trifluoromethanesulfonic acid (2.39 g, 10.31 mmol, 2 eq) were added. The mixture was stirred at 80°C for 2 hours. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution (20 mL x 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was stirred in petroleum ether at 25°C for 30 minutes, filtered, and the filtered cake was dried to obtain compound 40-3.

[0340] Step 3: Synthesis of compound 40-4 Compound 40-3 (1 g, 2.68 mmol, 1 eq) was dissolved in dioxane (30 mL), bis(pinacotato)diboronic acid (1.36 g, 5.36 mmol, 2 eq) and potassium acetate (789.13 mg, 8.04 mmol, 3 eq) were added, and finally Pd(dppf)Cl2 (437.76 mg, 536.06 μmol, 0.2 eq) was added. The mixture was stirred at 60°C for 8 hours. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain compound 40-4. LCMS (ESI) m / z: 339.0 (M+1).

[0341] Step 4: Synthesis of Compound 40-5 Compound 40-4 (1.5 g, 4.44 mmol, 1 eq) was dissolved in a mixed solution of THF (5 mL) and H2O (5 mL) to obtain sodium perborate tetrahydrate (1.37 g, 8.88 mmol, 1.71 mL, 2 eq). The mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 40 mL of saline solution (20 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 40-5. LCMS (ESI) m / z: 311.0 (M+1).

[0342] Step 5: Synthesis of compound 40-6 Compound 40-5 (200 mg, 644.75 μmol, 1 eq) was dissolved in acetonitrile (3 mL), potassium carbonate (133.67 mg, 967.12 μmol, 1.5 eq) and 2-iodomethylboronic acid pinacol ester (345.46 mg, 1.29 mmol, 2 eq) were added, and the mixture was stirred at 65°C for 4 hours. The reaction mixture was diluted with 20 mL of water and extracted with 30 mL of ethyl acetate (15 mL x 2). The combined organic layer was washed with saturated brine (20 mL x 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 40-6. LC-MS (ESI) m / z: 369.1 (M+1).

[0343] Step 6: Synthesis of Compound 40 Compound 40-6 (130 mg, 353.22 μmol, 1 eq) was dissolved in isopropanol (2 mL), and sodium hydroxide (2 M, 353.22 μL, 2 eq) was added. The mixture was stirred at 25°C for 0.5 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative HPLC (column: Waters Xbridge 150×25mm×5μm, mobile phase: water and acetonitrile containing 10mM NH4HCO3, acetonitrile content in mobile phase: 1%~20%, 8 min) to obtain compound 40. LCMS(ESI) m / z: 311.0 (M+1); 1 H NMR(400MHz,D2O)δ=8.35(br d,J=12.4Hz,1H),8.06-7.93(m,1H),5.93-5.65(m,2H),4.86-4.82(m,1H),4.67-4.59(m,1H),4.51(br d,J=11.4Hz,1H).

[0344] Example 41 [ka]

[0345] Step 1: Preparation of Compound 41-2 Compound 26-4 (1 g, 3.42 mmol, 1 eq) was dissolved in THF (10 mL), and 1,3-dichloro-5,5-dimethylhydantoin (876.52 mg, 4.45 mmol, 1.3 eq) was added at room temperature. The mixture was stirred at 50°C for 4 hours, and the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 20 mL of H2O, extracted with 40 mL of EA (20 mL x 2), washed with 40 mL of brine, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1~4 / 1) to obtain compound 41-2. LCMS (ESI) M / Z: 327.1 (M+ 1).

[0346] Step 2: Preparation of Compound 41-3 Compound 41-2 (774 mg, 2.37 mmol, 1 eq), 2-iodomethylboronic acid pinacol ester (952.18 mg, 3.55 mmol, 1.5 eq), and K2CO3 (392.98 mg, 2.84 mmol, 1.2 eq) were dissolved in acetonitrile (8 mL) and purged three times with nitrogen gas. The mixture was stirred at 60°C for 3 hours under nitrogen gas protection. The residue was diluted with 20 mL of H2O, extracted with 100 mL of EA (50 mL x 2), washed with 100 mL of saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This product was purified by preparative HPLC (chromatographic column: Phenomenex Synergi Max-RP 250 × 50 mm × 10 μm, mobile phase: water and acetonitrile containing 0.1% TFA, acetonitrile content in mobile phase 25%~55%, 23 min) to obtain compound 41-3. LCMS (ESI) m / z: 385.1 (M+1).

[0347] Step 3: Production of Compound 41 Compound 41-3 (200 mg, 520.16 μmol, 1 eq) was mixed with i-PrOH (2 m³). The compound was dissolved in (L), and an aqueous NaOH solution (2M, 520.16 μL, 2 eq) was added dropwise at room temperature. The mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with 1 mL of H2O and purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: water containing 10 mM NH4HCO3 and acetonitrile, acetonitrile content in mobile phase 1% to 12%, 6 min) to obtain compound 41. LCMS (ESI) m / z: 327.0 (M+1). 1 H NMR (400MHz, D2O) δ = 6.50 (s, 1H), 4.37 (q, J = 8.59Hz, 2H), 3.31 (s, 2H).

[0348] Example 42 [ka]

[0349] Step 1: Preparation of Compound 42-2 Compound 26-4 (1 g, 3.42 mmol, 1 eq) was dissolved in THF (10 mL), and 1,3-dichloro-5,5-dimethylhydantoin (876.52 mg, 4.45 mmol, 1.3 eq) was added at room temperature. The mixture was stirred at 50°C for 4 hours, and then the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 20 mL of H2O, extracted with 40 mL of EA (20 mL x 2), washed with 40 mL of brine, dried over Na2SO4, filtered, concentrated under reduced pressure, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1~4 / 1) to obtain compound 42-2. LCMS (ESI) m / z: 361.1 (M+1).

[0350] Step 2: Preparation of Compound 42-3 Compound 42-2 (774 mg, 2.37 mmol, 1 eq), 2-iodomethylboronic acid pinacol ester (952.18 mg, 3.55 mmol, 1.5 eq), and K2CO3 (392.98 mg, 2.84 mmol, 1.2 eq) were dissolved in acetonitrile (8 mL) and purged three times with nitrogen gas. The mixture was stirred at 60°C for 3 hours under nitrogen gas protection. The residue was diluted with 20 mL of H2O, extracted with 100 mL of EA (50 mL x 2), washed with 100 mL of saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. This product was purified by preparative HPLC (chromatographic column: Phenomenex Synergi Max-RP 250 × 50 mm × 10 μm, mobile phase: water and acetonitrile containing 0.1% TFA, acetonitrile content in mobile phase 25%~55%, 23 min) to obtain compound 42-3. LCMS (ESI) m / z: 419.1 (M+1).

[0351] Step 3: Production of Compound 42 Compound 42-3 (70 mg, 167.09 μmol, 1 eq) was dissolved in i-PrOH (1 mL), and an aqueous NaOH solution (2 M, 167.09 μL, 2 eqs) was added dropwise at room temperature. The mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with H2O (1 mL) and purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: water containing 10 mM NH4HCO3 and acetonitrile, acetonitrile content in mobile phase 2% to 32%, 9 min) to obtain compound 42. LCMS (ESI) m / z: 361.0 (M+1); 1 H NMR (400MHz, D2O) δ=4.41(q,J=8.63Hz,2H),3.39(s,2H).

[0352] Example 43 [ka]

[0353] Step 1: Preparation of Compound 43-2 Compound 15-8 (1.6 g, 6.72 mmol, 1 eq) was dissolved in THF (16 mL), and 1,3-dichloro-5,5-dimethylhydantoin (1.32 g, 6.72 mmol, 1 eq) was added at room temperature. The mixture was stirred at 50°C for 4 hours, and then the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 20 mL of H2O, extracted with 100 mL of EA (50 mL x 2), washed with 100 mL of saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (chromatographic column: Phenomenex luna C18 (250 × 70 mm, 10 μm), mobile phase: water (containing 0.1% TFA) and acetonitrile, acetonitrile content in mobile phase 30%~60%, 25 min) to obtain compound 43-2. LCMS(ESI)m / z:273.1(M+1).

[0354] Step 2: Preparation of Compound 43-3 Compound 43-2 (500 mg, 1.83 mmol, 1 eq), 2-iodomethylboronic acid pinacol ester (589.48 mg, 2.20 mmol, 1.2 eq), and K2CO3 (304.11 mg, 2.20 mmol, 1.2 eq) were dissolved in acetonitrile (5 mL) and purged three times with nitrogen gas. The mixture was stirred at 60°C for 4 hours under nitrogen gas protection. The residue was diluted with 20 mL of H2O and adjusted to pH=4 with 2 M hydrochloric acid. It was extracted with 200 mL of EA (50 mL x 4), washed with 200 mL of saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 43-3. LCMS (ESI) m / z: 331.1 (M+1).

[0355] Step 3: Production of Compound 43 Compound 43-3 (739 mg, 2.24 mmol, 1 eq) was dissolved in i-PrOH (7.5 mL), and NaOH (89.43 mg, 2.24 mmol, 1 eq) was added dropwise at room temperature. The mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with 4 mL of H2O and purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution of 10 mM NH4HCO3 and acetonitrile, acetonitrile content in mobile phase: 1% to 10%, 5 min) to obtain compound 43. LCMS (ESI) m / z: 255.1 (M+1-18). 1 H NMR(400MHz,D2O)δ=6.70-6.53(m,1H),3.86(br d,J=6.24Hz,2H),3.21-2.79(m,2H),1.15(t,J=7.03Hz,3H).

[0356] Example 44 [ka]

[0357] Step 1: Synthesis of compound 44-2 Compound 44-1 (350 mg, 1.14 mmol, 1 eq) was dissolved in acetonitrile (5 mL), and potassium carbonate (236.26 mg, 1.71 mmol, 1.5 eq) and 2-iodomethylboronic acid pinacol ester (396.89 mg, 1.48 mmol, 1.3 eq) were added. The mixture was stirred at 65°C for 4 hours. The reaction mixture was diluted with 20 mL of water and extracted with 30 mL of ethyl acetate (15 mL x 2). The pH was then adjusted with hydrochloric acid (0.5 N) to 5-7, and extracted with 15 mL of ethyl acetate (15 mL x 1). The combined organic layer was washed with 20 mL of saline solution (20 mL x 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. Compound 44-2 was obtained. LCMS (ESI) m / z: 365.1 (M+1).

[0358] Step 2: Synthesis of Compound 44 Compound 44-2 (310 mg, 849.38 μmol, 1 eq) was dissolved in isopropanol (3 mL), and sodium hydroxide (2 M, 849.38 μL, 2 eqs) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 1%~12%, 6 min) to obtain compound 44. LC-MS (ESI) m / z: 289.0 (M-18+1); 1 H NMR(400MHz,D2O)δ=3.97(d,J=7.1Hz,2H),3.35(s,2H),1.26(t,J=7.1Hz,3H).

[0359] Example 45 [ka]

[0360] Step 1: Preparation of Compound 45-2 To a solution of compound 35-1 (4 g, 28.54 mmol, 1 eq) in N,N-dimethylformamide (40 mL), cesium carbonate (11.16 g, 34.25 mmol, 1.2 eq) and 2-iodopropane (5.82 g, 34.25 mmol, 3.42 mL, 1.2 eq) were added. The mixture was stirred at 40°C for 1 hour. The reaction mixture was quenched by adding 50 mL of water, and then extracted with 100 mL of ethyl acetate (50 mL x 2). The combined organic layer was washed with 100 mL of saline solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 45-2.

