Fused ring derivatives containing 1,4-oxazepane

Abstract

To provide a series of fused ring derivatives containing 1,4-oxazepane, and a preparation method therefor.SOLUTION: Specifically, the present disclosure relates to a compound represented by formula (II) and a pharmaceutically acceptable salt thereof.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This application claims priority from: CN202110164857.7, February 5, 2021; CN202111138395.8, September 27, 2021.

[0002] The present invention relates to a series of fused ring derivatives containing 1,4-oxazepane and a method for preparing the same, and more particularly to a compound represented by formula (II) and a pharmaceutically acceptable salt thereof. [Background technology]

[0003] Dipeptidyl peptidase 1 (DPP1), also known as cathepsin C, is highly expressed in tissues such as the lungs, kidneys, liver, and spleen. DPP1 is a lysosomal cysteine ​​protease. It is a tetramer composed of four identical subunits, each consisting of a heavy chain, a light chain, and an exclusivity domain (Turk, D. et al. EMBO J. 2001, 20, 6570-6582). The primary physiological role of DPP1 is to activate pro-inflammatory neutrophil serine proteases (NSPs, including neutrophil elastase, proteinase 3, and cathepsin G) in the bone marrow by cleaving an N-terminal dipeptide. NSPs are closely related to inflammatory regulation, can activate various cytokines, and play an important role in the elimination of pathogenic microorganisms. Research has shown that the airways of patients with diseases such as chronic obstructive pulmonary disease (COPD) or bronchiectasis exhibit a massive, persistent inflammatory response and excessive activation of NSPs, which leads to the breakdown of lung elastin and other proteins, further damaging lung tissue and destroying bronchial wall tissue (Christine TN Pham, Nat. Rev. Immunol. 2006, 6, 541-550). DPP1 inhibitors can inhibit the inflammatory response and airway damage caused by neutrophils in the airways by fundamentally inhibiting the activation of pro-inflammatory neutrophil proteases.

[0004] Currently, there are no commercially available DPP1 inhibitors. The most rapidly progressing drug is brensocatib (INS1007, also known as AZD7986). Its Phase II clinical trial for bronchiectasis achieved its primary endpoint, and Phase III clinical trials are currently underway. Furthermore, AZD7986 is currently undergoing Phase II clinical trials for the treatment of chronic obstructive pulmonary disease. Therefore, the development of DPP1 inhibitors offers broad market prospects. Summary of the Invention

[0005] The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof:

[0006] [ka]

[0007] however, Z is selected from N and C;

[0008] Structural Unit [ka] wherein the structural unit is selected from

[0009] [ka] is selected from

[0010] [ka]

[0011] are each independently selected from a single bond and a double bond, [ka] is selected from a double bond, then R2 is absent;

[0012] Each T is independently selected from N and CR3;

[0013] Each R1 is independently H, F, Cl, Br, I, -OH, -NH2, -CN, or C 1-3 alkyl, wherein said C 1-3 Alkyl can be one, two or three R a is optionally replaced by

[0014] R2 is H, F, Cl, Br, I, =O, -OH, -NH2, -CN, C 1-3 alkyl and 5- to 6-membered heterocycloalkyl, wherein said C 1-3 Alkyl and The 5- to 6-membered heterocycloalkyl may each independently be one, two, or three R b is optionally replaced by

[0015] R3 is H, F, Cl, Br, I, -OH, -NH2, -CN and C 1-3 alkyl, wherein said C 1-3 Alkyl can be one, two or three R c is optionally replaced by

[0016] R4 is H, F, Cl, Br, I, -OH, -NH2, -CN and C 1-3 alkyl, wherein said C 1-3 Alkyl can be one, two or three R d is optionally replaced by

[0017] R5 is H, F, Cl, Br, I, -OH, -NH2, -CN and C 1-3 alkyl, wherein said C 1-3 Alkyl can be one, two or three R e is optionally replaced by

[0018] R6 is H, F, Cl, Br, I, -OH, -NH2, -CN and C 1-3 alkyl, wherein said C 1-3 Alkyl can be one, two or three R f is optionally replaced by

[0019] R a are each independently selected from F, Cl, Br, I, ═O, —OH, —NH and —CN;

[0020] R b are each independently F, Cl, Br, I, =O, -OH, -NH2, -CN and C 1-3 alkyl,

[0021] R c are each independently selected from F, Cl, Br, I, ═O, —OH, —NH and —CN;

[0022] R d are each independently selected from F, Cl, Br, I, ═O, —OH, —NH and —CN;

[0023] R e are each independently selected from F, Cl, Br, I, ═O, —OH, —NH and —CN;

[0024] R f are each independently selected from F, Cl, Br, I, ═O, —OH, —NH and —CN;

[0025] n is selected from 1, 2, 3 and 4;

[0026] The 5- to 6-membered heterocycloalkyl contains 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S-, and -N-.

[0027] The present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.

[0028] [ka]

[0029] however, [ka] is selected from a single bond and a double bond;

[0030] Structural Unit [ka] is selected from

[0031] T is selected from N and CR3;

[0032] R1 is H, F, Cl, Br, I, -OH, -NH2, -CN and C 1-3 alkyl, wherein said C 1-3 Alkyl can be one, two, or three R a is optionally replaced by

[0033] R2 is H and C 1-3 alkyl, wherein said C 1-3 Alkyl can be one, two or three R b is optionally replaced by

[0034] R3 is H and C 1-3 alkyl, wherein said C 1-3 Alkyl can be one, two or three R c is optionally replaced by

[0035] R4 is H and C 1-3 alkyl, wherein said C 1-3 Alkyl can be one, two or three R d is optionally replaced by

[0036] R5 is H and C 1-3 alkyl, wherein said C 1-3 Alkyl can be one, two or three R e is optionally replaced by

[0037] R a are each independently selected from F, Cl, Br, I, ═O, —OH, —NH and —CN;

[0038] R b are each independently selected from F, Cl, Br, I, ═O, —OH, —NH and —CN;

[0039] R c are each independently selected from F, Cl, Br, I, ═O, —OH, —NH and —CN;

[0040] R d are each independently selected from F, Cl, Br, I, ═O, —OH, —NH and —CN;

[0041] R e are each independently selected from F, Cl, Br, I, ═O, —OH, —NH and —CN;

[0042] n is selected from 1, 2, 3 and 4.

[0043] In some embodiments of the invention, the compound has a structure according to formula (II').

[0044] [ka]

[0045] However, the structural unit [ka] , Z, R1, R2, R6 and n are as defined herein;

[0046] Carbon atoms marked with "*" and "#" are chiral carbon atoms and exist in the form of either (R) or (S) single enantiomers or in a form enriched in one enantiomer.

[0047] In some embodiments of the invention, the compound has a structure according to formula (I').

[0048] [ka]

[0049] However, the structural unit [ka] , R1, R2 and n are as defined herein;

[0050] Carbon atoms marked with "*" and "#" are chiral carbon atoms and exist in the form of either (R) or (S) single enantiomers or in a form enriched in one enantiomer.

[0051] In some embodiments of the present invention, the R a , R c , R d and R e are each independently selected from F, Cl and Br, and other variables are as defined herein.

[0052] In some embodiments of the present invention, the R b is selected from F, Cl, Br and -CH3, and other variables are as defined herein.

[0053] In some embodiments of the present invention, R1 is selected from H, F, Cl, and -CH3, and other variables are as defined herein.

[0054] In some embodiments of the present invention, R1 is selected from H and F, and other variables are as defined herein.

[0055] In some embodiments of the present invention, R2 is H, -CH3, [ka] wherein said -CH3, [ka] each independently represents 1, 2 or 3 R b is optionally replaced by R b and other variables are as defined in the present invention.

[0056] In some embodiments of the present invention, R2 is H, -CH3, [ka]

[0057] and the other variables are as defined herein.

[0058] In some embodiments of the present invention, R2 is selected from H and -CH3, and other variables are as defined herein.

[0059] In some embodiments of the present invention, R3 is selected from H, F, Cl, and Br, and other variables are as defined herein. In some embodiments of the present invention, R3 is selected from H, and other variables are as defined herein.

[0060] In some embodiments of the present invention, R4 is selected from H, and other variables are as defined herein.

[0061] In some embodiments of the present invention, R5 is selected from H and -CH3, and other variables are as defined herein.

[0062] In some embodiments of the present invention, R6 is selected from H, F, Cl, and Br, and other variables are as defined herein.

[0063] In some embodiments of the present invention, the structural unit [ka] wherein R2, R3, R4, R5 and R6 and other variables are as defined herein.

[0064] In some embodiments of the present invention, the structural unit [ka] wherein R2, R3, R4, R5 and R6 and other variables are as defined herein.

[0065] In some embodiments of the present invention, the structural unit [ka] and the other variables are as defined herein.

[0066] In some embodiments of the present invention, the compound has a structure represented by formula (II-1).

[0067] [ka]

[0068] However, the structural unit [ka] , R1, R2, R6 and n are as defined in the present invention.

[0069] In some embodiments of the present invention, the compound has a structure represented by formula (II'-1).

[0070] [ka]

[0071] However, the structural unit [ka] , R1, R2, R6 and n are as defined herein;

[0072] Carbon atoms marked with "*" and "#" are chiral carbon atoms and exist in the form of either (R) or (S) single enantiomers or in a form enriched in one enantiomer.

[0073] In some embodiments of the present invention, the compound is a compound of formula (I) or a pharmaceutically acceptable salt thereof.

[0074] [ka]

[0075] however, Structural Unit [ka] is selected from [ka] are each independently selected from a single bond and a double bond, [ka] is selected from a double bond, then R2 is absent; T, R1, R2, R4, R5 and n are as defined in the present invention.

[0076] In some embodiments of the present invention, the compound has the structure represented by (I-1), (I-2), or (I-3).

[0077] [ka]

[0078] wherein T, R1, R2, R4, R5 and n are as defined in the present invention.

[0079] In some embodiments of the invention, the compound has a structure represented by formula (I-1A), (I-1B), (I-2A), (I-2B), or (I-3A).

[0080] [ka]

[0081] wherein T, R1, R2, R4 and R5 are as defined in the present invention.

[0082] In some embodiments of the present invention, the compound has the formula (I'-1A), (I'-1 B), (I'-2A), (I'-2B) or (I'-3A).

[0083] [ka]

[0084] wherein T, R1, R2, R4 and R5 are as defined herein;

[0085] Carbon atoms marked with "*" and "#" are chiral carbon atoms and exist in the form of either (R) or (S) single enantiomers or in a form enriched in one enantiomer.

[0086] In some embodiments of the present invention, the compound has a structure represented by formula (I'-1A-1), (I'-1B-1), (I'-2A-1), (I'-2B-1), or (I'-3A-1).

[0087] [ka]

[0088] [ka]

[0089] wherein T, R1, R2, R4 and R5 are as defined herein;

[0090] Further embodiments of the present invention are formed by any combination of the above variables.

[0091] The present invention further provides a compound of the formula: or a pharmaceutically acceptable salt thereof:

[0092] [ka]

[0093] [ka]

[0094] The present invention further provides a compound of the formula: or a pharmaceutically acceptable salt thereof:

[0095] [ka]

[0096] [ka]

[0097] [ka]

[0098] [ka] [Effects of the Invention]

[0099] The compounds provided by the present invention have significant inhibitory activity against DPP1 at the enzyme and cellular levels, high oral exposure in rats and mice, favorable pharmacokinetic properties, and strong distribution in the bone marrow, and significantly inhibit the activity of neutrophil elastase in rat bone marrow. It is possible.

[0100] Definitions and Explanations

[0101] Unless otherwise explained, the following terms and phrases used herein shall have the following meanings: Certain terms and phrases, unless otherwise defined, should not be considered indefinite or unclear and should be understood according to their ordinary meaning. When trade names are mentioned herein, it is intended to refer to the corresponding trade name or its active ingredient.

[0102] As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problem or complication, and are commensurate with a reasonable benefit / risk ratio.