[0361] Step 2: Preparation of Compound 45-3 At 0-5°C, lithium tetrahydroaluminate (1.15 g, 30.18 mmol, 1.1 eq) was added to tetrahydrofuran (50 mL), and a solution of compound 45-2 (5 g, 27.44 mmol, 1 eq) in tetrahydrofuran (20 mL) was gradually added dropwise, and the mixture was stirred at 20°C for 1 hour. At 0-10°C, water (1.15 mL), sodium hydroxide solution (15% by mass, 1.15 mL), and water (3.45 mL) were added sequentially to quench the reaction mixture, and then the mixture was stirred at 20°C for about 15 minutes, after which 2 g of magnesium sulfate was added, and the mixture was filtered and concentrated under reduced pressure to obtain compound 45-3.

[0362] Step 3: Production of Compound 45-5 At 0-5°C, triphenylphosphine (2.31g, 8.79 mmol, 1.2eq) and DIAD (1.78g, 8.79 mmol, 1.71mL, 1.2eq) were added to tetrahydrofuran (20mL) containing compound 22-1 (2g, 7.32 mmol, 1eq) and compound 45-3 (1.23g, 8.79 mmol, 1.2eq). The mixture was stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 5 / 1~3 / 1) to obtain compound 45-5. LCMS (ESI) m / z: 395.0 / 396.9 (M+1 / M+3).

[0363] Step 4: Preparation of Compound 45-6 Compound 45-5 (2.6 g, 6.58 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (3.34 g, 13.16 mmol, 2 eq), Pd(dppf)Cl2 (481.33 mg, 657.82 μmol, 0.1 eq), and potassium acetate (1.94 g, 19.73 mmol, 3 eq) were mixed in a 30 mL solution of dioxane, degassed, and purged three times with nitrogen gas. The mixture was then stirred at 70°C for 12 hours in a nitrogen atmosphere. The reaction mixture was quenched by adding 50 mL of water, and then extracted with 100 mL of ethyl acetate (50 mL x 2). The combined organic layers were washed with 50 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 4 / 1 to 2 / 1) to obtain compound 45-6. LCMS (ESI) m / z: 443.2 (M+1).

[0364] Step 5: Production of compound 45-7 Compound 45-6 (1.4 g, 3.17 mmol, 1 eq) was dissolved in a mixed solution of tetrahydrofuran (10 mL) and water (10 mL), and sodium perborate tetrahydrate (973.99 mg, 6.33 mmol, 1.22 mL, 2 eqs) was added. The mixture was stirred at 20°C for 0.5 hours. The reaction mixture was diluted with 50 mL of water and extracted with 50 mL of ethyl acetate. The organic layer was washed with 50 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 3 / 1 to 1 / 1) to obtain compound 45-7. LCMS (ESI) m / z: 333.0 (M+1). 1H NMR(400MHz,CDCl3)δ=7.69(s,1H),7.57(s,1H),7.14(d,J=9.0Hz,1H),6.65(d,J=9.0H z,1H),5.16(s,1H),5.07(s,2H),4.57-4.45(m,1H),1.77(s,6H),1.52(d,J=6.7Hz,6H).

[0365] Step 6: Preparation of Compound 45-8 Compound 45-7 (200 mg, 601.78 μmol, 1 eq), 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (153.15 mg, 571.69 μmol, 0.95 eq), and potassium carbonate (91.49 mg, 661.95 μmol, 1.1 eq) were mixed in acetonitrile (3 mL), degassed, and purged three times with nitrogen gas. The mixture was then stirred at 60°C for 4 hours in a nitrogen atmosphere. The reaction mixture was diluted with 10 mL of water and extracted with 10 mL of ethyl acetate. The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a partial crude product. The aqueous layer was then adjusted to pH < 5 with hydrochloric acid (1 N), extracted with 10 mL of ethyl acetate, dried the organic matter over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. Compound 45-8 was obtained. The crude product was used in the next step without purification. LC-MS (ESI) m / z: 391.0 (M+1).

[0366] Step 7: Production of Compound 45 Compound 45-8 (80 mg, 205.03 μmol, 1 eq) was dissolved in isopropanol (1 mL), and sodium hydroxide solution (2 M, 205.03 μL, 2 eqs) was added. The mixture was stirred at 20°C for 1 hour. The mixture was filtered to obtain the filtrate. The filtrate was purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase 0% to 10%, 7 min) to obtain compound 45. 1 H NMR(400MHz,D2O)δ=7.69(s,1H),7.5 1(s,1H),6.49(dd,J=6.8,8.5Hz,1H),6.22(dd,J=8.7,14.7Hz,1H),4.83(s,2H),4.48- 4.33(m,1H),3.21(d,J=12.5Hz,2H),1.34(d,J=6.8Hz,6H);LCMS(ESI)m / z:333.3(M+1).

[0367] Example 46 [ka]

[0368] Step 1: Preparation of Compound 46-2 Compound 45-7 (440 mg, 1.32 mmol, 1 eq) was dissolved in tetrahydrofuran (10 mL) and 1,3-dichloro-5,5-dimethylhydantoin (156.50 mg, 794.34 μmol, 0.6 eq) was added. The mixture was stirred at 45°C for 3 hours. The reaction mixture was concentrated under reduced pressure to obtain the residue. Compound 46-2 was obtained by silica gel flash column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 4 / 1). LC-MS (ESI) m / z: 367.0 (M+1).

[0369] Step 2: Preparation of Compound 46-3 Compound 46-2 (80.00 mg, 218.11 μmol, 1 eq), 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (58.43 mg, 218.11 μmol, 1 eq), and potassium carbonate (33.16 mg, 239.92 μmol, 1.1 eq) were mixed in acetonitrile (2 mL), degassed, and purged three times with nitrogen gas. The mixture was then stirred at 60°C for 3 hours in a nitrogen atmosphere. The reaction mixture was diluted with 5 mL of water and extracted with 5 mL of ethyl acetate. The aqueous layer was then adjusted to pH < 3 with aqueous hydrochloric acid (1 N), extracted with 5 mL of ethyl acetate, washed with 5 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 46-3. LCMS (ESI) m / z: 425.0 (M+1).

[0370] Step 3: Production of Compound 46 Compound 46-3 (92.00 mg, 216.65 μmol, 1 eq) was dissolved in isopropanol (1 mL), and sodium hydroxide solution (3 M, 158.88 μL, 2.2 eqs) was added. The mixture was stirred at 20°C for 1 hour. The mixture was filtered to obtain the filtrate. The residue was purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 1% to 6%, 4 min) to obtain compound 46. 1 H NMR(400MHz,D2O)δ=6.20(d,J=12.8Hz,1H),3.87(q,J=7.0Hz,2H),3.23(s,2H) ,1.18(t,J=7.0Hz,3H);LCMS(ESI)m / z:367.0(M+1).

[0371] Example 47 [ka]

[0372] Step 1: Preparation of Compound 47-2 Compound 47-1 (2 g, 11.89 mmol, 1 eq) was dissolved in DME (10 mL). Then, at 0°C, acetone (898.05 mg, 15.46 mmol, 1.14 mL, 1.3 eq), DMAP (72.66 mg, 594.72 μmol, 0.05 eq), and thionyl chloride (1.84 g, 15.46 mmol, 1.12 mL, 1.3 eq) were added to this mixture. The mixture was then stirred at 0-15°C for 16 hours. 20 mL of saturated NaHCO3 aqueous solution was added to the mixture, and the aqueous solution was extracted with methyl tert-butyl ether (20 mL x 3). The combined organic solution was washed with 100 mL of saturated NaCl aqueous solution, dried over anhydrous Na2SO4, and the solution was concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 1 / 0-80 / 1) to obtain compound 47-2. 1H NMR (400MHz, CDCl3) δ = 10.16 (s, 1H), 6.38 (s, 1H), 6.20 (s, 1H), 2.24 (s, 3H), 1.66 (s, 6H).

[0373] Step 2: Preparation of Compound 47-3 Compound 47-2 (1.42 g, 6.82 mmol, 1 eq) and iodoethane (1.28 g, 8.18 mmol, 654.57 μL, 1.2 eq) were dissolved in DMF (10 mL). Potassium carbonate (1.13 g, 8.18 mmol, 1.2 eq) was added to this mixture at 15 °C, and the mixture was stirred at 50 °C for 16 hours. The mixture was placed in water (30 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with saline solution (50 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 20 / 1) to obtain compound 47-3. 1 H NMR (400MHz, CDCl3) δ = 6.48-6.30 (m, 2H), 4.17 (q, J = 7.0Hz, 2H), 2.35 (s, 3H), 1.71 (s, 6H), 1.53 (t, J = 6.9Hz, 3H).

[0374] Step 3: Preparation of Compound 47-4 Compound 47-3 (3.38 g, 14.31 mmol, 1 eq) and NBS (2.80 g, 15.74 mmol, 1.1 eq) were dissolved in tetrahydrofuran (40 mL), and the mixture was stirred at 40°C for 4 hours. The mixture was placed in water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saline solution (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by washing with petroleum ether (30 mL), filtered, and the filter cake was dried under vacuum to obtain compound 47-4. 1 H NMR (400MHz, CDCl3) δ = 6.58 (s, 1H), 4.17 (q, J = 7.0Hz, 2H), 2.46 (s, 3H), 1.76 (s, 6H), 1.53 (t, J = 7.0Hz, 3H).

[0375] Step 4: Preparation of Compound 47-5 Compound 47-4 (3.46 g, 10.98 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (5.58 g, 21.96 mmol, 2 eq), potassium acetate (3.23 g, 32.94 mmol, 3 eq), and Pd(dppf)Cl2.CH2Cl2 (896.55 mg, 1.10 mmol, 0.1 eq) were dissolved in anhydrous dioxane (80 mL). The mixture was then purged three times with nitrogen gas, and finally, the mixture was stirred at 75°C for 16 hours under nitrogen gas protection. The mixture was placed in water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with saline solution (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to obtain compound 47-5. LCMS (ESI) m / z: 363.2 (M+1).

[0376] Step 5: Production of compound 47-6 Compound 47-5 (4.64 g, 12.81 mmol, 1 eq) was dissolved in a mixed solvent of tetrahydrofuran (50 mL) and water (25 mL). Sodium perborate tetrahydrate (3.94 g, 25.62 mmol, 4.93 mL, 2 eq) was added at 0°C, and the mixture was stirred at 15°C for 1 hour under the protection of nitrogen gas. 30 mL of water was added to the reaction mixture, extracted with ethyl acetate (50 mL x 3), washed with saline solution (100 mL x 1), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to obtain compound 47-6. 1 H NMR(400MHz,CDCl3)δ=6.43(s,1H),5.19-4.82(m,1H),4.12(q,J=7.0Hz,2H), 2.31(s,3H),1.76(s,6H),1.50(t,J=7.0Hz,3H);LCMS(ESI)m / z:253.2(M+1).

[0377] Step 6: Production of compound 47-7 Compound 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (190.52 mg, 711.16 μmol, 1.3 eq) and compound 47-6 (138 mg, 547.05 μmol, 1 eq) were dissolved in acetonitrile (2 mL). Potassium carbonate (113.41 mg, 820.57 μmol, 1.5 eq) was added to this mixture at 15 °C, and the mixture was then stirred at 60 °C for 2 hours. 10 mL of water was added to the mixture, extracted with ethyl acetate (20 mL x 3), washed with saline solution (30 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain compound 47-7. LCMS (ESI) m / z: 311.1 (M+1).

[0378] Step 7: Production of compound 47 Compound 47-7 (100 mg, 322.47 μmol, 1 eq) was dissolved in isopropanol (0.5 mL), and sodium hydroxide (2 M, 322.47 μL, 2 eqs) was added at 0°C. The mixture was then stirred at 15°C for 2 hours. The reaction mixture was filtered and purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: water containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 1% to 6%, 4 min) to obtain compound 47. 1 H NMR(400MHz,D2O)δ=6.21(s,1H),3.93(q,J=7.1Hz,2H),3.24(s,2H),2.03(s,3H),1.21(t,J=7.0Hz,3H);LCMS(ESI)m / z:253.1(M+1).

[0379] Example 48 [ka]

[0380] Step 1: Preparation of Compound 48-2 Compound 47-2 (2 g, 9.61 mmol, 1 eq) and 1-bromobutane (1.58 g, 11.53 mmol, 1.24 mL, 1.2 eq) were dissolved in DMF (20 mL). Then, potassium carbonate (1.59 g, 11.53 mmol, 1.2 eq) was added to this mixture at 15 °C, and finally, the mixture was stirred at 50 °C for 16 hours. The mixture was placed in water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saline solution (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 5 / 1) to obtain compound 48-2. 1 H NMR(400MHz,CDCl3)δ=6.45-6.31(m,2H),4.08(t,J=6.6Hz,2H),2.35(s,3H),1.9 4-1.83(m,2H),1.70(s,6H),1.57(dd,J=7.4,15.1Hz,2H),1.00(t,J=7.4Hz,3H).

[0381] Step 2: Preparation of Compound 48-3 Compound 48-2 (1.87 g, 7.07 mmol, 1 eq) and NBS (1.39 g, 7.78 mmol, 1.1 eq) were dissolved in anhydrous tetrahydrofuran (30 mL), and the mixture was stirred at 40°C for 4 hours. The mixture was placed in water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with saline solution (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by washing with petroleum ether (20 mL), filtered, and the filter cake was dried under vacuum to obtain compound 48-3.

[0382] Step 3: Preparation of Compound 48-4 Compound 48-3 (2.61 g, 7.60 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (3.86 g, 15.21 mmol, 2 eq), potassium acetate (2.24 g, 22.81 mmol, 3 eq), and Pd(dppf)Cl2.CH2Cl2 (621.02 mg, 760.46 μmol, 0.1 eq) were dissolved in anhydrous dioxane (50 mL). The mixture was then purged three times with nitrogen gas, and finally, the mixture was stirred at 75°C for 16 hours. The mixture was placed in water (100 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with saline solution (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 1 / 0 to 2 / 1) to obtain compound 48-4. LCMS (ESI) m / z: 391.1 (M+1).

[0383] Step 4: Preparation of Compound 48-5 Compound 48-4 (576 mg, 1.48 mmol, 1 eq) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (5 mL). Sodium perborate tetrahydrate (454.16 mg, 2.95 mmol, 567.70 μL, 2 eqs) was added at 0°C, and the mixture was stirred at 15°C for 1 hour under the protection of nitrogen gas. 20 mL of water was added to the reaction mixture, extracted with ethyl acetate (20 mL x 3), washed with saline solution (50 mL x 1), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to obtain compound 48-5. LCMS (ESI) m / z: 281.2 (M+1).

[0384] Step 5: Preparation of Compound 48-6 Compound 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (152.44 mg, 569.00 μmol, 1.1 eq) and compound 48-5 (145 mg, 517.27 μmol, 1 eq) were dissolved in acetonitrile (5 mL). Potassium carbonate (107.24 mg, 775.91 μmol, 1.5 eq) was added to this mixture at 15 °C, and the mixture was stirred at 60 °C for 2 hours. 10 mL of water was added to the mixture, extracted with ethyl acetate (20 mL x 3), washed with saline solution (30 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain compound 48-6. LCMS(ESI) m / z: 339.0 (M+1).

[0385] Step 6: Production of Compound 48 Compound 48-6 (176 mg, 520.46 μmol, 1 eq) was dissolved in isopropanol (1 mL), and sodium hydroxide (3 M, 346.98 μL, 2 eqs) was added at 0°C. The mixture was then stirred at 15°C for 2 hours. The reaction mixture was filtered to obtain compound 48. 1 H NMR(400MHz,D2O)δ=6.19(s,1H),3.85(t,J=6.5Hz,2H),3.28-3.18(m,2H),2.11-1.97(m,3H) ),1.63-1.52(m,2H),1.38-1.26(m,2H),0.82(t,J=7.4Hz,3H);LCMS(ESI)m / z:339.2(M+1).

[0386] Example 49 [ka]

[0387] Step 1: Synthesis of compound 49-2 Compound 22-1 (4 g, 14.65 mmol, 1 eq) was dissolved in N,N-dimethylformamide (30 mL), and potassium phosphate (7.77 g, 36.62 mmol, 2.5 eq) and 1-iodobutane (4.04 g, 21.97 mmol, 2.50 mL, 1.5 eq) were added. The mixture was stirred at 25°C for 8 hours. The residue was diluted with 10 mL of water and extracted with 20 mL of ethyl acetate (10 mL x 2). The combined organic layer was washed with 10 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. Compound 49-2 was obtained without purification. LCMS (ESI) m / z: 329.1 (M+1).

[0388] Step 2: Synthesis of Compound 49-3 Compound 49-2 (4.3g, 13.06 mmol, 1 eq) was dissolved in dioxane (50 mL), bis(pinacotato)diboronic acid (6.63g, 26.13 mmol, 2 eq) and potassium acetate (3.85g, 39.19 mmol, 3 eq) were added, and finally, Pd(dppf)Cl 2. CH2Cl2 (2.13 g, 2.61 mmol, 0.2 eq) was added. The mixture was stirred at 65°C for 8 hours, the reaction mixture was diluted with 20 mL of water, and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 0 / 1) to obtain compound 49-3. LCMS (ESI) m / z: 377.2 (M+1).

[0389] Step 3: Synthesis of Compound 49-4 Compound 49-3 (6.3 g, 16.74 mmol, 1 eq) was dissolved in a mixed solution of tetrahydrofuran (30 mL) and water (30 mL), and sodium perborate tetrahydrate (5.15 g, 33.49 mmol, 6.44 mL, 2 eqs) was added. The mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 20 / 1~4 / 1) to obtain compound 49-4. LCMS (ESI) m / z: 267.2 (M+1).

[0390] Step 4: Synthesis of compounds 49-5 and 49-6 Compound 49-4 (1.55 g, 5.82 mmol, 1 eq) was dissolved in tetrahydrofuran (20 mL), and 1,3-dichloro-5,5-dimethylhydantoin (1.15 g, 5.82 mmol, 1 eq) was added. The mixture was stirred at 50°C for 4 hours. Reaction mixture The substance was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The crude product was purified by preparative HPLC (chromatographic column: Phenomenex luna C18 250 × 70 mm × 10 μm, mobile phase: water (containing 1% trifluoroacetic acid) and acetonitrile, acetonitrile content in mobile phase 50%~80%, 20 min) to obtain compound 49-5. LCMS(ESI) m / z: 301.1 (M+1). Compound 49-6 was obtained. LCMS(ESI) m / z: 335.1 (M+1).

[0391] Step 5: Synthesis of compound 49-7 Compound 49-5 (380 mg, 1.26 mmol, 1 eq) was dissolved in acetonitrile (5 mL), and potassium carbonate (261.96 mg, 1.90 mmol, 1.5 eq) and 2-iodomethylboronic acid pinacol ester (440.06 mg, 1.64 mmol, 1.3 eq) were added. The mixture was stirred at 65°C for 4 hours. The reaction mixture was diluted with 20 mL of water and extracted with ethyl acetate (20 mL x 2). The combined organic layer was washed with saturated brine (20 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 49-7. LCMS (ESI) m / z: 359.1 (M+1).

[0392] Step 6: Synthesis of Compound 49 Compound 49-7 (400 mg, 1.12 mmol, 1 eq) was dissolved in isopropanol (3 mL), sodium hydroxide (2 M, 1.12 mL, 2 eq) was added, and the mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the residue, and compound 49 was obtained without purification. LC-MS (ESI) m / z: 283.1 (M-18+1); 1 H NMR(400MHz,D2O)δ=6.66(s,1H),3.96-3.86(m,2H),3.29-3.19(m,2H),1.70-1.57(m,2H),1.43-1.26(m,2H),0.85(t,J=7.4Hz,3H).

[0393] Example 50 [ka] Step 1: Synthesis of compound 50-2 Compound 49-6 (400 mg, 1.19 mmol, 1 eq) was dissolved in acetonitrile (5 mL), and potassium carbonate (247.41 mg, 1.79 mmol, 1.5 eq) and 2-iodomethylboronic acid pinacol ester (415.62 mg, 1.55 mmol, 1.3 eq) were added. The mixture was stirred at 65°C for 8 hours. The reaction mixture was diluted with 20 mL of water and extracted with 40 mL (20 mL x 2) of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution (20 mL x 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. Compound 50-2 was obtained without purification. LC-MS (ESI) m / z: 393.0 (M+1).

[0394] Step 2: Synthesis of compound 50 Compound 50-2 (500 mg, 1.27 mmol, 1 eq) was dissolved in isopropanol (3 mL), and sodium hydroxide (2 M, 1.27 mL, 2 eqs) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the residue. Preparative HPL Compound 50 was obtained by purification using 14C (column: Waters Xbridge 150×25mm×5μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 1%~30%, 9 min). LCMS(ESI) m / z: 317.0 (M-18+1); 1 H NMR(400MHz,D2O)δ=3.93(t,J=6.5Hz,2H),3.39(s,2H),1.71-1.56(m,2H),1.44-1.32(m,2H),0.90-0.80(m,3H).

[0395] Example 51 [ka]

[0396] Step 1: Preparation of Compound 51-2 At 0-5°C, a mixture of compound 51-1 (10 g, 95.66 mmol, 8.70 mL, 1 eq) and paraformaldehyde (2.87 g, 95.66 mmol, 2.64 mL, 1 eq) was mixed with zinc chloride (1 M, 1.91 mL, 0.02 eq), and the mixture was stirred at 20°C for 12 hours in a nitrogen atmosphere. Then, it was heated to 90°C and stirred for a further 4 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The crude product was distilled under reduced pressure (70°C, 133 Pa pressure / oil pump) to obtain compound 51-2. 1 H NMR (400MHz, CDCl3) δ = 5.64 (s, 2H), 1.61 (qd, J = 4.1, 8.4Hz, 1H), 1.08-0.99 (m, 2H), 0.96-0.86 (m, 2H).

[0397] Step 2: Production of Compound 51 Compound 15 (100 mg, 333.36 μmol, 1 eq), compound 51-2 (89.71 mg, 666.72 μmol, 2 eq), potassium iodide (166.01 mg, 1.00 mmol, 3 eq), and potassium carbonate (92.15 mg, 666.72 μmol, 2 eq) were mixed in N,N-dimethylformamide (1 mL), degassed, and purged three times with nitrogen gas. The mixture was then stirred in a nitrogen atmosphere at 50°C for 12 hours. The reaction mixture was quenched by adding 0.5 mL of water, and the filtrate was obtained by filtration. Compound 51 was purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: water containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 7% to 37%, 8 min). LCMS(ESI)m / z:672.0(2M); 1 H NMR(400MHz,CD3OD δ=6.67(d,J=8.8Hz,1H),6.25(d,J=8.9Hz,1H),5.90(s,2H),3.96(d,J=7.0Hz, 2H), 3.42 (s, 2H), 1.75-1.66 (m, 1H), 1.32 (t, J=7.0Hz, 3H), 1.09-0.90 (m, 4H).