[0103] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention prepared from a compound having certain substituents found in the present invention and a relatively non-toxic acid or base. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting such a compound with a sufficient amount of base in a pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting such a compound with a sufficient amount of acid in a pure solution or in a suitable inert solvent. Illustrative examples of pharmaceutically acceptable acid addition salts include inorganic and organic acid salts, as well as salts of amino acids (e.g., arginine) and organic acids such as glucuronic acid, such as inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like; and organic acids including, for example, 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, methanesulfonic acid, and the like. Certain compounds of the present invention contain both basic and acidic functional groups and can therefore be converted into either base or acid addition salts.

[0104] The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound that contains an acid or base group by conventional methods. Generally, such salts are prepared by reacting the free acid or free base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent, or a mixture of both.

[0105] The compounds of the present invention can exist in particular geometric or stereoisomeric forms. All such compounds contemplated by the present invention include cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as enantiomer- or diastereomer-enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All of these isomers and mixtures thereof are within the scope of the present invention.

[0106] Unless otherwise specified, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of each other.

[0107] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" refer to This is because the double bond or the single bond of the carbon atoms forming the ring cannot rotate freely.

[0108] Unless otherwise stated, the term "diastereomer" refers to stereoisomers whose molecules have two or more centers of chirality and whose molecules are not mirror images of each other.

[0109] Unless otherwise stated, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic.

[0110] [ka]

[0111] The compounds of the present invention may exist specifically. Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and are rapidly interconvertible. If tautomers are possible (e.g., in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enol isomerization. Valence tautomers include interconversions via recombination of some bond electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0112] Unless otherwise stated, the terms "enriched in one isomer," "enriched in an isomer," "enriched in one enantiomer," or "enantiomer-enriched" refer to less than 100% isomer or enantiomer content, and the content of that isomer or enantiomer is 60% or more, or 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.

[0113] Unless otherwise stated, the terms "isomeric excess" or "enantiomeric 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% and the other isomer or enantiomer is present in 10%, the isomeric or enantiomeric excess (ee) is 80%.

[0114] Optically active (R)- and (S)-isomers, as well as D- and L-isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. Single enantiomers of certain compounds of the invention can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting diastereomeric mixture is separated and the auxiliary is cleaved to provide the pure desired enantiomer. Alternatively, if the molecule contains a basic (e.g., amino) or acidic (e.g., carboxyl) functional group, a diastereomeric salt can be formed with a suitable optically active acid or base, followed by conventional methods known in the art. The diastereomers are separated using a chiral stationary phase, optionally in combination with chemical derivatization (e.g., carbamates from amines).

[0115] The compounds of the present invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute these compounds. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I), C-14( 14 The compounds of the present invention can be labeled with a radioactive isotope such as CI (C). Alternatively, for example, deuterium can be substituted for hydrogen to form a deuterated drug, where the bond formed between deuterium and carbon is stronger than the bond formed between normal hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have the advantages of reduced toxic side effects, increased drug stability, enhanced efficacy, and extended biological half-life. Conversion of the isotopic composition of the compounds of the present invention, whether radioactive or not, is included within the scope of the present invention.

[0116] The terms "optionally" and "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur.

[0117] The term "substituted" means that any one or more hydrogen atoms at a particular atom are replaced by a substituent, and the substituent may include variants of deuterium and hydrogen, so long as the valence of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur in aromatic groups. The term "optionally substituted" means substituted or unsubstituted, and unless otherwise specified, the type and number of substituents are chemically feasible and optional.

[0118] When any variable (e.g., R) occurs more than one time in any composition or structure of a compound, its definition is independent at each occurrence. Thus, for example, if a group is substituted with 0 to 2 R, then said group may optionally be substituted with up to 2 R, and each occurrence of R is independently optional. Also, combinations of substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0119] When the number of linking groups is 0, for example, -(CRR)0- means that the linking group is a single bond.

[0120] When one of the variables is a single bond, it means that the two groups to which it is attached are directly bonded. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0121] When a substituent is empty, it means that the substituent is not present, for example, when X in AX is empty, it means that the structure is actually A. When a recited substituent does not indicate through which atom it is bonded to the substituted group, such substituent can be bonded through any atom thereof, for example, pyridinyl as a substituent may be bonded to the substituted group through any carbon atom of the pyridine ring.

[0122] When the listed linking group does not indicate the direction of the link, the direction of the link is arbitrary, for example, [ka]

[0123] In the formula, the linking group L is -MW-, and in this case, -MW- connects ring A and ring B in the same direction as the reading order from left to right. [ka]

[0124] and by concatenating ring A and ring B in the reverse order of reading from left to right, [ka]

[0125] Combinations of the above linking groups, substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0126] 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 via a chemical bond. If the bonding mode of the chemical bond is delocalized and there is an H atom at the bondable site, when the chemical bond is bonded, the number of H atoms at the site is reduced to the group with the corresponding valence according to the number of bonded chemical bonds. The chemical bond that bonds the site to another group is:

[0127] [ka]

[0128] For example, the straight solid bond in -OCH3 represents a bond to another group via the oxygen atom within that group, [ka] The straight-dashed bond represents a bond between the nitrogen atoms in the group and another group, [ka] The wavy lines indicate that the phenyl is bonded to another group via the 1st and 2nd carbon atoms of the phenyl.

[0129] [ka]

[0130] indicates that any available bonding site of the piperidinyl can be bonded to another group via one chemical bond, and at least [ka] Even if the H atom is drawn as -N-, [ka] for [ka] When one chemical bond is bonded, the H at that site decreases by one to form the corresponding monovalent piperidinyl.

[0131] When a chemical bond of a substituent crosses the chemical bond between two atoms on a connecting ring, it means that the substituent can form a bond with any atom on the ring. If the atom bonded to a substituent is not specified, it means that the substituent may be bonded to any atom, and if the atom bonded to a substituent is a bicyclic or tricyclic ring system, it means that the substituent may be bonded to any atom of any ring within that system. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. For example, the structural unit [ka] or [ka] means that the substitution can occur at any position on the cyclohexyl or cyclopentyl.

[0132] Unless otherwise stated, [ka] The term refers to aromatic rings, including benzene rings and 5- to 6-membered heteroaryl rings, e.g., the ring [ka] teeth, [ka] Including, but not limited to, the following:

[0133] Unless otherwise stated, in the present invention, the terms "5- to 6-membered heteroaryl ring" and "5- to 6-membered heteroaryl" can be used interchangeably, and the term "5- to 6-membered heteroaryl" refers to a monocyclic group having a conjugated π-electron system consisting of 5 to 6 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S(═O)). p and p is 1 or 2). The 5- to 6-membered heteroaryl can be attached to the remainder of the molecule via a heteroatom or a carbon atom. The 5- to 6-membered heteroaryl includes 5- and 6-membered heteroaryls. Illustrative examples of the 5- to 6-membered heteroaryl include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, etc.), triazolyl (including 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl, etc.), and 5-triazolyl (including 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl). thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, etc.), furanyl (including 2-furanyl and 3-furanyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, etc.), pyrazinyl, or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).

[0134] Unless otherwise stated, "C 1-3 The term "alkyl" is used to refer to a straight or branched chain saturated hydrocarbon group of 1 to 3 carbon atoms. 1-3 C for alkyl 1-2 and C 2-3alkyl, which may be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). 1-3 Illustrative examples of alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.

[0135] Unless otherwise specified, the number of atoms in a ring is generally defined as the number of ring members, e.g., a "5- or 6-membered ring" refers to a "ring" of 5 or 6 atoms arranged around it.

[0136] Unless otherwise stated, the term "5- to 6-membered heterocycloalkyl," by itself or in combination with other terms, means a saturated cyclic group consisting of 5 to 6 ring atoms, each of which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C(=O), NO, and S(=O)). p、 (p is 1 or 2). It includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spiro rings, fused rings, and bridged rings. Also, with respect to the "5- to 6-membered heterocycloalkyl," a heteroatom can occupy the position connecting the heterocycloalkyl to the rest of the molecule. The 5- to 6-membered heterocycloalkyl includes 5- and 6-membered heterocycloalkyl. Illustrative examples of 5- to 6-membered heterocycloalkyl are pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridinyl, and the like. The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate, and the like; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like; and the like.

[0137] Unless otherwise stated, C n-n+m or C n -C n+m includes any one specific embodiment of n to n+m carbons, for example, C 1-12 are C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 and any one of the ranges 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 Similarly, n- to n+m-membered rings indicate that the number of atoms in the ring is n to n+m, and for example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any one range of n to n+m, and for example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, and a 6- to 10-membered ring, etc.

[0138] The term "protecting group" includes, but is not limited to, an "amino-protecting group," a "hydroxy-protecting group," or a "mercapto-protecting group." The term "amino-protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen. Representative amino acid protecting groups include, but are not limited to, formyl; acyl such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl such as benzyl (Bn), triphenylmethyl (Tr), 1,1-di-(4'-methoxyphenyl)methyl; silyl such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS). The term "hydroxyl-protecting group" refers to a protecting group suitable for preventing side reactions of hydroxyl. Representative hydroxyl protecting groups include, but are not limited to, alkyl such as methyl, ethyl, and tert-butyl; acyl such as alkanoyl (e.g., acetyl); arylmethyl such as benzyl (Bn), p-formyloxybenzyl (PMB), 9-fluorenylthyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS); and the like.

[0139] The compounds of the present invention can be prepared by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining with other chemical synthetic methods, and equivalent alternative methods known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

[0140] The structure of the compound of the present invention can be confirmed by conventional methods known to those skilled in the art. When the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the grown single crystal is collected by a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuKα radiation, and the scanning method is φ / ω scanning. After collecting the relevant data, the crystal structure can be analyzed by a direct method (Shelxs97) to confirm the absolute configuration.

[0141] The solvents used in the present invention can be obtained commercially.

[0142] The following abbreviations are used in the present invention: Alloc represents allyloxycarbonyl; SEM represents trimethylsilylethoxymethyl; OTs represents 4-toluenesulfonyloxy; OMs represents methanesulfonyloxy; Boc represents tert-butoxycarbonyl; DCM represents dichloromethane; DIEA represents N,N-diisopropylethylamine; MeI represents iodomethane; PE represents petroleum ether; EA represents ethyl acetate; THF represents tetrahydrofuran; EtOH represents ethanol; MeOH represents methanol; DMF represents N,N-dimethylformamide; Boc2O represents di-tert-butyl dicarbonate; NH4Cl represents ammonium chloride; T3 P represents propylphosphonic anhydride; Pd / C represents palladium / carbon catalyst; TMSN3 represents trimethylsilyl azide; NCS represents N-chlorosuccinimide; HBr represents hydrobromic acid; AcOH represents acetic acid; HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate; DBU represents 1,8-diazabicyclo[5.4.0]undec-7-ene; FA represents formic acid; ACN represents acetonitrile; TLC represents thin layer chromatography; HPLC represents high performance liquid chromatography; LCMS represents liquid chromatography mass spectrometry; and SFC represents supercritical fluid chromatography. DMSO represents dimethyl sulfoxide; DMSO-d6 represents deuterated dimethyl sulfoxide; CD3OD represents deuterated methanol; CDCl3 represents deuterated chloroform; DO represents deuterated water; Solutol represents polyethylene glycol (15)-hydroxystearate.

[0143] Compounds are named according to conventional naming principles in the art or using ChemDraw® software, commercially available compounds are named in the supplier's product catalogue. [Brief explanation of the drawings]

[0144] [Figure 1]1 shows the results of an in vivo efficacy test of the compound of the present invention on the activity of neutrophil elastase in rat bone marrow. DETAILED DESCRIPTION OF THE INVENTION

[0145] The present invention will be described in detail below with reference to examples, but these examples do not limit the present invention in any way. The compounds of the present invention can be produced by various synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining with other chemical synthesis methods, and equivalent alternative methods known to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention. Various changes and modifications to the specific embodiments of the present invention will be apparent to those skilled in the art without departing from the spirit and scope of the present invention.

[0146] Intermediate A Synthesis Route: [ka]

[0147] Step 1 Intermediate A-1 (12.5 g, 31.95 mmol) was dissolved in DMF (50 mL), and DIEA (6.19 g, 47.93 mmol) and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (10.26 g, 31.95 mmol) were added sequentially. The mixture was stirred at 25 °C for 30 minutes. After that, aqueous ammonia (12 M, 4.79 mL, 57.52 mmol) was added and the mixture was stirred at 25 °C for 12 hours. After the reaction was completed, water (50 mL) was added to the reaction solution, and the mixture was stirred for 15 minutes. The mixture was filtered, and the cake was collected and dried to obtain Intermediate A-2, which was used directly in the next step. MS-ESI calculated value [M + Na] + 413, measured value 413.

[0148] Step 2 Intermediate A-2 (20.0 g, 50.11 mmol) was dissolved in dichloromethane (200 mL), and methyl N-(triethylammoniosulfonyl)carbamate (29.26 mg, 122.77 mmol) was added. The mixture was stirred at 25°C for 12 hours. After the reaction was completed, the reaction solution was extracted with water (200 mL). The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 15 / 1 to 1 / 1, V / V) to obtain Intermediate A-3. MS-ESI calculated values ​​[M+H] + 373, actual value 373.

[0149] Step 3 Intermediate A-3 (9.6 g, 25.79 mmol) was dissolved in THF (100 mL), methanesulfonic acid (18.59 g, 193.44 mmol) was added, and the mixture was stirred at 25 °C for 12 hours. After the reaction was completed, the mixture was adjusted to pH > 8 with saturated sodium bicarbonate solution and extracted with ethyl acetate (500 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Intermediate A-4, which was used directly in the next step of the reaction. MS-ESI calculated values ​​[M + H] + 273, actual value 273.

[0150] Step 4 A solution of T3P in ethyl acetate (14.03 g, 22.05 mmol) was added to DMF (100 mL), and intermediate A-4 (4.0 g, 14.7 mmol), intermediate A-5 (3.79 g, 15.44 mmol), and triethylamine (6.69 g, 66.2 mmol) were added sequentially and stirred at 25 °C for 12 hours. After completion of the reaction, saturated brine (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (250 mL × 3). The combined organic phases were washed with saturated brine (500 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1 to 0 / 1, V / V) to obtain intermediate A. 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.0 Hz, 2H), 7.12-6.93 (m, 3H), 5.20-5.12 (m, 1H), 4.25-3.95 (m, 3H), 3.82-3.68 (m, 0.5H), 3.60-3.22 (m, 3H), 3.12-2.90 (m, 2.5H), 2.12-1.82 (m, 2H), 1.48 (s, 9H). MS-ESI calculated value [M+Na] + 522, actual value 522.

[0151] Intermediate B Synthesis Route: [ka]

[0152] Intermediate A (600 mg, 1200 μmol), potassium acetate (354 mg, 3600 μmol), and bis(pinacolato)diboron (397 mg, 1560 μmol) were added to dimethyl sulfoxide (6 mL), followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (49 mg, 60 μmol). The reaction solution was heated to 85 °C under nitrogen gas protection and reacted for 5 hours. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1 to 0 / 1, v / v) to obtain Intermediate B. 1 H NMR (400 MHz, CDCl3) δ 7.82 (d, J = 7.8 Hz, 2H), 7.40-7.25 (m, 2H), 7.08-6.98 (m, 1H), 5.25-5.05 (m, 1H), 4.25-3.98 (m, 3H), 3.78-3.68 (m, 0.5H), 3.52-2.96 (m, 5.5H), 2.15-1.80 (m, 2H), 1.47 (s, 9H), 1.25 (s, 12H). MS-ESI calculated value [M+H] +500, actual measured value 500.

[0153] Intermediate C Synthesis Route: [ka]

[0154] Step 1 Intermediate C-1a (15.0 g, 81.42 mmol) was dissolved in tetrahydrofuran (30 mL) and n-butyllithium (2.5 M, 40.71 mL, 102.8 mmol) was slowly added dropwise at -78 °C. The reaction was allowed to proceed for 30 minutes. Intermediate C-1b (21.81 g, 81.42 mmol) dissolved in tetrahydrofuran (150 mL) was slowly added at -78 °C and the reaction was allowed to proceed for 12 hours at 25 °C. The reaction solution was quenched with saturated ammonium chloride solution (300 mL) and extracted with ethyl acetate (300 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain intermediate C-1c. MS-ESI calculated values ​​[M+H] + 371 and 373, actual measurements 371 and 373.

[0155] Step 2 Intermediate C-1c (24.85 g, 66.94 mmol) was dissolved in acetonitrile (200 mL), and hydrochloric acid (0.2 M, 840 mL, 167.34 mmol) was slowly added. The reaction was allowed to proceed at 25 °C for 12 hours. The reaction solution was washed with methyl tert-butyl ether (200 mL), and the pH of the aqueous phase was adjusted to 8 with saturated aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate (1000 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate C-1d, which was used directly in the next step. MS-ESI calculated values ​​[M+H] + 276 and 278, actual measurements 276 and 278.

[0156] Step 3 Hydrochloric acid (3M, 119 mL, 356 mmol) was slowly added to intermediate C-1d (6.56 g, 23.76 mmol) and the mixture was allowed to react at 60 °C for 12 hours. The reaction solution was cooled to room temperature, the pH of the solution was adjusted to 7 with aqueous sodium hydroxide, and the mixture was washed three times with water. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give intermediate C-1e, which was used directly in the next step. MS-ESI calculated values ​​[M+H] + 262 and 264, actual measurements 262 and 264.

[0157] Step 4 Intermediate C-1e (3.38 g, 12.9 mmol) was dissolved in dioxane (50 mL) and water (100 mL), and sodium carbonate (1.50 g, 14.9 mmol) and BocO (3.27 g, 14.96 mmol) were added. The mixture was allowed to react at 25 °C for 4 hours. The pH of the reaction mixture was adjusted to 4-5 with saturated aqueous citric acid, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give intermediate C-1f, which was used directly in the next step. MS-ESI calculated value [M -56 + 1]. + 306 and 308, actual measurements 306 and 308.

[0158] Step 5 Intermediate C-1f (2.90 g, 8.01 mmol) was dissolved in DMF (50 mL), N-methylmorpholine (1.21 g, 12.01 mmol) and O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (2.57 g, 8.01 mmol) were added, and the mixture was stirred at 25 °C for 30 min. An aqueous ammonium chloride solution (0.35 M, 45.75 mL, 16.01 mmol) was then added, and the mixture was stirred at 25 °C for 12 h. Water (160 mL) was added to the reaction solution, filtered, and the cake was collected and dried to obtain intermediate C-1, which was used directly in the next step. MS-ESI calculated value [M -56 + 1]. + 305 and 307, actual measurements 305 and 307.

[0159] Step 6 Intermediate C-1 (1810 mg, 5010 μmol) was dissolved in tetrahydrofuran (25 mL), methanesulfonic acid (4820 mg, 50100 μmol) was added, and the mixture was allowed to react at 30° C. for 15 hours. The reaction solution was added to saturated sodium bicarbonate solution (25 mL), the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated by silica gel column chromatography (dichloromethane / methanol, 10 / 1 to 5 / 1, V / V) to obtain Intermediate C-2. 1 H NMR (400 MHz, CD3OD) δ 7.33-7.27 (m, 2H), 7.24-7.18 (m, 1H), 3.58 (t, J = 6.8 Hz, 1H), 3.03-2.95 (m, 1H), 2.92-2.83 (m, 1H). MS-ESI calculated value [M+H] + 261 and 263, actual measurements 261 and 263.

[0160] Step 7 A 50% solution of T3P in ethyl acetate (1870 mg, 2940 μmol) was added to DMF (10 mL), followed by the addition of Intermediate C-2 (591 mg, 2260 μmol), Intermediate A-5 (610 mg, 2490 μmol), and triethylamine (916 mg, 9050 μmol), and the mixture was allowed to react at 25°C for 4 hours. The reaction solution was added to saturated brine (50 mL), extracted with ethyl acetate (50 mL x 3), and the combined organic phases were washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated by silica gel column chromatography (dichloromethane / methanol, 100 / 1 to 10 / 1, V / V) to obtain Intermediate C. 1H NMR (400 MHz, CDCl3) δ 7.26-7.19 (m, 2H), 7.16-7.10 (m, 1H), 4.70-4.55 (m, 1H), 4.25-3.94 (m, 3H), 3.88-3.75 (m, 0.5H), 3.57-3.28 (m, 2H), 3.27-2.95 (m, 3.5H), 2.07-1.78 (m, 2H), 1.46 (s, 9H). MS-ESI calculated value [M+Na] + 510 and 512, actual measurements 510 and 512.

[0161] Intermediate D Synthesis Route: [ka]

[0162] Intermediate C (52 mg, 106 μmol) was dissolved in dichloromethane (5 mL), and methyl N-(triethylammoniosulfonyl)carbamate (76 mg, 319 μmol) was added, followed by a reaction at 25° C. for 18 hours. The reaction solution was added to water (50 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 1 / 3, V / V) to obtain Intermediate D. 1 H NMR (400 MHz, CDCl3) δ 7.34-7.25 (m, 2H), 7.22-7.14 (m, 1H), 5.42-5.10 (m, 1H), 4.23-3.96 (m, 3H), 3.83-3.70 (m, 0.5H), 3.59-2.96 (m, 5.5H), 2.03-1.72 (m, 2H), 1.46 (s, 9H). MS-ESI calculated value [M+Na] + 492 and 494, actual measurements 492 and 494.

[0163] Intermediate E Synthesis Route: [ka]

[0164] Intermediate E-1 (300 mg, 1410 μmol), potassium phosphate (600 mg, 2830 μmol), and bis(pinacolato)diboron (539 mg, 2120 μmol) were added to 1,4-dioxane (8 mL), followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (104 mg, 141 μmol). The reaction solution was heated to 110 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 3 / 2, v / v) to obtain intermediate E. 1 H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 4.31 (s, 3H), 1.39 (s, 12H). MS-ESI calculated value [M+H] + 260, actual measured value 260.

[0165] Intermediate F Synthesis Route: [ka]

[0166] Intermediate F-1 (300 mg, 1410 μmol), potassium acetate (277 mg, 2830 μmol), and bis(pinacolato)diboron (539 mg, 2120 μmol) were added to 1,4-dioxane (8 mL), followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (207 mg, 282 μmol). The reaction solution was heated to 110 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 10 / 3, v / v) to obtain intermediate F. 1H NMR (400 MHz, CDCl3) δ 8.06-8.02 (m, 2H), 7.83-7.77 (m, 1H), 4.33 (s, 3H), 1.40 (s, 12H). MS-ESI calculated value [M+H] + 260, actual measured value 260.

[0167] intermediate G Synthesis Route: [ka]

[0168] Step 1 Intermediate G-1 (20.0 g, 139.3 mmol) was dissolved in THF (100 mL), and carbonyldiimidazole (24.85 g, 153.23 mmol) was added. The mixture was reacted at 80 °C for 1 hour. The pH of the reaction solution was adjusted to 6 with 1 M diluted hydrochloric acid, filtered, and the cake was collected and dried to obtain intermediate G-2, which was used directly in the next step of the reaction. MS-ESI calculated values ​​[M+H] + 170, actual measured value 170.

[0169] Step 2 Intermediate G-2 (25.3 g, 149.2 mmol) and cesium carbonate (97.2 g, 298.41 mmol) were added to DMF (100 mL). After stirring at 25 °C for 20 minutes, iodomethane (25.4 g, 179.05 mmol) was added, and the reaction was continued at 25 °C for 2 hours. Water (500 mL) was added to the reaction solution, filtered, and the cake was collected and dried to obtain intermediate G-3, which was used directly in the next step of the reaction. MS-ESI calculated [M+H] + 184, measured value 184.