[0398] Example 52 [ka]

[0399] Step 1: Synthesis of compound 52-2 Compound 22-1 (2 g, 7.32 mmol, 1 eq) was dissolved in N,N-dimethylformamide (20 mL), and potassium carbonate (1.52 g, 10.98 mmol, 1.5 eq) and 1-fluoro-4-bromobutane (1.48 g, 9.52 mmol, 1.02 mL, 1.3 eq) were added. The mixture was stirred at 25°C for 8 hours. The residue was diluted with 10 mL of water and extracted with ethyl acetate (10 mL x 2). The combined organic layer was washed with 10 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 52-2.

[0400] Step 2: Synthesis of compound 52-3 Compound 52-2 (2.6 g, 7.49 mmol, 1 eq) was dissolved in dioxane (50 mL), bis(pinacotato)diboronic acid (3.80 g, 14.98 mmol, 2 eq) and potassium acetate (2.20 g, 22.47 mmol, 3 eq) were added, and finally, Pd(dppf)Cl2 (1.22 g, 1.50 mmol, 0.2 eq) was added, and the mixture was purged three times with nitrogen gas. The mixture was stirred at 65°C for 8 hours. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 20 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1~0 / 1) to obtain compound 52-3. LCMS(ESI) m / z: 313.0 (M+1).

[0401] Step 3: Synthesis of compound 52-4 Compound 52-3 (3.4 g, 8.62 mmol, 1 eq) was dissolved in tetrahydrofuran (15 mL) and water (15 mL), and sodium perborate tetrahydrate (2.65 g, 17.25 mmol, 3.32 mL, 2 eq) was added. The mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with 20 mL of water and extracted with 20 mL of ethyl acetate. The combined organic layer was washed with 40 mL of saline solution (20 mL x 2), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 1 / 1) to obtain compound 52-4. LCMS (ESI) m / z: 285.0 (M+1).

[0402] Step 4: Synthesis of Compound 52-5 Compound 52-4 (200 mg, 703.53 μmol, 1 eq) was dissolved in acetonitrile (3 mL), and potassium carbonate (145.85 mg, 1.06 mmol, 1.5 eq) and 2-iodomethylboronic acid pinacol ester (245.02 mg, 914.59 μmol, 1.3 eq) were added. The mixture was stirred at 65°C for 8 hours. The reaction mixture was diluted with 20 mL of water and extracted with 40 mL of ethyl acetate (20 mL x 2). The combined organic layer was washed with 20 mL of saline solution (20 mL x 1), dried over sodium sulfate, and filtered. The compound 52-5 was obtained by concentration under reduced pressure. LC-MS (ESI) m / z: 343.0 (M+1).

[0403] Step 5: Synthesis of Compound 52 Compound 52-5 (200 mg, 584.58 μmol, 1 eq) was dissolved in isopropanol (2 mL), and sodium hydroxide (2 M, 584.58 μL, 2 eqs) was added. The mixture was stirred at 25°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain the residue. Compound 52 was obtained by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: water containing 10 mM NH4HCO3 and acetonitrile, acetonitrile content in mobile phase 1% to 15%, 9 min). LC-MS (ESI) m / z: 267.0 (M-18+1);1 H NMR(400MHz,D2O)δ=6.54(d,J=8.7Hz,1H),6.28(d,J=8.7Hz,1H),4.56(t,J=5.9Hz,1H),4.44(br t,J=5.7Hz,1H),3.92(t,J=6.1Hz,2H),3.22(s,2H),1.87-1.66(m,4H),1.14(s,1H).

[0404] Example 53 [ka]

[0405] Step 1: Preparation of Compound 53-2 Compound 22-1 (2.63 g, 9.63 mmol, 1 eq) and 4-bromobutoxy-tert-butyl-dimethylsilane (2.83 g, 10.59 mmol, 1.1 eq) were dissolved in DMF (30 mL). Then, potassium carbonate (2.00 g, 14.44 mmol, 1.5 eq) was added to this mixture at 15 °C, and finally, the mixture was stirred at 80 °C for 16 hours. Water (50 mL) was added to the mixture, and it was extracted with ethyl acetate (100 mL x 3). The combined organic layer was washed with saline solution (100 mL x 2), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 1 / 0~0 / 1) to obtain compound 53-2. LCMS (ESI) m / z: 460.9 (M+3).

[0406] Step 2: Preparation of Compound 53-3 Compound 53-2 (1.85 g, 4.03 mmol, 1 eq) was mixed with anhydrous dichloromethane (2 The mixture was dissolved in 0 mL, and then N,N-diethylethaneamine and hydrogen trifluoride (6.49 g, 40.27 mmol, 6.56 mL, 10 eq) were added to the mixture at 0°C. The mixture was then stirred at 25°C for 2 hours. Water (30 mL) was added to the mixture, and it was extracted with dichloromethane (30 mL x 2). The combined organic layer was washed with saline solution (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 53-3.

[0407] Step 3: Preparation of Compound 53-4 Compound 53-3 (1.5 g, 4.35 mmol, 1 eq) was dissolved in anhydrous dichloromethane (20 mL), and Dess-Martin periodinane (2.40 g, 5.65 mmol, 1.75 mL, 1.3 eq) was added to this mixture at 0°C. The mixture was then stirred at 15°C for 16 hours. The reaction mixture was quenched by adding 50 mL of saturated sodium thiosulfate aqueous solution and extracted with dichloromethane (50 mL x 2). The combined organic layer was washed with saturated sodium bicarbonate (50 mL) and brine (100 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain compound 53-4. LCMS (ESI) m / z: 343.0 (M+1).

[0408] Step 4: Preparation of Compound 53-5 Compound 53-4 (1.5 g, 4.37 mmol, 1 eq) was dissolved in anhydrous dichloromethane (20 mL). Diethylaminosulfur trifluoride (1.41 g, 8.74 mmol, 1.16 mL, 2 eq) was added to this mixture at 0°C, and the mixture was stirred at 25°C for 3 hours. The reaction mixture was placed in cooled saturated sodium bicarbonate (50 mL) and extracted with dichloromethane (50 mL x 2). The combined organic layer was washed with saline solution (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 50 / 1~5 / 1) to obtain compound 53-5. LCMS (ESI) m / z: 367.0 (M+3).

[0409] Step 5: Production of Compound 53-6 Compound 53-5 (774 mg, 2.12 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (1.08 g, 4.24 mmol, 2 eq), potassium acetate (624.05 mg, 6.36 mmol, 3 eq), and Pd(dppf)Cl2.CH2Cl2 (346.19 mg, 423.92 μmol, 0.2 eq) were dissolved in anhydrous dioxane (20 mL). The mixture was then purged three times with nitrogen gas, and finally, the mixture was stirred at 75°C for 16 hours under nitrogen gas protection. The mixture was placed in water (20 mL) and extracted with ethyl acetate (30 mL x 3). The combined organic layer was washed with saline solution (50 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 1 / 0~2 / 1) to obtain compound 53-6. LCMS (ESI) m / z: 413.2 (M+1).

[0410] Step 6: Production of Compound 53-7 Compound 53-6 (1 g, 2.43 mmol, 1 eq) was dissolved in a mixed solvent of tetrahydrofuran (10 mL) and water (5 mL). Sodium perborate tetrahydrate (373.24 mg, 2.43 mmol, 466.55 μL, 1 eq) was added at 0°C, and the mixture was stirred at 15°C for 1 hour under the protection of nitrogen gas. 20 mL of water was added to the reaction mixture, extracted with ethyl acetate (20 mL x 3), washed with saline solution (50 mL), dried over Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 0 / 1) to obtain compound 53-7. LCMS (ESI) m / z: 303.1 (M+1).

[0411] Step 7: Preparation of Compound 53-8 Compound 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (105.29 mg, 393.03 μmol, 1.1 eq) and compound 53-7 (108 mg, 357.30 μmol, 1 eq) were dissolved in acetonitrile (5 mL). Potassium carbonate (74.07 mg, 535.94 μmol, 1.5 eq) was added to this mixture at 15 °C, and the mixture was stirred at 60 °C for 2 hours. 10 mL of water was added to the mixture, extracted with ethyl acetate (20 mL x 3), washed with saline solution (30 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain compound 53-8. LCMS (ESI) m / z: 361.1 (M+1).

[0412] Process 8: Production of Compound 53 Compound 53-8 (117 mg, 324.90 μmol, 1 eq) was dissolved in isopropanol (0.5 mL), and sodium hydroxide (2 M, 324.90 μL, 2 eqs) was added at 0°C. The mixture was then stirred at 20°C for 2 hours. The reaction solution was filtered and purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 1% to 6%, 4 min) to obtain compound 53. 1 H NMR(400MHz,D2O)δ=6.52(d,J=8.8Hz,1H),6.25(d,J=8.8Hz,1H),6.11-5.75(m,1H),3.91(t,J= 6.1Hz,2H),3.21(s,2H),2.03-1.82(m,2H),1.81-1.69(m,2H);LCMS(ESI)m / z:285.1(M-18+1).

[0413] Example 54 [ka]

[0414] Step 1: Preparation of Compound 54-2 To a solution of compound 54-1 (28 g, 159.01 mmol, 1 eq) in N-methylpyrrolidone (280 mL), sodium hydroxide (25.44 g, 636.03 mmol, 4 eqs) was added. The mixture was stirred at 130 °C for 2 hours. The reaction mixture was quenched by adding aqueous hydrochloric acid (350 mL, 2N) at 20 °C, and then extracted with 500 mL of ethyl acetate. The organic layer was washed with 900 mL of saline solution (300 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was stirred with petroleum ether / methyl-tert-butyl ether (5 / 1, 100 mL), filtered to obtain a filtrate cake, concentrated, and then purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1). Compound 54-2 was obtained by combining the product obtained by purifying the filtrate cake by column chromatography with the filtrate cake. 1 H NMR (400MHz, DMSO-d6) δ = 6.84-6.71 (m, 1H), 6.65 (br d, J = 10.5Hz, 1H).

[0415] Step 2: Preparation of Compound 54-3 Compound 54-2 (7.5 g, 43.08 mmol, 1 eq), iodoethane (20.16 g, 129.23 mmol, 10.34 mL, 3 eq), and potassium carbonate (14.88 g, 107.70 mmol, 2.5 eq) were mixed in N,N-dimethylformamide (80 mL), degassed, and purged three times with nitrogen gas. The mixture was then stirred at 80°C for 12 hours in a nitrogen atmosphere. 50 mL of water was added to the reaction mixture, and then extracted with 50 mL of ethyl acetate. The organic layer was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 54-3. 1 H NMR (400MHz, CDCl3) δ=6.46(d,J=10.2Hz,2H),4.47-4.36(m,2H),4.07(d,J=6.9Hz,2H),1.41(td,J=7.1,18.6Hz,6H).

[0416] Step 3: Preparation of Compound 54-4 At 0-5°C, sodium hydride (3.36 g, 84.10 mmol, 60% purity, 2.2 eqs) was added in multiple portions to a solution of compound 54-3 (8.8 g, 38.23 mmol, 1 eq) and 2-methylsulfonylethanol (5.22 g, 42.05 mmol, 1.1 eq) in N,N-dimethylformamide (90 mL) at 0-5°C. The mixture was stirred at 20°C for 1 hour. The reaction mixture was quenched by adding aqueous hydrochloric acid (200 mL, 0.5 N), and then extracted with 50 mL of ethyl acetate. The organic layer was washed with 50 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 100 / 1 to 50 / 1) to obtain compound 54-4. 1 H NMR(400MHz,CDCl3)δ=12.01(d,J=1.4Hz,1H),6.30(dd,J=2.4,10.1Hz,1H),6.13(dd ,J=2.4,11.2Hz,1H),4.40(q,J=7.1Hz,2H),4.04(q,J=6.9Hz,2H),1.52-1.36(m,6H). LCMS(ESI)m / z:229.0(M+1).

[0417] Step 4: Preparation of Compound 54-5 Compound 54-4 (6.3 g, 27.61 mmol, 1 eq) was dissolved in ethanol (40 mL), to which a solution of sodium hydroxide (4.42 g, 110.42 mmol, 4 eq) in water (20 mL) was added. The mixture was stirred at 80°C for 12 hours. The pH of the reaction mixture was adjusted to < 3 with aqueous hydrochloric acid (200 mL, 1 N), and then extracted with 100 mL of ethyl acetate. The organic layer was washed with 100 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. Compound 54-5 was obtained. LCMS(ESI) m / z: 201.1(M+1); 1 H NMR (400MHz, CDCl3) δ=12.53(d,J=1.5Hz,1H),6.44(dd,J=2.4,10.1Hz,1H),6.24(dd,J=2.3,10.3Hz,1H),4.32(q,J=7.1Hz,2H),1.61(t,J=7.0Hz,3H).

[0418] Step 5: Production of Compounds 54-6 At 0-5℃, the trifluorinated compound 54-5 (5.1g, 25.48 mmol, 1 eq) To a 30 mL solution of trifluoroacetic acid, acetone (23.70 g, 408.06 mmol, 30 mL, 16.02 eq) and anhydrous trifluoroacetic acid (21.41 g, 101.92 mmol, 14.18 mL, 4 eq) were added. The mixture was stirred at 100°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 100 mL of aqueous sodium bicarbonate solution and extracted with 100 mL of ethyl acetate. The organic layer was washed with 30 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1), stirred with petroleum ether (20 mL), filtered, and the filter cake was dried to obtain compound 54-6. LCMS(ESI) m / z: 241.0 (M+1); 1 H NMR (400MHz, CDCl3) δ=6.25(dd,J=2.2,11.3Hz,1H),6.19(dd,J=2.3,9.1Hz,1H),4.07(q,J=7.0Hz,2H),1.63(s,6H),1.50-1.40(m,3H).

[0419] Step 6: Preparation of Compound 54-7 To a solution of compound 54-6 (2.5 g, 10.41 mmol, 1 eq) in tetrahydrofuran (25 mL), N-bromosuccinimide (2.78 g, 15.61 mmol, 1.5 eq.) was added, followed by the addition of acetic acid (2.50 g, 41.63 mmol, 2.38 mL, 4 eq). The mixture was stirred at 80°C for 1 hour, then NBS (926.12 mg, 5.20 mmol, 0.5 eq) was added, and the mixture was stirred at 80°C for 1 hour. A further 2 hours were allowed to pass. The reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 50 mL of aqueous sodium bicarbonate solution and extracted with ethyl acetate (50 mL x 2). The combined organic layer was washed with 20 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 20 / 1 to 10 / 1) to obtain compound 54-7. LCMS(ESI)m / z:318.8 / 320.8(M+1 / M+3); 1 H NMR (400MHz, CDCl3) δ=6.49(d,J=10.9Hz,1H),4.17(q,J=7.0Hz,2H),1.78(s,6H),1.57-1.49(m,3H).

[0420] Step 7: Production of Compound 54-8 Compound 54-7 (1.8 g, 5.64 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (4.30 g, 16.92 mmol, 3 eq), potassium acetate (1.94 g, 19.74 mmol, 3.5 eq), and Pd(dppf)Cl2.CH2Cl2 (460.62 mg, 564.05 μmol, 0.1 eq) were mixed in 20 mL of dioxane, degassed, and purged three times with nitrogen gas. The mixture was then stirred at 90°C and reacted in a nitrogen atmosphere for 12 hours. The reaction mixture was quenched by adding 100 mL of water and extracted with 100 mL of ethyl acetate. The organic layer was washed with 50 mL of saline solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 10 / 1 to 6 / 1) to obtain compound 54-8. LCMS (ESI) m / z: 367.0 (M+1).

[0421] Process 8: Production of Compound 54-9 Compound 54-8 (550 mg, 1.50 mmol, 1 eq) was dissolved in a mixed solution of tetrahydrofuran (5 mL) and water (5 mL), and sodium perborate tetrahydrate (462.18 mg, 3.00 mmol, 577.73 μL, 2 eqs) was added. The mixture was stirred at 20°C for 1 hour. The reaction mixture was diluted with 10 mL of water and adjusted to pH < 7 in aqueous hydrochloric acid solution (0.5 N), and then extracted with 20 mL of ethyl acetate. The organic layer was washed with 10 mL of saline solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by silica gel flash column chromatography (petroleum ether / ethyl acetate = 5 / 1 to 3 / 1) to obtain compound 54-9. LCMS (ESI) m / z: 257.1 (M+1).

[0422] Process 9: Production of Compound 54-10 Compound 54-9 (180 mg, 702.50 μmol, 1 eq), 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (263.48 mg, 983.50 μmol, 1.4 eq), and potassium carbonate (145.64 mg, 1.05 mmol, 1.5 eq) were mixed in acetonitrile (2 mL), degassed, and purged three times with nitrogen gas. The mixture was then stirred at 60°C for 4 hours in a nitrogen atmosphere. The pH of the reaction mixture was adjusted to <3 with aqueous hydrochloric acid (1 N), then extracted with 10 mL of ethyl acetate. The organic layer was washed with 10 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 54-10. LCMS (ESI) m / z: 315.1 (M+1).

[0423] Step 10: Production of Compound 54 Compound 54-10 (220 mg, 700.48 μmol, 1 eq) was dissolved in isopropanol (2 mL), and sodium hydroxide (2 M, 875.60 μL, 2.5 eq) was added. The mixture was stirred at 20°C for 1 hour. The mixture was filtered to obtain the filtrate. The residue was purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 1% to 6%, 4 min) to obtain compound 54. 1 H NMR(400MHz,D2O)δ=6.20(d,J=12.8Hz,1H),3.87(q,J=7.0Hz,2H),3.23(s,2H),1.18(t,J=7.0Hz,3H);LCMS(ESI)m / z:257.0(M+1).

[0424] Example 55 [ka]

[0425] Step 1: Preparation of Compound 55-2 Compound 54-2 (10 g, 57.44 mmol, 1 eq) was dissolved in dimethylformamide (100 mL) solution, and potassium carbonate (19.85 g, 143.59 mmol, 2.5 eq) and 1-bromobutane (19.68 g, 143.59 mmol, 15.49 mL) were added. (L, 2.5 eq) was added and stirred at 25°C, then at 80°C for 16 hours. The residue was concentrated under vacuum, water (50 mL) was added, and the aqueous phase was extracted with ethyl acetate (100 mL × 1). The combined organic phase was washed with saline solution (100 mL × 1), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 100 / 1, 10 / 1) to obtain compound 55-2. LCMS: 287.1(M+1); 1 H NMR(400MHz, CDCl3)δ=6.52-6.40(m,2H),4.35(t,J=6.6Hz,2H),3.99(t,J=6.4Hz ,2H),1.86-1.68(m,4H),1.48(quind,J=7.4,14.9Hz,4H),0.98(t,J=7.4Hz,6H).

[0426] Step 2: Preparation of Compound 55-3 Compound 55-2 (14 g, 48.90 mmol, 1 eq) and 2-methylsulfonylethanol (6.37 g, 51.34 mmol, 1.05 eq) were dissolved in dimethylformamide (160 mL) solution, and NaH (4.11 g, 102.68 mmol, 60% purity, 2.1 eq) was added in multiple portions at 0-5°C. The mixture was stirred at 20°C for 1 hour. The reaction mixture was quenched by adding aqueous HCl (200 mL, 0.5 N), and then extracted with 300 mL of EA. The organic layer was washed with 300 mL of saline solution, dried over Na₂SO₄, filtered, concentrated under reduced pressure, and the crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 300 / 1, 10 / 1) to obtain compound 55-3. LCMS: 285.4(M+1); 1H NMR(400MHz,CDCl3)δ=12.01(d,J=1.5Hz,1H),6.20(dd,J=2.4,10.0Hz,1H),6.05(dd,J=2.4,11.4Hz,1H),4. 26(t,J=6.5Hz,2H),3.87(t,J=6.3Hz,2H),1.81-1.59(m,4H),1.54-1.32(m,4H),0.91(dt,J=3.7,7.4Hz,6H).

[0427] Step 3: Preparation of Compound 55-4 Compound 55-3 (430 mg, 1.51 mmol, 1 eq) was dissolved in ethanol (5 mL) solution, and a solution of NaOH (241.96 mg, 6.05 mmol, 4 eq) in H2O (1 mL) was added at 20 °C. The mixture was stirred at 85 °C for 16 hours. The pH of the reaction mixture was adjusted to < 3 with aqueous HCl (10 mL, 1 N), and then extracted with 10 mL of EA. The organic layer was washed with 10 mL of saline solution, dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. Compound 55-4 was obtained. LCMS (ESI) m / z: 229.1 (M+1).

[0428] Step 4: Production of Compound 55-5 Compound 55-5 (500 mg, 2.19 mmol, 1 eq) was dissolved in a 5 mL solution of dichloromethane. At -30°C, a 0.5 mL solution of liquid bromine (350.12 mg, 2.19 mmol, 112.94 μL, 1 eq) in dichloromethane was added, and the mixture was then gradually heated to 20°C and stirred for 1 hour. The crude product was placed in 10 mL of Na₂SO₃ and stirred for 10 minutes. The aqueous phase was extracted with dichloromethane (10 mL x 2). The combined organic phase was washed with saline solution (20 mL x 1), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum to obtain compound 55-5. LC-MS (ESI) m / z: 307.3 (M+1); 1H NMR(400MHz,CDCl3)δ=13.31(d,J=1.6Hz,1H),11.34(s,1H),6.40(d,J=10.0Hz,1H),4 .26(t,J=6.5Hz,2H),2.05-1.87(m,2H),1.55(s,J=7.5Hz,2H),1.05(t,J=7.3Hz,3H).

[0429] Step 5: Production of Compounds 55-6 Compound 55-5 (4.9g, 15.96 mmol, 1 eq) was mixed with trifluoroacetic acid (30 The compound was dissolved in a solution (mL), and acetone (23.70 g, 408.06 mmol, 30 mL, 25.58 eq) and anhydrous trifluoroacetic acid (13.40 g, 63.82 mmol, 8.88 mL, 4 eq) were added. The mixture was stirred at 0°C, then at 100°C for 16 hours. This solution was concentrated under vacuum, then H2O (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The combined organic phase was washed with NaHCO3 (100 mL × 1) and saline solution (100 mL × 1), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 100 / 1, 50 / 1) to obtain compound 55-6. LCMS(ESI) m / z: 347 (M+1); 1 H NMR(400MHz, CDCl3)δ=6.40(d,J=10.9Hz,1H),3.98(t,J=6.5Hz,2H),1.86-1 .76(m,2H),1.68(s,6H),1.48(qd,J=7.4,15.0Hz,2H),0.92(t,J=7.4Hz,3H).

[0430] Step 6: Production of Compound 55-7 Compound 55-6 (2.5 g, 7.20 mmol, 1 eq), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolan (4.57 g, 18.00 mmol, 2.5 eq), potassium acetate (2.12 g, 21.60 mmol, 3 eq), and Pd(dppf)Cl2.CH2Cl2 (588.06 mg, 720.10 μmol, 0.1 eq) were dissolved in a 25 mL solution of dioxane, and the mixture was stirred at 82°C for 16 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent. H2O (30 mL) was added to the solution, and the aqueous phase was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saline solution (100 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 0 / 1) to obtain compound 55-7. LC-MS (ESI) m / z: 395.2 (M+1).