[0170] Step 3 Intermediate G-3 (1800 mg, 9800 μmol), potassium acetate (2890 mg, 29410 μmol), and bis(pinacolato)diboron (4980 mg, 19610 μmol) were added to 1,4-dioxane (20 mL). Palladium acetate (132 mg, 588 μmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (280 mg, 588 μmol) were then added to the reaction solution. The reaction solution was heated to 80 °C under nitrogen gas protection and reacted for 3 hours. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1 to 3 / 1, v / v) to obtain intermediate G. 1 H NMR (400 MHz, CDCl3) δ 7.64 (d, J=8.0 Hz, 1H), 7.42 (s, 1H), 7.22 (d, J=8.0 Hz, 1H), 3.44 (s, 3H), 1.38 (s, 12H). MS-ESI calculated value [M+H] + 276, actual value 276.

[0171] Intermediate H Synthesis Route: [ka]

[0172] Intermediate H-1 (995 mg, 4400 μmol), potassium acetate (1300 mg, 13200 μmol), and bis(pinacolato)diboron (2240 ​​mg, 8800 μmol) were added to 1,4-dioxane (10 mL), followed by the addition of palladium acetate (60 mg, 264 μmol) and 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (126 mg, 264 μmol). The reaction solution was heated to 80 °C under nitrogen gas protection and reacted for 3 hours. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 1 / 1, v / v) to obtain intermediate H. 1H NMR (400 MHz, CDCl3) δ7.96-7.86 (m, 2H), 7.86-7.81 (m, 1H), 4.41-4.34 (s, 2H), 3.21 (s, 3H), 1.32 (s, 12H). MS-ESI calculated value [M+H] + 274, actual value 274.

[0173] Intermediate I Synthesis Route: [ka]

[0174] Step 1 Intermediate I-1 (50 mg, 254 μmol), I-2 (106 mg, 381 μmol), and potassium carbonate (87 mg, 634 μmol) were added to DMF (3 mL). The reaction solution was heated to 120 °C and reacted for 14 hours. The reaction solution was added to saturated brine (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by thin-layer chromatography (developing solvent: petroleum ether / ethyl acetate, 3 / 1, v / v) to obtain intermediates I-3 and I-4.

[0175] Intermediate I-3: 1 H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.63 (s, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.24 (d, J=8.5 Hz, 1H), 4.54-4.46 (m, 1H), 4.38-4.22 (m, 2H), 3.05-2.88 (m, 2H), 2.28-2.16 (m, 2H), 2.06-1.94 (m, 2H), 1.49 (s, 9H).

[0176] Intermediate I-4: 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.80 (s, 1H), 7.44 (d, J=8.8 Hz, 1H), 7.08 (d, J=8.8 Hz, 1H), 4.52-4.40 (m, 1H), 4.35-4.14 (m, 2H), 2.94-2.76 (m, 2H), 2.20-2.12 (m, 2H), 2.09-1.92 (m, 2H), 1.41 (m, 9H).

[0177] Step 2 Intermediate I-3 (50 mg, 131 μmol), potassium acetate (32 mg, 329 μmol), and bis(pinacolato)diboron (67 mg, 263 μmol) were added to 1,4-dioxane (3 mL), followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19 mg, 26 μmol). The reaction solution was heated to 110 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 100 / 1 to 4 / 1, v / v) to obtain intermediate I. 1 H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.94 (s, 1H), 7.74 (d, J=8.1 Hz, 1H), 7.57 (d, J=8.1 Hz, 1H), 4.74-4.61 (m, 1H), 4.42-4.25 (m, 2H), 3.05-2.90 (m, 2H), 2.33-2.18 (m, 2H), 2.04- 1.95 (m, 2H), 1.50 (s, 9H), 1.40 (s, 12H). MS-ESI calculated value [M-56+1] + 372, actual value 372.

[0178] Intermediate J Synthesis Route: [ka]

[0179] Intermediate I-4 (50 mg, 131 μmol), potassium acetate (32 mg, 329 μmol), and bis(pinacolato)diboron (67 mg, 263 μmol) were added to 1,4-dioxane (3 mL), followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (19 mg, 26 μmol). The reaction solution was heated to 110 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 100 / 1 to 4 / 1, v / v) to obtain intermediate J. 1 H NMR (400 MHz, CDCl3) δ 8.27 (s, 1H), 7.97-7.91 (m, 1H), 7.67-7.61 (m, 1H), 7.49-7.42 (m, 1H), 4.69-4.55 (m, 1H), 4.42-4.22 (m, 2H), 3.04-2.86 (m, 2H), 2.32-2.23 (m, 2H), 2.11-2.07 (m, 2H), 1.50 (s, 9H), 1.28 (s, 12H). MS-ESI calculated value [M+H] + 428, actual value 428.

[0180] Intermediate K Synthesis Route: [ka]

[0181] Step 1 Intermediate I-3 (500 mg, 1310 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1540 mg, 13510 μmol) was added, and the mixture was allowed to react at 25° C. for 1 hour. The reaction solution was concentrated under reduced pressure to give a crude product containing intermediate K-1, which was used directly in the next step of the reaction. MS-ESI calculated values ​​[M+H] + 280 and 282, actual measurements 280 and 282.

[0182] Step 2 Intermediate K-1 (364 mg, 1300 μmol) was dissolved in tetrahydrofuran (10 mL), and an aqueous solution of formaldehyde (37%, 0.67 mL, 9090 μmol) was added. After stirring at 25°C for 30 minutes, sodium triacetoxyborohydride (550 mg, 2600 μmol) and acetic acid (117 mg, 1950 μmol) were added, and the mixture was stirred at 25°C for 2 hours. The reaction solution was added to saturated sodium bicarbonate solution (100 mL), and extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (dichloromethane / methanol). The mixture was separated using a solvent (ethanol, 20 / 1 to 10 / 1, V / V) to obtain intermediate K-2. 1 H NMR (400 MHz, CDCl3) δ 7.96 (s, 1H), 7.67 (s, 1H), 7.59 (d, J=8.5 Hz, 1H), 7.25 (d, J=8.5 Hz, 1H), 4.47-4.34 (m, 1H), 3.23-3.05 (m, 2H), 2.53-2.19 (m, 7H), 2.16-2.01 (m, 2H). MS-ESI calculated value [M+H] + 294 and 296, actual measurements 294 and 296.

[0183] Step 3 Intermediate K-2 (320 mg, 1090 μmol), potassium acetate (267 mg, 2720 μmol), and bis(pinacolato)diboron (414 mg, 1630 μmol) were added to 1,4-dioxane (3 mL), followed by the addition of [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (80 mg, 109 μmol). The reaction solution was heated to 110 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane / methanol, 10 / 1 to 20 / 3, V / V) to obtain intermediate K. 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.92 (s, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.58 (d, J=8.3 Hz, 1H), 4.80-4.71 (m, 1H), 3.46-3.36 (m, 2H), 2.90-2.76 (m, 2H), 2.62 (s, 3H), 2.52-2.28 (m, 4H), 1.39 (m, 12H). MS-ESI calculated value [M+H] + 342, actual value 342.

[0184] Intermediate L Synthesis Route: [ka]

[0185] Step 1 Intermediate I-1 (500 mg, 2.54 mmol) was dissolved in dimethyl sulfoxide (5 mL), potassium carbonate (491 mg, 3.55 mmol), and 2-iodopropane (518 mg, 3.05 mmol) were slowly added, and the mixture was allowed to react at 15 °C for 12 hours. The reaction solution was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, v / v) to obtain intermediate L-1. MS-ESI calculated values ​​[M+H] + 239 and 241, actual measurements 239 and 241.

[0186] Step 2 Intermediate L-1 (233 mg, 974 μmol), potassium acetate (191 mg, 1.95 mmol), and bis(pinacolato)diboron (371 mg, 1.46 mmol) were added to 1,4-dioxane (3 mL), and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (143 mg, 195 μmol) was added to the reaction solution. The reaction solution was heated to 110 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was concentrated under reduced pressure to obtain intermediate L, which was used directly in the next step. MS-ESI calculated values ​​[M+H] + 287, actual value 287.

[0187] Intermediate M Synthesis Route: [ka]

[0188] Step 1 Intermediate I-1 (500 mg, 2.54 mmol) and intermediate M-1 (686 mg, 3.81 mmol) were dissolved in DMF (5 mL), and potassium carbonate (879 mg, 6.34 mmol) and tetrabutylammonium iodide (94 mg, 254 μmol) were slowly added. The mixture was reacted at 120 °C for 14 hours under nitrogen gas protection. The reaction solution was extracted with water (20 mL × 3). The combined organic phase was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, v / v) to obtain intermediate M-2. 1 H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.68 (s, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.34 - 7.21 (m, 1H), 4.67 - 4.54 (m, 1H), 4.27 - 4.13 (m, 2H), 3.72 - 3.57 (m, 2H), 2.51 - 2.28 (m, 2H), 2.09 - 1.92 (m, 2H). MS-ESI calculated value [M+H] +281 and 283, actual measurements 281 and 283.

[0189] Step 2 Intermediate M-2 (237 mg, 843 μmol), potassium acetate (248 mg, 2.53 mmol), and bis(pinacolato)diboron (321.09 mg, 1.26 mmol) were added to 1,4-dioxane (3 mL), and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (62 mg, 84 μmol) was added to the reaction solution. The reaction solution was heated to 110 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was concentrated under reduced pressure to obtain intermediate M, which was used directly in the next step. MS-ESI calculated value [M+H] + 329, actual value 329.

[0190] Intermediate N Synthesis Route: [ka]

[0191] Intermediate N-1 (201 mg, 1.02 mmol), potassium acetate (298 mg, 3.04 mmol), and bis(pinacolato)diboron (385 mg, 1.52 mmol) were added to 1,4-dioxane (2 mL), and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (74 mg, 101 μmol) was added to the reaction solution. The reaction solution was heated to 90 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain intermediate N, which was used directly in the next step of the reaction. MS-ESI calculated values ​​[M+H] + 245, actual value 245.

[0192] Intermediate O Synthesis Route: [ka]

[0193] Intermediate O-1 (200 mg, 1.02 mmol), potassium acetate (297 mg, 3.03 mmol), and bis(pinacolato)diboron (385 mg, 1.52 mmol) were added to 1,4-dioxane (2 mL), and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (74 mg, 101 μmol) was added to the reaction solution. The reaction solution was heated to 90 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was extracted with ethyl acetate (10 mL × 3), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain intermediate O, which was used directly in the next step of the reaction. MS-ESI calculated values ​​[M+H] + 245, actual value 245.

[0194] Intermediate P Synthesis Route: [ka]

[0195] Step 1 Intermediate P-1 (500 mg, 2.34 mmol) was dissolved in acetonitrile (5 mL), potassium carbonate (516 mg, 3.74 mmol), and iodomethane (1.66 g, 3.05 mmol) were slowly added, and the mixture was allowed to react at 50 °C for 12 hours. The reaction solution was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, v / v) to obtain Intermediate P-2. MS-ESI calculated values ​​[M+H] + 228 and 230, actual measurements 228 and 230.

[0196] Step 2 Intermediate P-2 (174 mg, 762.87 μmol), potassium acetate (225 mg, 2.29 mmol), and bis(pinacolato)diboron (291 mg, 1.14 mmol) were added to 1,4-dioxane (2 mL), and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (56 mg, 76.29 μmol) was added to the reaction solution. The reaction solution was heated to 90 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was concentrated under reduced pressure to obtain intermediate P, which was used directly in the next step. MS-ESI calculated values ​​[M+H] + 276, actual value 276.