[0431] Step 7: Production of Compound 55-8 Compound 55-7 (3.7 g, 9.39 mmol, 1 eq) was dissolved in tetrahydrofuran (20 mL) and H2O (20 mL). Sodium perborate tetrahydrate (4.33 g, 28.16 mmol, 5.41 mL, 3 eq) was added, and the mixture was stirred at 25°C for 2 hours. H2O (50 mL) was added to the solution, and it was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with saline solution (100 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel chromatography (petroleum ether / ethyl acetate = 10 / 1 to 5 / 1) to obtain compound 55-8. LCMS (ESI) m / z: 285.3 (M+1); 1 H NMR (400MHz, CDCl3) δ=6.42(d,J=12.8Hz,1H),4.01(t,J=6.6Hz,2H),1.88(br d,J=7.0Hz,2H),1.77(s,6H),1.60-1.52(m,2H),1.00(t,J=7.4Hz,3H).

[0432] Process 8: Production of Compound 55-9 Compound 55-8 (300 mg, 1.06 mmol, 1 eq) was dissolved in acetonitrile (5 mL) solution, and 2-(iodomethyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (424.07 mg, 1.58 mmol, 1.5 eq) and K2CO3 (218.78 mg, 1.58 mmol, 1.5 eq) were added. The mixture was stirred at 25°C, then at 60°C for 2 hours. H2O (5 mL) was added to the solution, and the aqueous phase was extracted with ethyl acetate (10 mL x 2). The combined organic phase was washed with saline solution (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound 55-9. LCMS (ESI) m / z: 343.3 (M+1).

[0433] Process 9: Production of Compound 55 Compound 55-9 (200 mg, 479.36 μmol, 82% purity, 1 eq) was dissolved in i-PrOH (2 mL) solution, and NaOH (3 M, 319.57 μL, 2 eqs) was added. The mixture was then stirred at 25°C for 2 hours. The mixture was filtered, and the filtrate was purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 1%~20%, 7 min) to obtain compound 55. LC-MS (ESI) m / z: 285 (M+1), 267.1 (M-18+1); 1 H NMR(400MHz,D2O)δ=6.19(br d,J=12.8Hz,1H),3.81(t,J=6.5Hz,2H),3.32-3.18(m,2H),1.59-1.50(m,2H),1.34-1.25(m,2H),0.79(t,J=7.4Hz,3H).

[0434] Example 56 [ka]

[0435] Step 1: Preparation of Compound 56-2 Compound 56-1 (7.2 g, 39.31 mmol, 1 eq) and 2-methylsulfonylethanol (4.88 g, 39.31 mmol, 1 eq) were dissolved in DMF (72 mL), and NaH (3.14 g, 78.62 mmol, 60% purity, 2 eq) was added in several portions at 0°C. The mixture was stirred at 20°C for 0.5 hours. The reaction mixture was gradually added to ice water (100 mL) and extracted with ethyl acetate (150 mL). The aqueous phase was adjusted to pH=2 with HCl and extracted with 300 mL of ethyl acetate (400 mL (200 mL x 2)). The organic phase was combined and washed with brine (300 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure to obtain compound 56-2.

[0436] Step 2: Preparation of Compound 56-3 Compound 56-2 (6.2 g, 34.22 mmol, 1 eq) was dissolved in ethanol (20 mL), and NaOH (8 M, 42.78 mL, 10 eq) was added at room temperature. The mixture was stirred at 120 °C for 48 hours. The mixture was concentrated under reduced pressure to remove the ethanol, then diluted with 100 mL of H2O and adjusted with HCl to pH=3. After extraction with 150 mL of ethyl acetate (150 mL x 1), the aqueous phase was adjusted with HCl to pH=2, filtered, and then... The filtered cake was dried under reduced pressure to obtain the crude product. The crude product was stirred with petroleum ether / ethyl acetate = 10 / 1 (55 mL) at 20°C for 30 minutes, filtered, and the filtered cake was dried to obtain compound 56-3. LCMS (ESI) m / z: 201.1 (M+1).

[0437] Step 3: Preparation of Compound 56-4 Compound 56-3 (3.12 g, 15.59 mmol, 1 eq) was dissolved in DCM (30 mL), and NBS (2.77 g, 15.59 mmol, 1 eq) was added at room temperature. The mixture was stirred at 0°C for 2 hours, and the reaction mixture was concentrated under reduced pressure to remove the solvent. The residue was diluted with 60 mL of H2O, extracted with EA (30 mL x 2), washed with saline solution (30 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative HPLC (chromatographic column: Phenomenex Synergi Max-RP 250 × 50 mm × 10 μm, mobile phase: water (0.1% TFA) and acetonitrile, acetonitrile content in mobile phase 30%~60%, 20 min) to obtain compound 56-4. 1 H NMR (400MHz, DMSO-d6) δ = 6.73-6.64 (m, 1H), 4.24-4.13 (m, 2H), 1.41-1.31 (m, 3H).

[0438] Step 4: Preparation of Compound 56-5 Compound 56-4 (637 mg, 2.28 mmol, 1 eq) was dissolved in TFA (6 mL), acetone (1.33 g, 22.83 mmol, 1.68 mL, 10 eq) was added at 0°C, and TFAA (1.44 g, 6.85 mmol, 952.51 μL, 3 eq) was added dropwise. After several substitutions with nitrogen gas, the reaction mixture was stirred in N2 at 100°C for 12 hours. The mixture was concentrated under reduced pressure to remove the solvent, diluted with 20 mL of H2O, and extracted with EA (30 mL x 2). The mixture was washed with 30 mL of saline solution (30 mL), dried over Na2SO4, filtered, concentrated under reduced pressure to obtain the residue, and purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1) to obtain compound 56-5. LCMS (ESI) m / z: 321.0 (M+3).

[0439] Step 5: Production of compound 56-6 Compound 56-5 (484 mg, 758.33 μmol, 50% purity, 1 eq) was dissolved in dioxane (10 mL), and then pinacolborate (577.70 mg, 2.27 mmol, 3 eq), potassium acetate (260.48 mg, 2.65 mmol, 3.5 eq), and Pd(dppf)Cl2 (262.89 mg, 227.50 μmol, 0.3 eq) were added under a nitrogen gas flow. The mixture was stirred at 70°C for 48 hours under nitrogen gas protection. The reaction mixture was filtered, then diluted with 30 mL of water, extracted with ethyl acetate (30 mL x 2), washed with 30 mL of saline solution (30 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain the residue. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 5 / 1 to 2 / 1) to obtain compound 56-6. LCMS(ESI)m / z:367.2(M+1).

[0440] Step 6: Preparation of Compound 56-7 Compound 56-6 (806 mg, 2.20 mmol, 1 eq) was dissolved in a mixed solution of THF (8 mL) and H2O (8 mL). Sodium perborate tetrahydrate (1.02 g, 6.60 mmol, 3 eq) was added at 20°C, and the mixture was stirred at 20°C for 1 hour. The reaction solution was diluted with 20 mL of water, then extracted with 80 mL of ethyl acetate (40 mL x 2), washed with saline solution (40 mL), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 10 / 1 to 4 / 1) to obtain compound 56-7. LCMS (ESI) m / z: 257.2 (M+1).

[0441] Step 7: Preparation of Compound 56-8 Compound 56-7 (20 mg, 78.06 μmol, 1 eq) was dissolved in CH3CN (1 mL), and 2-iodomethyl pinacolborate (25.09 mg, 93.67 μmol, 1.2 eq) and K2CO3 (12.95 mg, 93.67 μmol, 1.2 eq) were sequentially added at room temperature. After the additions were complete, the mixture was purged three times with nitrogen gas, and then stirred in N2 at 60°C for 6 hours. The reaction mixture was concentrated under reduced pressure to remove the solvent CH3CN. The residue was diluted with 20 mL of H2O, adjusted to pH=3 with 1 M HCl, and extracted with 60 mL of ethyl acetate (30 mL x 2). The combined organic layer was washed with 20 mL of saline solution (20 mL x 1), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain yellow oily compound 56-8. LCMS(ESI) m / z: 315.1 (M+1).

[0442] Process 8: Production of Compound 56 Compound 56-8 (24 mg, 76.42 μmol, 1 eq) was dissolved in i-PrOH (1 mL), and NaOH (2 M, 76.42 μL, 2 eq) was added dropwise at room temperature. The mixture was stirred at 20°C for 2 hours. The reaction mixture was diluted with 1 mL of H2O and purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase 0%~10%, 10 min) to obtain compound 56. LCMS (ESI) m / z: 257.1 (M+1). 1 H NMR(400MHz,D2O)δ=6.33(d,J=12.72Hz,1H),4.03(q,J=6.97Hz,2H),3.27(s,2H),1.31(t,J=7.03Hz,3H).

[0443] Example 57 [ka]

[0444] Step 1: Preparation of Compound 57-2 Compound 57-1 (5.12 g, 39.71 mmol, 3.53 mL, 1 eq) was dissolved in DCM (100 mL), pyridine (3.20 g, 40.50 mmol, 3.27 mL, 1.02 eq) was added at room temperature, and 4-hydroxytetrahydropyran (5 g, 48.96 mmol, 4.90 mL, 1.23 eq) was added at 0 °C. The mixture was stirred at 20 °C for 4 hours, quenched by adding 50 mL of H2O at 20 °C, extracted with 100 mL of DCM (50 mL x 2), the organic phase was combined and washed with 200 mL of saline (100 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound 57-2. 1 H NMR (400MHz, CDCl3)δ=5.73-5.63(s,2H),4.90-4.77(m,1H),3.93-3.81(m,2H),3.53-3.40(m,2H),2.01-1.91(m,2H),1.77-1.63(m,2H).

[0445] Step 2: Production of Compound 57 Compound 15 (126.04 mg, 420.17 μmol, 1 eq), Compound 57-2 (163.54 mg, 840.33 μmol, 2 eq), K2CO3 (116.14 mg, 840.33 μmol, 2 eq), and potassium iodide (139.50 mg, 840.33 μmol, 2 eq) were dissolved in DMF (2 mL), and the mixture was purged three times with nitrogen gas. The mixture was stirred in N2 at 50°C for 12 hours, the reaction mixture was diluted with 1 mL of H2O and 1 mL of acetonitrile, and purified by preparative HPLC (chromatographic column: Waters An Xbridge measuring device measuring 150 × 25 mm × 5 μm was used. The mobile phase consisted of an aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile (acetonitrile content in the mobile phase was 10% to 40%, and the mixture was run for 10 minutes). Compound 57 was obtained. LC-MS (ESI) m / z: 792.1 (2M). 1H NMR(400MHz,CD3OD)δ=6.69(d,J=8.78Hz,1H),6.29(d,J=8.78Hz,1H),5.92(s,2H),3.99(s,1H),3.99-3.93(m,1H),3.93-3.88(m,2H),3. 57(ddd,J=11.80,8.78,3.01Hz,2H),3.44(s,2H),2.07-1.95(m,2H),1.72(dtd,J=13.05,8.75,8.75,3.95Hz,2H),1.31(t,J=6.96Hz,3H).