[0197] Intermediate Q Synthesis Route: [ka]

[0198] Step 1 Intermediate C-1a (3 g, 16.28 mmol) was dissolved in tetrahydrofuran (30 mL), n-butyllithium (2.5 M, 13.03 mL) was slowly added at -78 ° C, and the reaction was continued for 30 minutes. Intermediate Q-1 (4.86 g, 17.1 mmol) dissolved in tetrahydrofuran (10 mL) was slowly added at -78 ° C, and the reaction was continued for 12 hours at 25 ° C. The reaction solution was quenched with ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 100 / 1, V / V) to obtain intermediate Q-2. 1H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 2.0 Hz, 1H), 7.31 - 7.28 (m, 1H), 7.09 (d, J = 8.3 Hz, 1H), 4.26 - 4.33 (m, 1H), 3.74 (s, 3H), 3.68-3.60 (m, 4H), 3.45 - 3.37 (m, 1H), 2.94 - 2.86 (m, 1H), 2.25 - 2.17 (m, 1H), 1.01 (m, J = 6.8 Hz, 3H), 0.65 (d, J = 6.8 Hz, 3H). MS-ESI calculated value [M+H] + 387 and 389, actual measurements 387 and 389.

[0199] Step 2 Intermediate Q-2 (6.4 g, 16.51 mmol) was dissolved in acetonitrile (30 mL), and hydrochloric acid (0.2 M, 173 mL) was slowly added thereto, followed by a reaction at 25° C. for 12 hours. The reaction solution was washed with n-heptane (30 mL×2), and the pH of the aqueous phase was adjusted to 8 with saturated aqueous sodium bicarbonate solution. The solution was extracted with ethyl acetate (30 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain Intermediate Q-3, which was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ 7.57 - 7.52 (m, 1H), 7.37 - 7.32 (m, 1H), 7.12 (d, J = 8.2 Hz, 1H), 3.82 - 3.76 (m, 1H), 3.71 (s, 3H), 3.22 - 3.15 (m, 1H), 2.92 - 2.85(m, 1H). MS-ESI calculated value [M+H] + 292 and 294, Actual measurements: 292 and 294.

[0200] Step 3 Intermediate Q-3 (3.42 g, 11.69 mmol) was slowly added with hydrochloric acid (3 M, 55 mL) and reacted at 60 °C for 16 hours. The reaction solution was cooled to room temperature, adjusted to pH 7 with aqueous sodium hydroxide, washed three times with water, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain intermediate Q-4, which was used directly in the next step. MS-ESI calculated value [M+H] + 278 and 280, actual measurements 278 and 280.

[0201] Step 4 Intermediate Q-4 (4 g, 14.36 mmol) was dissolved in dioxane (40 mL), and sodium carbonate solution (2 M, 7.90 mL) and BocO (3.64 g, 16.66 mmol) were added. The mixture was allowed to react for 4 hours at 25° C. The pH of the reaction mixture was adjusted to 4-5 with saturated aqueous citric acid, extracted with ethyl acetate (50 mL × 3), and the combined organic phases were washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. n-Heptane (15 mL) was added and stirred for 15 minutes. The mixture was filtered, and the cake was collected and dried to obtain intermediate Q-5, which was used directly in the next step. 1 H NMR (400 MHz, MeOD-d4) δ 7.68 - 7.54 (m, 1H), 7.48 - 7.37 (m, 1H), 7.24 (d, J = 8.2 Hz, 1H), 4.59 - 4.40 (m, 1H), 3.43 - 3.36 (m, 1H), 3.02 - 2.83 (m, 1H), 1.37 (s, 9H). MS-ESI calculated value [M+H] + 378 and 380, actual measurements 378 and 380.

[0202] Step 5 Intermediate Q-5 (1.06 g, 2.79 mmol) was dissolved in DMF (5 mL), and aqueous ammonia (12 M, 696.56 μL) and N-methylmorpholine (423 mg, 4.18 mmol) were slowly added thereto, followed by stirring at 25° C. for 30 minutes. HATU (1.06 g, 2.79 mmol) was then added at 0° C., and the mixture was allowed to react at 25° C. for 12 hours. Water (20 mL) was added to the reaction solution, which was then filtered. The cake was washed three times with water and then dried to obtain intermediate Q-6, which was used directly in the next step of the reaction. 1 H NMR (400 MHz, DMSO-d6) δ 7.66 (d, J = 1.8 Hz, 1H), 7.53 - 7.44 (m, 1H), 6.90 (d, J = 9.0 Hz, 1H), 4.22 - 4.15 (m, 1H), 3.18 - 3.07 (m, 1H), 2.85 - 2.74 (m, 1H), 1.28 (s, 9H). MS-ESI calculated value [M+Na] + 399 and 401, actual measurements 399 and 401.

[0203] Step 6 Intermediate Q-6 (1 g, 2.65 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (12.13 g, 106.35 mmol) was slowly added. The mixture was allowed to react at 25 °C for 12 hours. The reaction solution was adjusted to pH > 8 with saturated aqueous sodium bicarbonate, extracted with ethyl acetate (10 mL x 3), washed with saturated brine (10 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give intermediate Q-7, which was used directly in the next step. MS-ESI calculated values ​​[M+H] + 277 and 279, actual measurements 277 and 279.

[0204] Step 7 T3P (50% ethyl acetate solution, 278.58 mg, 876 μmol) was dissolved in DMF (3 mL), and intermediate Q-7 (243 mg, 876 μmol) and intermediate A-5 (143 mg, 584 μmol) were added, followed by triethylamine (266 mg, 2.63 mmol), and the reaction was carried out at 25°C for 12 hours. The reaction solution was added to water (50 mL), and the ethyl acetate was added. The mixture was extracted with ethanol (50 mL x 3), washed with saturated brine (10 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to give intermediate Q-8. MS-ESI calculated values ​​[M+Na] + 526 and 528, actual measurements 526 and 528.

[0205] Step 8 Intermediate Q-8 (350 mg, 693 μmol) and methyl N-(triethylammoniosulfonyl)carbamate (826 mg, 3.47 mmol) were added to dichloromethane (3 mL) and reacted at 25° C. for 12 hours. The reaction solution was added to water (20 mL), extracted with ethyl acetate (10 mL x 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate Q, which was used directly in the next step. MS-ESI calculated value [M+Na] + 508 and 510, actual measurements 508 and 510.

[0206] Intermediate R Synthesis Route: [ka]

[0207] Step 1 Intermediate C-1a (2.0 g, 10.86 mmol) was dissolved in tetrahydrofuran (30 mL), and n-butyllithium (2.5 M, 6.08 mL, 15.20 mmol) was added dropwise at -78 °C. The reaction was allowed to proceed for 30 minutes. Intermediate R-1 (2.87 g, 10.86 mmol) dissolved in tetrahydrofuran (15 mL) was added dropwise at -78 °C. The reaction was allowed to proceed for 12 hours at 25 °C. The reaction solution was quenched with saturated ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL × 2), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 10 / 1, v / v) to obtain intermediate R-2. 1H NMR (400 MHz, CDCl3) δ 7.27 (s, 1H), 7.21 (d, J = 8.0 Hz, 1H), 6.97 (d, J = 8.3 Hz, 1H), 4.30 - 4.21 (m, 1H), 3.73 (s, 3H), 3.64 (s, 3H), 3.59-3.54 (m, 1H), 3.26 - 3.17 (m, 1H), 2.92-2.83 (m, 1H), 2.33 (s, 3H), 2.26-2.15 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H), 0.64 (d, J = 6.8 Hz, 3H). MS-ESI calculated value [M+H] + 367 and 369, actual measurements 367 and 369.

[0208] Step 2 Intermediate R-2 (2.7 g, 7.35 mmol) was dissolved in acetonitrile (9 mL), and hydrochloric acid (0.2 M, 77 mL, 15.44 mmol) was slowly added thereto, followed by a reaction at 25° C. for 12 hours. The reaction solution was washed with methyl tert-butyl ether (20 mL), and the pH of the aqueous phase was adjusted to 8 with saturated aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (100 mL×3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate R-3, which was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ 7.33 (s, 1H), 7.29-7.27 (m, 1H), 7.02 (d, J=8.0 Hz, 1H), 3.71 (s, 3H), 3.70-3.66 (m, 1H), 3.12-3.03 (m, 1H), 2.81-2.72 (m, 1H), 2.33 (s, 3H). MS-ESI calculated value [M+H] + 272 and 274, actual measurements 272 and 274.

[0209] Step 3 Intermediate R-3 (2.0 g, 7.35 mmol) was slowly added with hydrochloric acid (3 M, 37 mL, 110 mmol) and reacted at 60 °C for 16 hours. The reaction solution was cooled to room temperature, adjusted to pH 7 with aqueous sodium hydroxide, washed three times with water, and the combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain Intermediate R-4, which was used directly in the next step. MS-ESI calculated values ​​[M+H] + 258 and 260, actual measurements 258 and 260.

[0210] Step 4 Intermediate R-4 (1.93 g, 7.48 mmol) was dissolved in dioxane (20 mL) and water (80 mL), and sodium carbonate (1.59 g, 14.95 mmol) and BocO (1.71 g, 7.85 mmol) were added. The mixture was allowed to react at 25 °C for 4 hours. The pH of the reaction mixture was adjusted to 4-5 with saturated aqueous citric acid, and the mixture was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to give intermediate R-5, which was used directly in the next step. MS-ESI calculated value [M−H]. - 356 and 358, actual measurements 356 and 358.

[0211] Step 5 Intermediate R-5 (2.68 g, 7.48 mmol) was dissolved in DMF (15 mL), N-methylmorpholine (1.14 g, 11.22 mmol) and HATU (2.84 g, 7.48 mmol) were added, and the mixture was stirred at 0 °C for 30 minutes. Aqueous ammonia (865 μL, 22.44 mmol) was then added, and the mixture was stirred at 25 °C for 12 hours. Water (100 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 mL × 3). The organic phases were combined, washed with saturated brine (200 mL × 3), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 4 to 1 / 3, v / v) to obtain intermediate R-6. 1 H NMR (400 MHz, MeOD-d4) δ 7.31 (s, 1H), 7.23 (d, J=8.0 Hz, 1H), 7.08 (s, 1H), 4.34-4.20 (m, 1H), 3.17-3.08 (m, 1H), 2.81-2.73 (m, 1H), 2.35 (s, 3H), 1.35 (s, 9H). MS-ESI calculated value [M-100] + 257 and 259, actual measurements 257 and 259.

[0212] Step 6 Intermediate R-6 (2.3 g, 6.44 mmol) was dissolved in THF (40 mL), and methanesulfonic acid (6.19 g, 64.38 mmol) was slowly added, followed by a reaction at 25° C. for 12 hours. The reaction solution was adjusted to pH 8 or higher with saturated aqueous sodium bicarbonate, extracted with ethyl acetate (10 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by silica gel column chromatography (dichloromethane / methanol, 20 / ~10 / 1, V / V) to obtain Intermediate R-7. 1 H NMR (400 MHz, MeOD-d4) δ 7.37-7.34 (m, 1H), 7.29-7.25 (m, 1H), 7.12 (d, J=8.0 Hz, 1H), 3.31 - 3.26 (m, 1H), 2.92-2.81 (m, 1H), 2.59 - 2.52 (m, 1H), 2.29 (s, 3H). MS-ESI calculated value [M+H] + 257 and 259, actual measurements 257 and 259.

[0213] Step 7 T3P (50% ethyl acetate solution, 389 mg, 612 μmol) was dissolved in DMF (5 mL), and intermediate R-7 (115 mg, 448 μmol), intermediate A-5 (100 mg, 407 μmol), and then triethylamine (187 mg, 1.83 mmol) were added. The mixture was allowed to react at 25° C. for 12 hours. The reaction solution was added to water (50 mL), extracted with ethyl acetate (50 mL × 3), washed with saturated brine (100 mL × 3), and the combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 4, v / v) to obtain intermediate R-8. 1 H NMR (400 MHz, CDCl3) δ 7.29-7.11 (m, 3H), 6.95 (d, J=8.4 Hz, 1H), 4.67-4.50 (m, 1H), 4.13-3.81 (m, 3H), 3.80-3.68 (m, 0.5H), 3.54-3.33 (m, 1.5H), 3.28-3.15 (m, 0.5H), 3.12-2.82 (m, 3.5H), 2.26 (s, 3H), 1.94 - 1.71 (m, 2H), 1.38 (s, 9H). MS-ESI calculated value [M+Na] + 506 and 508, actual measurements 506 and 508.

[0214] Step 8 Intermediate R-8 (190 mg, 393 μmol) and methyl N-(triethylammoniosulfonyl)carbamate (280 mg, 1.18 mmol) were added to dichloromethane (5 mL) and reacted for 12 hours at 25° C. The reaction solution was added to water (50 mL), extracted with ethyl acetate (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 3, v / v) to obtain intermediate R. 1H NMR (400 MHz, CDCl3) δ 7.37-7.34 (s, 1H), 7.33-7.28 (m, 1H), 7.23-7.12 (m, 1H), 7.11-7.05 (m, 1H), 5.13-4.98 (m, 1H), 4.25-3.97 (m, 3H), 3.82-3.70 (m, 0.5H), 3.56-3.17 (m, 3H), 3.15-2.94 (m, 2.5H), 2.36 (s, 3H), 2.01-1.80 (m, 2H), 1.45 (m, 9H). MS-ESI calculated value [M+Na] + 488 and 490, actual measurements 488 and 490.

[0215] Intermediate S Synthesis Route: [ka]

[0216] Step 1 Intermediate S-1 (200 mg, 948 μmol) was dissolved in acetonitrile (10 mL), and 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (419 mg, 1.18 mmol) was added, followed by reaction at 90° C. for 2 hours. The reaction solution was poured into water (50 mL) and extracted with ethyl acetate (30 mL × 2). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting crude product was separated by thin-layer chromatography (petroleum ether / ethyl acetate, 20 / 3, V / V) to obtain Intermediate S-2. 1 H NMR (400 MHz, CDCl3) δ 7.53-7.47 (m, 2H), 7.24 (d, J = 8.8 Hz, 1H), 3.89 (s, 3H). MS-ESI calculated value [M+H] + 229 and 231, actual measurements 229 and 231.

[0217] Step 2 Intermediate S-2 (33 mg, 144 μmol), potassium acetate (35 mg, 369 μmol), and bis(pinacolato)diboron (55 mg, 216 μmol) were added to 1,4-dioxane (3 mL), and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (21 mg, 29 μmol) was added to the reaction solution. The reaction solution was heated to 90 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 3, v / v) to obtain intermediate S. 1 H NMR (400 MHz, CDCl3) δ 7.73 (d, J=1.8 Hz, 1H), 7.56 (d, J=8.0 Hz, 1H), 7.49-7.43 (m, 1H), 3.87 (s, 3H), 1.31 (s, 12H). MS-ESI calculated value [M+H] + 277, actual value 277.

[0218] Intermediate T Synthesis Route: [ka]

[0219] Intermediate T-1 (500 mg, 2.33 mmol), potassium acetate (571 mg, 5.81 mmol), and bis(pinacolato)diboron (886 mg, 3.49 mmol) were added to 1,4-dioxane (6 mL), and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (170 mg, 232 μmol) was added to the reaction solution. The reaction solution was heated to 100 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 2, v / v) to obtain Intermediate T. 1 H NMR (400 MHz, CDCl3) δ 8.28-8.10 (m, 1H), 7.79 (s, 1H), 7. 24-7.18 (m, 1H), 1.38 (s, 12H). MS-ESI calculated value [M+H] +263, actual value 263.

[0220] Intermediate U Synthesis Route: [ka]

[0221] Intermediate U-1 (50 mg, 237 μmol), potassium acetate (58 mg, 593 μmol), and bis(pinacolato)diboron (90 mg, 355 μmol) were added to 1,4-dioxane (3 mL), and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (35 mg, 47 μmol) was added to the reaction solution. The reaction solution was heated to 100 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was concentrated under reduced pressure to obtain intermediate U, which was used directly in the next step. MS-ESI calculated values ​​[M+H] + 177, measured value 177.

[0222] Intermediate V Synthesis Route: [ka]

[0223] Intermediate V-1 (100 mg, 507 μmol), potassium acetate (125 mg, 1.27 mmol), and bis(pinacolato)diboron (193 mg, 761 μmol) were added to 1,4-dioxane (3 mL), and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (74 mg, 101 μmol) was added to the reaction solution. The reaction solution was heated to 100 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was concentrated under reduced pressure to obtain intermediate V, which was used directly in the next step. MS-ESI calculated value [M + Na] + 267, actual value 267.

[0224] Example 1 Synthesis Route: [ka]

[0225] Step 1 Intermediate A (60 mg, 120 μmol), Intermediate E (41 mg, 156 μmol), and potassium carbonate (50 mg, 360 μmol) were added to acetonitrile (8 mL) and water (2 mL). Under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (20 mg, 24 μmol) was added to the reaction solution. The reaction solution was heated to 80 °C under nitrogen gas protection and reacted for 2 hours. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 1 / 4, v / v) to obtain compound 1-1. MS-ESI calculated values ​​[M + Na] + 527, actual value 527.

[0226] Step 2 Compound 1-1 (60 mg, 119 μmol) was added to formic acid (2 mL) and the reaction solution was reacted at 50 °C for 10 minutes. The reaction solution was added to saturated sodium bicarbonate solution (30 mL), the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by SFC (separation column: DAICEL CHIRALPAK AD 250 mm × 30 mm × 10 μm; mobile phase: phase A is supercritical CO2, phase B is ethanol solution containing 0.1% aqueous ammonia; gradient: phase B 50%-50%) to obtain compound 1. The ee value was then measured using SFC (chromatographic column: Chiralcel AD-3 50 mm × 4.6 mm × 3 μm; mobile phase: phase A was supercritical CO2, phase B was an ethanol solution containing 0.05% diethylamine; gradient: phase B 5%–40%).

[0227] Compound 1: ee%=100.00%, RT=2.547 min. 1H NMR (400 MHz, CDCl3) δ 8.23 ​​(s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.8 Hz, 1H), 5.27-5.19 (m, 1H), 4.35 (s, 3H), 4.13-4.10 (m, 1H), 4.03-3.96 (m, 1H), 3.79-3.71 (m, 1H), 3.34-3.26 (m, 1H), 3.22-3.15 (m, 2H), 3.10-3.03 (m, 1H), 3.02-2.93 (m, 1H), 2.92-2.84 (m, 1H), 1.93-1.77 (m, 2H). MS-ESI calculated value [M+H] + 405, actual value 405.

[0228] Example 2 Synthesis Route: [ka]

[0229] Step 1 Intermediate A (80 mg, 160 μmol), compound 2-1 (42 mg, 240 μmol), and potassium carbonate (66 mg, 480 μmol) were added to acetonitrile (6 mL) and water (2 mL). Under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (26 mg, 32 μmol) was added to the reaction solution. The reaction solution was heated to 80 °C under nitrogen gas protection and reacted for 2 hours. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 3 / 7, v / v) to obtain compound 2-2. MS-ESI calculated values ​​[M + Na]+ 526, actual value 526.

[0230] Step 2 Compound 2-2 (80 mg, 158 μmol) was added to formic acid (1.5 mL) and water (0.15 mL), and the reaction solution was reacted at 25 °C for 2 hours. The reaction solution was added to saturated sodium bicarbonate solution (30 mL), the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by SFC (separation column: DAICEL CHIRALPAK AD 250 mm × 30 mm × 10 μm; mobile phase: phase A was supercritical CO2, phase B was an ethanol solution containing 0.1% aqueous ammonia; gradient: phase B 60% to 60%) to obtain compound 2. The ee value was then measured using SFC (chromatographic column: Chiralcel IG-3 50 mm × 4.6 mm × 3 μm; mobile phase: phase A was supercritical CO2, phase B was an ethanol solution containing 0.05% diethylamine; gradient: phase B 5% to 40%).

[0231] Compound 2: ee%=100.00%, RT=2.759 min. 1 H NMR (400 MHz, CD3OD) δ 8.00 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.78-7.68 (m, 3H), 7.48-7.37 (m, 3H), 5.38-5.20 (m, 1H), 4.19-4.11 (m, 1H), 4.10 (s, 3H), 4.02-3.96 (m, 1H), 3.83-3.74 (m, 1H), 3.32-3.15 (m, 3H), 2.98-2.88 (m, 1H), 2.86-2.77 (m, 1H), 2.74-2.65 (m, 1H), 1.99-1.77 (m, 2H). MS-ESI calculated value [M+H] + 404, actual value 404.

[0232] Example 3 Synthesis Route: [ka]

[0233] Step 1 Intermediate A (80 mg, 160 μmol), compound 3-1 (42 mg, 240 μmol), and potassium carbonate (66 mg, 480 μmol) were added to acetonitrile (8 mL) and water (2 mL). Under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (26 mg, 32 μmol) was added to the reaction solution. The reaction solution was heated to 80 °C under nitrogen gas protection and reacted for 2 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained was separated by silica gel column chromatography (dichloromethane / methanol, 100 / 1 to 20 / 1, v / v) to obtain compound 3-2. MS-ESI calculated values ​​[M + Na] + 526, actual value 526.

[0234] Step 2 Compound 3-2 (74 mg, 147 μmol) was added to formic acid (1.5 mL) and water (0.15 mL), and the reaction solution was reacted at 25 °C for 2 hours. The reaction solution was added to saturated sodium bicarbonate solution (30 mL), the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by SFC (separation column: DAICEL CHIRALPAK AD 250 mm × 30 mm × 10 μm; mobile phase: phase A was supercritical CO2, phase B was an ethanol solution containing 0.1% aqueous ammonia; gradient: phase B 50%-50%) to obtain compound 3. The ee value was then measured using SFC (chromatographic column: Chiralcel AD-3 50 mm × 4.6 mm × 3 μm; mobile phase: phase A was supercritical CO2, phase B was an ethanol solution containing 0.05% diethylamine; gradient: phase B 5%–40%).

[0235] Compound 3: ee%=100.00%, RT=2.456 min. 1 H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 7.97 (s, 1H), 7.74-7.69 (m, 1H), 7.68-7.60 (m, 3H), 7.39 (d, J = 8.0 Hz, 2H), 5.14-5.08 (m, 1H), 4.14-4.10 (m, 1H), 4.09 (s, 3H), 4.02-3.93 (m, 1H), 3.82-3.74 (m, 1H), 3.31-3.26 (m, 1H), 3.23-3.15 (m, 2H), 2.93-2.85 (m, 1H), 2.82-2.72 (m, 1H), 2.68-2.61 (m, 1H), 1.95-1.77 (m, 2H). MS-ESI calculated value [M+H] + 404, actual value 404.

[0236] Example 4 Synthesis Route: [ka]

[0237] Step 1 Intermediate A (60 mg, 120 μmol), intermediate F (47 mg, 180 μmol), and potassium carbonate (33 mg, 240 μmol) were added to acetonitrile (8 mL) and water (2 mL). Under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (20 mg, 24 μmol) was added to the reaction solution. The reaction solution was heated to 80 °C under nitrogen gas protection and reacted for 2 hours. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 1 / 3, v / v) to obtain compound 4-1. MS-ESI calculated values ​​[M + Na] + 527, actual value 527.

[0238] Step 2 Compound 4-1 (58 mg, 115 μmol) was added to formic acid (1.5 mL) and water (0.15 mL), and the reaction solution was reacted at 25 °C for 2 hours. The reaction solution was added to saturated sodium bicarbonate solution (30 mL), the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by SFC (separation column: DAICEL CHIRALPAK AD 250 mm × 30 mm × 10 μm; mobile phase: phase A was supercritical CO2, phase B was an ethanol solution containing 0.1% aqueous ammonia; gradient: phase B 50% to 50%) to obtain compound 4. The ee value was then measured using SFC (chromatographic column: Chiralcel AD-3 50 mm × 4.6 mm × 3 μm; mobile phase: phase A was supercritical CO2, phase B was an ethanol solution containing 0.05% diethylamine; gradient: phase B 5%–40%).