[0446] Example 58 [ka]

[0447] Step 1: Preparation of Compound 58-2 Compound 57-1 (5 g, 38.78 mmol, 3.45 mL, 1 eq) and pyridine (3.13 g, 39.55 mmol, 3.19 mL, 1.02 eq) were dissolved in dichloromethane solution, and then isopropanol (2.33 g, 38.78 mmol, 2.97 mL, 1 eq) was added. The mixture was stirred at 0°C, then gradually heated to 20°C for 5 hours. Ice water (50 mL) was added to the solution and stirred for 10 minutes. The aqueous phase was extracted with DCM (50 mL x 2). The combined organic phase was washed with saline solution (200 mL x 1), dried over anhydrous Na2SO4, filtered, and concentrated under vacuum to obtain compound 58-2. 1 H NMR (400MHz, CDCl3) δ = 5.70-5.64 (m, 2H), 4.89 (s, J = 6.3Hz, 1H), 1.27 (d, J = 6.3Hz, 6H).

[0448] Step 2: Production of Compound 58 Compound 15 (0.1 g, 333.36 μmol, 1 eq), potassium carbonate (138.22 mg, 1.00 mmol, 3 eq), and potassium iodide (166.01 mg, 1.00 mmol, 3 eq) were added to DMF (2 mL) and chloromethyl carbonate isopropyl (i.e., compound 58-2, 101.72 mg, 666.71 μmol, 2 eq) in a nitrogen atmosphere at 25°C. The mixture was heated to 50°C and maintained for 12 hours. H2O (2 mL) was added to the solution, filtered, and the filtrate was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: aqueous solution containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase: 14%~44%, 10 min) to obtain compound 58. LCMS(ESI)m / z:708(2M); 1 H NMR(400MHz,CD3OD)δ=6.67(d,J=8.7Hz,1H),6.26(d,J=9.0Hz,1H),5.90(s,2H),3.96(q,J=7.0Hz,2H),3.42(s,2H),3.34(br s,1H),1.32(d,J=6.4Hz,9H).

[0449] Example 59 [ka]

[0450] Step 1: Preparation of Compound 59-2 At 0-5°C, a solution of compound 57-1 (3 g, 23.27 mmol, 2.07 mL, 1 eq) in dichloromethane (50 mL) was prepared by adding pyridine (1.93 g, 24.43 mmol, 1.97 mL, 1.05 eq) and 2-methoxyethanol (1.86 g, 24.43 mmol, 1.05 eq). The mixture was stirred at 20°C for 12 hours. The reaction mixture was quenched by adding 50 mL of water, and the organic layer was then washed with 20 mL of aqueous hydrochloric acid and water (20 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 59-2. 1H NMR (400MHz, CDCl3) δ=5.76(s,2H),4.39(dd,J=3.8,5.4Hz,2H),3.66(dd,J=3.9,5.4Hz,2H),3.42(s,3H).

[0451] Step 2: Production of compound 59 Compound 15 (100 mg, 333.36 μmol, 1 eq), compound 59-2 (112.39 mg, 666.72 μmol, 2 eq), potassium iodide (166.01 mg, 1.00 mmol, 3 eq), and potassium carbonate (92.15 mg, 666.72 μmol, 2 eq) were mixed in N,N-dimethylformamide (1 mL), degassed, and purged three times with nitrogen gas. The mixture was then stirred in a nitrogen atmosphere at 50°C for 12 hours. The reaction mixture was quenched by adding 0.5 mL of water, and the filtrate was obtained by filtration. The filtrate was purified by preparative HPLC (column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: water containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase 5% to 35%, 8 min) to obtain compound 59. LCMS(ESI)m / z:739.9(2M); 1 H NMR(400MHz,CD3OD)δ=6.65(d,J=8.7Hz,1H),6.22(d,J=8.8Hz,1H),5.92(s,2H),4.36-4 .30(m,2H),3.95(q,J=6.9Hz,2H),3.68-3.60(m,2H),3.38(s,5H),1.30(t,J=7.0Hz,3H).

[0452] Example 60 [ka]

[0453] Step 1: Synthesis of compound 60-2 At 0-5°C, compound 57-1 (3 g, 23.27 mmol, 2.07 mL, 1 eq) was dissolved in dichloromethane (100 mL), and pyridine (1.88 g, 23.73 mmol, 1.92 mL, 1.02 eq) and ethanol (1.07 g, 23.27 mmol, 1 eq) were added. The mixture was then stirred at 25°C for 8 hours. The reaction mixture was diluted with 20 mL of water and extracted with 60 mL of dichloromethane (30 mL x 2). The combined organic layer was washed with 30 mL of saline solution (30 mL x 1), dried over sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 60-2. 1 H NMR (400MHz, CDCl3) δ = 5.78-5.66 (m, 2H), 4.29 (q, J = 7.2Hz, 2H), 1.41-1.30 (m, 3H).

[0454] Step 2: Synthesis of compound 60 Compound 15 (100 mg, 333.36 μmol, 1 eq), potassium carbonate (138.22 mg, 1.00 mmol, 3 eq), and potassium iodide (166.01 mg, 1.00 mmol, 3 eq) were mixed in N,N-dimethylformamide (2 mL), purged three times with nitrogen gas, and then compound 60-2 (184.74 mg, 1.33 mmol, 4 eq) was added in a nitrogen gas atmosphere at 25°C. The mixture was then stirred at 50°C for 16 hours. 10 mL of water was added to the mixture. The crude product was purified by preparative HPLC (chromatographic column: Waters Xbridge 150 × 25 mm × 5 μm, mobile phase: water containing 10 mmol / L ammonium bicarbonate and acetonitrile, acetonitrile content in mobile phase 11%~41%, 10 min) to obtain compound 60. LCMS(ESI)m / z:680.1(2M). 1 H NMR(400MHz,CD3OD δ=6.70(d,J=8.9Hz,1H),6.30(d,J=8.9Hz,1H),5.92(s,2H),4.24(q,J=7.2Hz,2H),4.04-3.90(m,2H),3.44(s,2H),1.31(dt,J=4.6,7.0Hz,6H).

[0455] Biological activity measurement Test Example 1: Detection of a compound to restore the bacteriostatic effect of an antibiotic (MIC shift) The minimum inhibitory concentrations (MICs) of the compounds against three strains of Klebsiella pneumoniae (ATCC BAA-1705 (KPC-2), ATCC BAA-2470 (NDM-1), ARLG-1196 (CTM-1 group, SHV, NDM, TEM)) and one strain of Escherichia coli (ARLG-2829 (NDM-5, OXA-1)) were measured. In accordance with the requirements of the Institute of Clinical and Laboratory Standards (CLSI), the minimum inhibitory concentration (MIC) of each drug combination was measured using a microdilution method, with the meropenem concentration fixed at 4 μg / mL.

[0456] Preparation of compound master plates: On the day of the test, the compound to be measured (final concentration 0.3125 μg / mL to 20 μg / mL) and meropenem (final concentration range 1 μg / mL to 64 μg / mL) were dissolved in the appropriate solvent (sterile ddH2O or DMSO) to obtain a 100× mother liquor with the highest measurable concentration. Then, the compound to be measured and meropenem were sequentially diluted 2-fold in a V-bottom 96-well plate to obtain a diluted standard solution with a final concentration of 100×.

[0457] Preparation of seed solution: Fresh bacterial microorganisms were extracted overnight from Mueller Hinton II Agar (MHA, Cat. No. 211438, BD BBL™) plates. Pick up the noclonal, suspend it in sterile saline solution, and adjust the concentration to 1 × 10⁻⁶. 8 The solution was adjusted to CFU / mL and then fermented in cation-adjusted Mueller Hinton II Broth (MHB, Catalog# 212332, BD BBL™) for 5 × 10⁻¹⁰ units. 5 Diluted to CFU / mL.

[0458] Detection of the minimum inhibitory concentration (MIC): 1 μL of the compound to be measured and a diluted meropenem standard solution were transferred to the corresponding measurement well of a round-bottom 96-well plate (Catalog # 3788, Corning). 98 μL of the seed solution was taken and added to the round-bottom 96-well plate containing the drug. This was used as the MIC assay plate. The plate was inverted and incubated at 37°C for 20-24 hours. The MIC value was then read, and the lowest drug concentration that inhibited bacterial growth was defined as the MIC. The results are shown in Table 1.

[0459] As is clear from the test results, the series of compounds of the present invention can restore the inhibitory activity of meropenem against target bacterial strains. Compared to the use of meropenem alone, after using each compound in combination at a certain concentration, the minimum inhibitory concentration (MIC) of meropenem can be restored to below the drug resistance breakpoint (MIC = 4 μg / mL), showing a clear shift in MIC. The synthetic compounds were found to have excellent inhibitory activity against β-lactamases expressed by target bacterial strains (KPC-2, SHV, CTM-1 and its subtypes, NDM, TEM, and OXA-1, etc.).

[0460] [Table 1-1] [Table 1-2]

[0461] Test Example 2: Detection of a compound to restore the bacteriostatic effect of an antibiotic (MIC shift) The minimum inhibitory concentrations of the compound were measured against five strains of Klebsiella pneumoniae (ATCC) BAA-1705 (KPC-2), ATCC BAA-2470 (NDM-1), ARLG-1196 (CTM-1 group, SHV, NDM, TEM), NCTC 13440 (VIM-1), NCTC 13439 (VIM), and one strain of Escherichia coli (ARLG-2829) (NDM-5, OXA-1). (Institute of Clinical and Industrial Laboratory Standards) In accordance with the requirements of the laboratory standard (CLSI), the minimum inhibitory concentration (MIC) of each drug combination was measured using a micro-liquid dilution method, with the concentration of the compound to be measured fixed at 8 μg / mL. The measurement method was the same as described above, and the concentration range for meropenem was 0.125 μg / mL to 8 μg / mL. The results are shown in Table 2.

[0462] As is clear from the test results, the compounds in the present invention are effective against meropenem target strains. The inhibitory activity could be restored, and compared to meropenem alone, the minimum inhibitory concentration (MIC) of meropenem was significantly reduced after co-administration of each compound at 8 μg / mL, indicating a clear shift in MIC. The synthesized series of compounds demonstrated excellent inhibitory activity against β-lactamases expressed by target bacterial strains (KPC-2, SHV, CTM-1 and its subtypes, NDM, NDM-1, NDM-5, TEM, VIM, VIM-1, and OXA-1, etc.).

[0463] [Table 2-1] [Table 2-2]

[0464] Test Example 3: Pharmacokinetic Study of Compounds in Rat The pharmacokinetic characteristics of compounds in rodents were measured after intravenous and oral administration using standard methods. Specifically, candidate compounds were administered intravenously and orally to fasted SD male rats. Both the oral and intravenous formulations were prepared as clarified solutions of 10 mg / mL or 30 mg / mL in physiological saline and administered intravenously or gastrically over 5 minutes. Plasma samples were collected and analyzed by LC-MS / MS to calculate pharmacokinetic parameters. The pharmacokinetic parameters for compound 15 are shown in Table 3.

[0465] As is clear from the test results, the series of compounds of the present invention have good exposure levels whether administered orally or intravenously, show no apparent toxic effects when administered intravenously at 300 milligrams / kilogram, have good safety, and exhibit excellent pharmacokinetic properties.

[0466] [Table 3]

[0467] Test Example 4: Pharmacodynamic studies of compounds in thigh muscle and lungs 1) Model of the thigh muscle 36 CD-1 female mice were divided into 12 cages, with 3 mice per cage, and the day of infection was designated as day 0.

[0468] -On day 4, the immunosuppressant cyclophosphamide (150 mg / kg) was injected intraperitoneally, and on day 1, another immunosuppressant, cyclophosphamide (100 mg / kg), was injected intraperitoneally to obtain immunodeficient mice.