[0239] Compound 4: ee%=100.00%, RT=2.247 min. 1 H NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.8 Hz, 1H), 7.73-7.65 (m, 3H), 7.62 (d, J = 8.8 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.25-7.19 (m, 1H), 5.30-5.18 (m, 1H), 4.36 (s, 3H), 4.15-4.08 (m, 1H), 4.05-3.96 (m, 1H), 3.83-3.72 (m, 1H), 3.38-3.28 (m, 1H), 3.24-3.12 (m, 2H), 3.11-3.03 (m, 1H), 3.02-2.93 (m, 1H), 2.93-2.83 (m, 1H), 1.95-1.77 (m, 2H). MS-ESI calculated value [M+H] + 405, actual value 4 05.

[0240] Example 5 Synthesis Route: [ka]

[0241] [ka]

[0242] Step 1 Intermediate A (100 mg, 200 μmol), Intermediate H (76 mg, 280 μmol), and potassium carbonate (55 mg, 400 μmol) were added to acetonitrile (8 mL) and water (2 mL). Under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (32 mg, 40 μmol) was added to the reaction solution. The reaction solution was heated to 80 °C under nitrogen gas protection and reacted for 3 hours. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated by thin-layer chromatography (petroleum ether / ethyl acetate, 0 / 1, v / v) to obtain compound 5-1. MS-ESI calculated value [M+Na] + 541, actual value 541.

[0243] Step 2 Compound 5-1 (56 mg, 108 μmol) was added to formic acid (1.0 mL) and water (0.1 mL), and the reaction solution was reacted at 25 °C for 2 hours. The reaction solution was added to saturated sodium bicarbonate solution (30 mL), the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (column: Waters Xbridge 150 mm × 25 mm × 5 μm; mobile phase: phase A is an aqueous solution containing 0.05% ammonia monohydrate, phase B is acetonitrile; gradient: phase B 16% to 46%, 10 min) to obtain compound 5. The ee value was then measured by SFC (chromatographic column: Chiralcel AD-3 50 mm × 4.6 mm × 3 μm; mobile phase: phase A is supercritical CO2, phase B is an isopropanol solution containing 0.05% diethylamine; gradient: phase B is 40%).

[0244] Compound 5: ee%=100.00%, RT=0.747 min. 1 H NMR (400 MHz, CDCl3) δ7.91 (d, J=8.0 Hz, 1H), 7.70-7.65 (m, 1H), 7.65-7.60 (m, 3H), 7.43 (d, J=8.0 Hz, 2H), 7.24-7.17 (m, 1H) , 5.28-5.16 (m, 1H), 4.45 (s, 2H), 4.14-4.08 (m, 1H), 4.04-3.96 (m, 1H), 3.82-3.71 (m, 1H), 3.37-3.28 (m, 1H), 3.24 (s, 3H), 3.19-3.14 (m, 2H), 3.09-3.03 (m, 1H), 3.01-2.85 (m, 2H), 1.95-1.79 (m, 2H). MS-ESI calculated value [M+H] + 419, actual value 419.

[0245] Example 6 Synthesis Route: [ka]

[0246] Step 1 Intermediate C (80 mg, 164 μmol), intermediate G (90 mg, 328 μmol), and potassium phosphate (104 mg, 491 μmol) were added to tetrahydrofuran (8 mL) and water (3 mL). Under nitrogen gas protection, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (21 mg, 32 μmol) was added to the reaction solution. The reaction solution was heated to 60 °C under nitrogen gas protection and reacted for 6 hours. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated by thin-layer chromatography (developing solvent: dichloromethane / methanol, 20 / 1, V / V) to obtain compound 6-1. MS-ESI calculated value [M+H] + 557, actual value 557.

[0247] Step 2 Compound 6-1 (104 mg, 187 μmol) was dissolved in dichloromethane (10 mL), and methyl N-(triethylammoniosulfonyl)carbamate (67 mg, 280 μmol) was added. The mixture was allowed to react at 25° C. for 12 hours. The reaction solution was added to water (50 mL), extracted with ethyl acetate (50 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product containing compound 6-2, which was used directly in the next step. MS-ESI calculated values ​​[M + Na] + 561, actual value 561.

[0248] Step 3 Compound 6-2 (95 mg, 177 μmol) was added to formic acid (1.7 mL) and water (0.5 mL), and the reaction solution was reacted at 25 °C for 2 hours. The reaction solution was added to saturated sodium bicarbonate solution (30 mL), the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by preparative high-performance liquid chromatography (column: Waters Xbridge 150 mm × 25 mm × 5 μm; mobile phase: phase A is an aqueous solution containing 0.05% ammonia monohydrate, phase B is acetonitrile; gradient: phase B 22% ~ The compound was separated by SFC (chromatographic column: Chiralcel OJ-3 50 mm × 4.6 mm × 3 μm; mobile phase: phase A was supercritical CO2, phase B was ethanol solution containing 0.05% diethylamine; gradient: phase B 5% to 40%) to obtain compound 6. The ee value was then measured.

[0249] Compound 6: ee%=100.00%, RT=2.123min. 1 H NMR (400 MHz, CD3OD) δ7.51-7.39 (m, 5H), 7.32 (d, J=8.2 Hz, 1H), 5.19-5.14 (m, 1H), 4.15-4.08 (m, 1H), 4.05-3.95 (m, 1H), 3.84-3.74 (m, 1H), 3.46 (s, 3H), 3.29-3.16 (m, 3H), 2.97-2.88 (m, 1H), 2.85-2.75 (m, 1H), 2.70-2.62 (m, 1H), 1.98-1.79 (m, 2H). MS-ESI calculated value [M+H] + 439, actual value 439.

[0250] Example 7 Synthesis Route: [ka]

[0251] Step 1 Intermediate C (100 mg, 205 μmol), intermediate F (69 mg, 266 μmol), and potassium phosphate (130 mg, 614 μmol) were added to tetrahydrofuran (8 mL) and water (3 mL). Under nitrogen gas protection, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (27 mg, 41 μmol) was added to the reaction solution. The reaction solution was heated to 70 °C under nitrogen gas protection and reacted for 5 hours. Water (20 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product obtained was separated by silica gel column chromatography (dichloromethane / methanol, 100 / 1 to 20 / 1, V / V) to obtain compound 7-1. MS-ESI calculated values ​​[M + Na] + 563, actual value 563.

[0252] Step 2 Compound 7-1 (110 mg, 203 μmol) was dissolved in dichloromethane (5 mL), N-(triethylammoniosulfonyl)methylcarbamate (122 mg, 512 μmol) was added, and the mixture was allowed to react at 25°C for 22 hours. The reaction solution was added to water (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 1 / 4, V / V) to obtain compound 7-2. MS-ESI calculated values ​​[M+Na] + 545, actual value 545.

[0253] Step 3 Compound 7-2 (101 mg, 193 μmol) was added to formic acid (1.5 mL) and water (0.3 mL), and the reaction solution was reacted at 25 °C for 2 h. The reaction solution was added to saturated sodium bicarbonate solution (30 mL), the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (column: Phenomenex Gemini-NX 80 mm × 40 mm × 3 μm; mobile phase: phase A is an aqueous solution containing 0.05% ammonia monohydrate, phase B is acetonitrile; gradient: phase B 26% to 56%, 8 min) to obtain compound 7. The ee value was then measured using SFC (chromatographic column: Chiralcel AD-3 150 mm × 4.6 mm × 3 μm; mobile phase: phase A was supercritical CO2, phase B was an ethanol solution containing 0.05% diethylamine; gradient: phase B 5%–40%).

[0254] Compound 7: ee%=91.78%, RT=6.090 min. 1 H NMR (400 MHz, CD3OD) δ 8.10-7.98 (m, 2H), 7.74 (d, J=8.8 Hz, 1H), 7.63-7.53 (m, 2H), 7.48 (t, J=8.0 Hz, 1H), 5.21-5.16 (m, 1H), 4.38 (s, 3H), 4.16-4.09 (m, 1H), 4.06-3.97 (m, 1H), 3.84-3.74 (m, 1H), 3.40-3.24 (m, 2H), 3.23-3.16 (m, 1H), 2.99-2.88 (m, 1H), 2.85-2.74 (m, 1H), 2.70-2.62 (m, 1H), 1.99-1.78 (m, 2H). MS-ESI calculated value [M+H] + 423, actual value 423.

[0255] Example 8 Synthesis Route: [ka]

[0256] Step 1 Intermediate C (100 mg, 205 μmol), compound 8-1 (43 mg, 245 μmol), and potassium carbonate (85 mg, 614 μmol) were added to acetonitrile (4 mL) and water (1 mL). Under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (33 mg, 41 μmol) was added to the reaction solution. The reaction solution was heated to 80 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was added to water (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated by thin-layer chromatography (developing solvent: petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain compound 8-2. MS-ESI calculated value [M+H] + 540, actual value 540.

[0257] Step 2 Compound 8-2 (100 mg, 185 μmol) was dissolved in dichloromethane (6 mL), N-(triethylammoniosulfonyl)methylcarbamate (66 mg, 278 μmol) was added, and the mixture was allowed to react at 25 °C for 12 hours. The reaction solution was added to water (50 mL) and extracted with ethyl acetate (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated by silica gel column chromatography (developing solvent: dichloromethane / methanol, 20 / 1, v / v) to obtain compound 8-3. MS-ESI calculated value [M-56 + H] + 466, actual value 466.

[0258] Step 3 Compound 8-3 (95 mg, 182 μmol) was added to formic acid (1.5 mL) and water (0.1 mL), and the reaction solution was reacted at 40 °C for 12 h. The reaction solution was added to saturated sodium bicarbonate solution (30 mL), the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (column: Phenomenex Gemini-NX C18 75 mm × 30 mm × 3 μm; mobile phase: phase A is an aqueous solution containing 0.05% ammonia monohydrate, phase B is acetonitrile; gradient: phase B 23% to 53%, 7 min) to obtain compound 8. The ee value was then measured using SFC (chromatographic column: Chiralcel AD-3 50 mm × 4.6 mm × 3 μm; mobile phase: phase A was supercritical CO2, phase B was an ethanol solution containing 0.05% diethylamine; gradient: phase B 5%–40%).

[0259] Compound 8: ee%=84.21%, RT=2.200 min. 1 H NMR (400 MHz, CD3OD) δ8.00 (s, 1H), 7.87-7.71 (m, 2H), 7.58-7.31 (m, 4H), 5.23-5.15 (m, 1H), 4.16 - 4.10 (m, 1H), 4.09 (s, 3H), 4.03-3.94 (m, 1H), 3.82-3.73 (m, 1H), 3.39-3.15 (m, 3H), 2.94-2.86 (m, 1H), 2.84-2.73 (m, 1H), 2.69-2.61 (m, 1H), 1.98-1.77 (m, 2H). MS-ESI calculated value [M+H] + 422, actual value 422.

[0260] Example 9 Synthesis Route: [ka]

[0261] Step 1 Intermediate A (250 mg, 874 μmol), intermediate L (392.6 mg, 786 μmol), and potassium carbonate (241 mg, 1.75 mmol) were dissolved in acetonitrile (2 mL) and The reaction mixture was added to water (0.5 mL). Under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (143 mg, 175 μmol) was added to the reaction mixture. The reaction mixture was heated to 80°C under nitrogen gas protection and reacted for 3 hours. The reaction mixture was concentrated under reduced pressure, and the resulting crude product was separated by silica gel column chromatography (dichloromethane / methanol, 10 / 1, V / V) to obtain compound 9-1. MS-ESI calculated value [M+H] + 532, actual value 532.