[0469] - Day 1: MHA plate containing the strain Klebsiella pneumoniae ATCC BAA-1705 was resuscitated. Resuscitated colonies were picked and dissolved in sterile saline to prepare a bacterial suspension at a concentration of 5.6E+07 CFU / mL, which was used to infect the thigh muscles of mice. The time of infection onset was defined as 0h, and at 0h, 100 μL of the bacterial suspension was injected into the thigh muscle of each mouse, i.e., the dispersal rate was 5.6E+06 CFU / mouse. At 2h post-infection, administration was carried out according to the test protocol. The specific test protocol is as follows (see Table 4).

[0470] (1) Two hours after infection: For the mice in the first cage, thigh muscle tissue was taken at the endpoint, left in 10 mL of sterile physiological saline, the tissue was homogenized with a homogenizer, the homogenized slurry was sequentially diluted and seeded onto a plate, and this was repeated twice for each mouse.

[0471] (2) Two hours after infection, the second to twelfth cages were each administered 10 mL / kg in volume according to the body weight of the mice. For the mice in cage 2, the solvent was administered intravenously every two hours, with the treatment ending at 12 hours. For the mice in cage 3, 100 mg / kg of meropenem was administered intravenously every two hours, with the treatment ending at 12 hours. For the mice in cage 4, 100 mg / kg of meropenem and 20 mg / kg were administered every two hours. QPX7728 was administered intravenously, with 12 hours as the endpoint. For the mice in the 5th cage, 100 mg / kg of meropenem and 100 mg / kg of compound 15 were administered intravenously every 2 hours, with 12 hours as the endpoint. For the mice in the 6th cage, 100 mg / kg of meropenem and 20 mg / kg of compound 15 were administered intravenously every 2 hours, with 12 hours as the endpoint. For the mice in the 7th cage, 100 mg / kg of meropenem and 4 mg / kg of compound 15 were administered intravenously every 2 hours, with 12 hours as the endpoint. For the mice in the 8th cage, 100 mg / kg of cefepime was administered intravenously every 2 hours, with 12 hours as the endpoint. In the 9th cage, mice were administered intravenously at a dose of 100 mg / kg of cefepime and 20 mg / kg of QPX7728 every 2 hours, with the treatment ending at 12 hours. In the 10th cage, mice were administered intravenously at a dose of 100 mg / kg of cefepime and 100 mg / kg of compound 15 every 2 hours, with the treatment ending at 12 hours. In the 11th cage, mice were administered intravenously at a dose of 100 mg / kg of cefepime and 20 mg / kg of compound 15 every 2 hours, with the treatment ending at 12 hours. In the 12th cage, mice were administered intravenously at a dose of 100 mg / kg of cefepime and 4 mg / kg of compound 15 every 2 hours, with the treatment ending at 12 hours. At the 12-hour endpoint, thigh muscle tissue was left in 10 mL of sterile saline to homogenize the homogenized tissue. The homogenized slurry was then sequentially diluted and seeded onto plates, and the process was repeated twice for each mouse. The bacterial load on the mouse thigh muscle tissue was counted, and the experiment was summarized as follows (see Table 5).

[0472] [Table 4]

[0473] [Table 5]

[0474] 2) Lung infection model 36 female CD-1 mice were divided into 12 cages, with 3 mice per cage. The day of infection was designated as day 0.

[0475] -On day 4, the immunosuppressant cyclophosphamide (150 mg / kg) was injected intraperitoneally, and on day 1, another immunosuppressant, cyclophosphamide (100 mg / kg), was injected intraperitoneally to obtain immunodeficient mice.

[0476] - Day 1: MHA plate containing the strain Klebsiella pneumoniae ATCC BAA-1705 was resuscitated. Resuscitated colonies were picked and dissolved in sterile saline to prepare a bacterial suspension at a concentration of 2.75E+08 CFU / mL, which was then administered as nasal drops to the lungs for infection. The time of infection onset was defined as 0h, and at 0h, 50 μL of the bacterial suspension was injected intranasally into each mouse, resulting in a dispersal rate of 1.38E+07 CFU / mouse. At 2h post-infection, administration was carried out according to the test protocol. The specific test protocol is as follows (see Table 6).

[0477] (1) Two hours after infection: For the mice in the first cage, lung tissue was taken at the endpoint, left in 10 mL of sterile saline, the tissue was homogenized with a homogenizer, the homogenized slurry was sequentially diluted and seeded onto plates, and this was repeated twice for each mouse.

[0478] (2) Two hours after infection, the second to twelfth cages were each administered 10 mL / kg in volume according to the body weight of the mice. For the mice in cage 2, the solvent was administered intravenously every two hours, with the treatment ending at 12 hours. For the mice in cage 3, 100 mg / kg of meropenem was administered intravenously every two hours, with the treatment ending at 12 hours. For the mice in cage 4, 100 mg / kg of meropenem and 20 mg / kg of QPX7728 were administered intravenously every two hours, with the treatment ending at 12 hours. For the mice in cage 6, 100 mg / kg of meropenem and 100 mg / kg of compound 15 were administered intravenously every 2 hours, with 12 hours as the endpoint. For the mice in cage 6, 100 mg / kg of meropenem and 20 mg / kg of compound 15 were administered intravenously every 2 hours, with 12 hours as the endpoint. For the mice in cage 7, 100 mg / kg of meropenem and 4 mg / kg of compound 15 were administered intravenously every 2 hours, with 12 hours as the endpoint. For the mice in cage 8, 100 mg / kg of cefepime was administered intravenously every 2 hours, with 12 hours as the endpoint. For the mice in cage 9, 100 mg / kg of cefepime and 20 mg / kg of QPX7728 were administered intravenously every 2 hours, with 12 hours as the endpoint. For mice in cage 10, 100 mg / kg of cefepime and 100 mg / kg of compound 15 were administered intravenously every 2 hours, with 12 hours as the endpoint. For mice in cage 11, 100 mg / kg of cefepime and 20 mg / kg of compound 15 were administered intravenously every 2 hours, with 12 hours as the endpoint. For mice in cage 12, 100 mg / kg of cefepime and 4 mg / kg of compound 15 were administered intravenously every 2 hours, with 12 hours as the endpoint. At the endpoint, lung tissue was left in 10 mL of sterile saline to homogenize the tissue, and the homogenized slurry was sequentially diluted and seeded onto plates. This process was repeated twice for each mouse. The bacterial load on the mouse lung tissue was counted, and the tests were summarized as follows (see Table 7).

[0479] [Table 6]

[0480] [Table 7]

[0481] Conclusion: Mouse thigh muscle infection models and mouse lung infection models demonstrated a significant inhibitory effect on infection in the body when the compound of the present invention was used in combination with meropenem or cefepime.

Claims

1. Formula (II) or (II') 【Chemistry 1】 [In the formula, B is boron.] T is either -O- or -S-. R １ It is -OH. R ２ and R ３ H is H. R ４ H, C １－３ alkyl group or C １－３ It is an alkoxy group. R ５ is H, F, Cl, Br, I, or C １－３ It is an alkoxy group. R ６ is H or -ORa. Alternatively, R ５ and R ６ These, together with the carbon atoms they link to, form a 5-6 member oxygen-containing nonaryl heterocycle. R ７ H, C １－３ alkyl group, -C(R ｂ ) ２ OC(=O)R ｃ or -C(R ｂ ) ２ OC (=O)OR ｃ And among them, C １－３ The alkyl groups are independently F, Cl, Br, I, -OH, and -OCH, with 1, 2, or 3 groups. ３ It may be substituted with substituents selected from the following. R ａ is a C1-3 alkyl group or 【Chemistry 2】 In particular, the C1-3 alkyl group has 1, 2, or 3 R ａ１ It may be replaced by this. Each R ｂ H or C are independent. １－３ It is an alkyl group. R ｃ H, C １－３ alkyl group, 【Transformation 3】 And among them, C １－３ The alkyl group consists of 1, 2, or 3 R ｃ１ It may be replaced by this. Each R ａ１ These are F, Cl, Br, I, and C independently. １－３ alkyl group, C １－３ The alkoxy group, 【Chemistry 4】 And among them, C １－３ The alkyl group may be substituted with one, two, or three R atoms. Each R ｃ１ These are F, Cl, Br, I, -OH, and C independently. １－３ alkyl group or C １－３ It is an alkoxy group. Each R is independently F, Cl, Br, or I. The compound indicated by or a pharmaceutically acceptable salt thereof.

2. The compounds are of the formula (II-1), (II'-1), (II-2), or (II'-2). 【Transformation 5】 [In the formula, R １ , R ２ , R ３ , R ４ , R ５ , R ６ and R ７ This is as defined in claim 1. Having the structure shown, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

3. R4 is H, -CH3 or -OCH2CH3, and / or R5 is H, F, Cl, or -OCH3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

4. Each R ａ１ These are F, Cl, Br, I, and -OCH independently. ３ , 【Transformation 6】 That is, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

5. R ａ is, -CH ３ ien-CH ２ CH ３ , 【Transformation 7】 And the above-CH ３ ien-CH ２ CH ３ , 【Transformation 8】 Each of these consists of 1, 2, or 3 R components, each independently. ａ１ It may be replaced by The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

6. Ra is -CH3, 【Chemistry 9】 That is, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

7. R ６ is H, -OCH ３ , -OCH ２ CH ３ , 【Chemistry 10】 That is, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

8. constituent units 【Chemistry 11】 but, 【Chemistry 12】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

9. Each R ｂ H is independently and / or Each R ｃ１ It is independent of -OCH ３ That is, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

10. R c is H, -CH3, -CH2CH3, 【Chemistry 13】 In particular, the -CH3, -CH2CH3 and 【Chemistry 14】 Each of these may be independently substituted by one, two, or three R c1s. The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

11. R c is H, -CH3, -CH2CH3, 【Chemistry 15】 That is, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. R ７ H, 【Chemistry 16】 The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

13. The compound is of formula (I) or (I') 【Chemistry 17】 [In the formula, T, R １ , R ２ , R ３ , R ４ , R ５ and R ６ This is as defined in claim 1. Having the structure shown, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

14. The compound is of formula (I-1), (I'-1), (I-2), or (I'-2) [Chemistry 18] [In the formula, R1, R2, R3, R4, R5, and R6 are as defined in claim 1.] Having the structure shown, The compound according to claim 1 or a pharmaceutically acceptable salt thereof.

15. The compound represented by the following formula or a pharmaceutically acceptable salt thereof. 【Chemistry 19】 【Chemistry 20】 【Chemistry 21】

16. The compound represented by the following formula. 【Chemistry 22】 【Chemistry 23】 【Chemistry 24】 【Chemistry 25】 【Chemistry 26】

17. A drug composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof, a β-lactam bacteriostatic agent, and a pharmaceutically acceptable carrier.

18. The drug composition according to claim 17, wherein the β-lactam bacteriostatic agent is penicillins, cephalosporins, cephamycins, oxacephems, carbapenems, or monobactams.

19. The drug composition according to claim 17, wherein the β-lactam bacteriostatic agent is amoxicillin, piperacillin, ticarcillin, azurocillin, mezlocillin, cefazolin, cefradin, cephalothin, cefuroxime, cefaclor, cefotiam, cefprodil, cefotaxime, ceftriaxone, ceftazidime, cefoperazone, ceftizoxime, cefmenoxime, cefozidime, cefpodoximeproxetil, cefixime, ceftibuten, cefpirom, cefepime, cefoxitin, cefmetazole, panipenem, aztreonam, carmonam, cefoxitin, cefmetazole, latamoxef, flomoxef, imipenem, meropenem, ceftolozane, or cefiderocol.

20. A β-lactamase inhibitor drug comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.

21. A therapeutic agent for bacterial infection-related diseases comprising a compound according to any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof.

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