[0262] Step 2 Compound 9-1 (169 mg, 318 μmol) was added to formic acid (2.0 mL) and water (0.2 mL), and the reaction solution was reacted at 25 °C for 3 h. The reaction solution was added to saturated sodium bicarbonate solution (20 mL), the pH was adjusted to 8-9 with saturated sodium bicarbonate solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (column: Welch Ultimate XB-CN 250 mm × 50 mm × 10 μm; mobile phase: phase A is n-hexane, phase B is ethanol solution containing 0.1% ammonia monohydrate; gradient: phase B 25% to 65%, 15 min) to obtain compound 9. The ee value of compound 9 was measured by SFC (chromatography column: Chiralcel OJ-3 50 mm × 4.6 mm ID, 3 μm; mobile phase: phase A was supercritical CO2, phase B was methanol solution containing 0.05% diethylamine; gradient: phase B 5% to 40%).

[0263] Compound 9: ee%=93.00%, RT=1.896 min. 1H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 7.85 - 7.77 (m, 2H), 7.73 (d, J = 8.3 Hz, 2H), 7.51 - 7.39 (m, 3H), 5.20 - 5.13 (m, 1H), 5.12 - 5.03 (m, 1H), 4.20 - 4.13 (m, 1H), 4.05 - 3.95 (m, 1H), 3.85 - 3.76 (m, 1H), 3.32-3.28 (m, 1H), 3.27 - 3.18 (m, 2H), 2.98 - 2.89 (m, 1H), 2.87 - 2.78 (m, 1H), 2.76 - 2.67 (m, 1H), 1.98 - 1.83 (m, 2H), 1.60 (d, J = 6.6 Hz, 6H). MS-ESI calculated value [M+H] + 432, actual value 432.

[0264] Example 10 Synthesis Route: [ka]

[0265] Step 1 Intermediate C (200 mg, 699 μmol), Intermediate L (341 mg, 699 μmol), and potassium phosphate (371 mg, 1.75 mmol) were added to tetrahydrofuran (3 mL) and water (1 mL). Under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (143 mg, 175 μmol) was added to the reaction solution. The reaction solution was heated to 80 °C under nitrogen gas protection and reacted for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was separated by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to obtain compound 10-1. MS-ESI calculated value [M -56 + 1]. + 512, measured value 512.

[0266] Step 2 Compound 10-1 (300 mg, 528 μmol) and methyl N-(triethylammoniosulfonyl)carbamate (309 mg, 1.29 mmol) were added to dichloromethane (3 mL). The reaction solution was reacted at 25 °C for 12 hours. The reaction solution was washed with water (10 × 3 mL) and saturated brine (10 × 3 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 10-2, which was used directly in the next step. MS-ESI calculated values ​​[M+H] + 550, actual value 550.

[0267] Step 3 Compound 10-2 (200 mg, 364 μmol) was added to formic acid (2.0 mL) and water (0.2 mL), and the reaction solution was reacted at 25 °C for 3 hours. The reaction solution was extracted with dichloromethane (5 mL × 3). The organic phases were combined, washed with saturated brine (5 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (column: Unisil 3-100 C18 Ultra 150 mm × 50 mm × 3 μm; mobile phase: Phase A is an aqueous solution containing 0.225% formic acid, Phase B is acetonitrile; gradient: Phase B 15% to 45%, 10 min) to obtain the formate salt of compound 10. The formate salt of compound 10 was analyzed by SFC (chromatography column: Chiralpak AD-3 50 mm × 4.6 mm ID, 3 μm; mobile phase: phase A was supercritical CO2, phase B was methanol solution containing 0.05% diethylamine; gradient: phase B 5% to 40%).

[0268] Compound 10: ee%=83.46%, RT=1.879 min. 1 H NMR (400 MHz, CD3OD) δ 8.10 - 8.03 (m, 1H), 7.91 - 7.81 (m, 2H), 7.65 - 7.43 (m, 4H), 5.24 - 5.15 (m, 1H), 5.13 - 5.04 (m, 1H), 4.46 - 4.35 (m, 1H), 4.16 - 4.04 (m, 1H), 3.92 - 3.81 (m, 1H), 3.60 - 3.47 (m, 1H), 3.42 - 3.36 (m, 1H), 3.30 - 3.24 (m, 1H), 3.23 - 3.13 (m, 1H), 3.08 - 2.95 (m, 1H), 2.20 - 1.99 (m, 2H), 1.60 (d, J = 6.7 Hz, 6H). MS-ESI calculated value [M+H] + 450, actual measured value 450.

[0269] Example 11 Synthesis Route: [ka]

[0270] Step 1 Intermediate A (250 mg, 762 μmol), intermediate M (342 mg, 685 μmol), and potassium carbonate (210 mg, 1.52 mmol) were added to acetonitrile (2 mL) and water (0.5 mL). Under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (124 mg, 152 μmol) was added to the reaction solution. The reaction solution was heated to 80°C under nitrogen gas protection and reacted for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was separated by silica gel column chromatography (dichloromethane / methanol, 20 / 1, V / V) to obtain compound 11-1. MS-ESI calculated value [M+H] + 574, actual value 574.

[0271] Step 2 Compound 11-1 (100 mg, 174 μmol) was added to formic acid (2.0 mL) and water (0.2 mL), and the reaction solution was reacted at 25 °C for 3 hours. The reaction solution was quenched with sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (Waters Xbridge 150 mm × 25 mm × 5 μm column; mobile phase: Phase A is an aqueous solution containing 0.05% ammonia hydrate, Phase B is acetonitrile; gradient: Phase B 25% to 55%, 9 min) to obtain Compound 11. The ee value of compound 11 was measured by SFC (chromatography column: Chiralcel OD-3 50 mm × 4.6 mm ID, 3 μm; mobile phase: phase A was supercritical CO2, phase B was a methanol solution containing 0.05% diethylamine; gradient: phase B 5% to 40%).

[0272] Compound 11: ee%=95.846%, RT=2.026 min. 1 H NMR (400 MHz, CD3OD) δ 8.06 (s, 1H), 7.91 - 7.79 (m, 2H), 7.75 (d, J = 7.2 Hz, 2H), 7.54 - 7.42 (m, 3H), 5.24 - 5.08 (m, 1H), 4.26 - 4.08 (m, 3H), 4.06 - 3.95 (m, 1H), 3.85 - 3.60 (m, 5H), 3.09 - 2.66 (m, 5H), 2.50 - 2.26 (m, 2H), 2.10 - 1.79 (m, 4H). MS-ESI calculated value [M+H] + 474, actual value 474.

[0273] Example 12 Synthesis Route: [ka]

[0274] Step 1 Intermediate C (200 mg, 609 μmol), intermediate M (297.58 mg, 609 μmol), and potassium phosphate (323 mg, 1.52 mmol) were added to tetrahydrofuran (3 mL) and water (1 mL). Under nitrogen gas protection, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (79 mg, 122 μmol) was added to the reaction solution. The reaction solution was heated to 60 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1 to 0 / 1, V / V) to obtain compound 12-1. MS-ESI calculated values ​​[M+H] + 610, actual measured value 610.

[0275] Step 2 Compound 12-1 (107 mg, 176 μmol) and methyl N-(triethylammoniosulfonyl)carbamate (102 mg, 430 μmol) were added to dichloromethane (3 mL). The reaction solution was reacted at 25 °C for 12 hours. The reaction solution was washed with water (10 mL × 3) and saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 12-2, which was used directly in the next step. MS-ESI calculated values ​​[M+H] + 592, actual value 592.

[0276] Step 3 Compound 12-2 (90 mg, 152 μmol) was added to formic acid (2.0 mL) and water (0.2 mL), and the reaction solution was reacted at 25 °C for 3 hours. The reaction solution was quenched with sodium bicarbonate solution (30 mL) and extracted with dichloromethane (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (column: Welch Ultimate XB-CN 250 mm × 50 mm × 10 μm; mobile phase: phase A is n-hexane, phase B is ethanol solution containing 0.1% ammonia monohydrate; gradient: phase B 25% to 65%, 15 min) to obtain compound 12. Compound 12 was purified by SFC (chromatography column: Chiralcel OJ-3 50 mm × 4.6 mm) to obtain the crude product. The ID was 3 μm; the mobile phase was supercritical CO2 in phase A and methanol solution containing 0.05% diethylamine in phase B; the gradient was 5% to 40% in phase B, and the ee value was measured.

[0277] Compound 12: ee%=96.59%, RT=2.110min. 1 H NMR (400 MHz, CD3OD) δ 8.07 (s, 1H), 7.92 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.62 - 7.52 (m, 2H), 7.50 - 7.44 (m, 2H), 5.23 - 5.17 (m, 1H), 5.02 - 4.92 (m, 1H), 4.20 - 4.10 (m, 3H), 4.07 - 3.96 (m, 1H), 3. 86 - 3.68 (m, 3H), 3.41 - 3.35 (m, 1H), 3.30 - 3.18 (m, 2H), 2.98 - 2.89 (m, 1H), 2.86 - 2.77 (m, 1H), 2.72 - 2.63 (m, 1H), 2.42 - 2.27 (m, 2H), 2.03 - 1.81 (m, 4H). MS-ESI calculated value [M+H] +492, actual value 492.

[0278] Example 13 Synthesis Route: [ka]

[0279] Step 1 Intermediate D (58 mg, 236 μmol), intermediate N (100 mg, 213 μmol), and potassium phosphate (125 mg, 591 μmol) were added to tetrahydrofuran (3 mL) and water (1 mL). Under nitrogen gas protection, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (31 mg, 47 μmol) was added to the reaction solution. The reaction solution was heated to 60 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was extracted with ethyl acetate (10 mL x 3), washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude product obtained after vacuum concentration was separated by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to give compound 13-1. MS-ESI calculated values ​​[M+H] + 508, measured value 508.

[0280] Step 2 Compound 13-1 (95 mg, 187 μmol) was added to formic acid (0.5 mL) and water (0.1 mL), and the reaction solution was reacted at 25 °C for 3 hours. The reaction solution was quenched with sodium bicarbonate solution (20 mL) and extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (Waters Xbridge 150 mm × 25 mm × 5 μm column; mobile phase: Phase A is an aqueous solution containing 0.05% ammonia monohydrate, Phase B is acetonitrile; gradient: Phase B 18% to 48%, 9 min) to obtain compound 13. The ee value of compound 13 was measured by SFC (chromatographic column: Chiralcel OJ-3 50 mm × 4.6 mm ID, 3 μm; mobile phase: phase A was supercritical CO2, phase B was 0.05% diethylamine in methanol; gradient: phase B 5% to 40%).

[0281] Compound 13: ee%=88.24%, RT=1.769min. 1 H NMR (400 MHz, CD3OD) δ 8.58 - 8.48 (m, 1H), 7.90 (s, 1H), 7.83 (s, 1H), 7.66 - 7.55 (m, 3H), 7.50 (t, J = 8.0 Hz, 1H), 7.35 - 7.25 (m, 1H), 5.23-5.17 (m, 1H), 4.22 - 4.13 (m, 1H), 4.06 - 3.98 (m, 1H), 3.87 - 3.78 (m, 1H), 3.50-3.41 (m, 1H), 3.29-3.20 (m, 2H), 3.02-2.78 (m, 2H), 2.75 - 2.62 (m, 1H), 2.01 - 1.82 (m, 2H). MS-ESI calculated value [M+H] + 408, actual value 408.

[0282] Example 14 Synthesis Route: [ka]

[0283] Step 1 Intermediate D (58 mg, 236 μmol), intermediate O (100 mg, 213 μmol), and potassium phosphate (125 mg, 591 μmol) were added to tetrahydrofuran (3 mL) and water (1 mL). Under nitrogen gas protection, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (31 mg, 47.25 μmol) was added to the reaction solution. The reaction solution was heated to 60 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was extracted with ethyl acetate (10 mL x 3), washed with saturated brine (10 mL x 3), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude product obtained after vacuum concentration was separated by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to obtain compound 14. MS-ESI calculated value [M+H] + 508, measured value 508.

[0284] Step 2 Compound 14-1 (100 mg, 197 μmol) was added to formic acid (0.5 mL) and water (0.1 mL), and the reaction solution was reacted at 25 °C for 3 hours. The reaction solution was quenched with sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL × 3), washed with saturated brine (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (column: Waters Xbridge 150 mm × 25 mm × 5 μm; mobile phase: phase A is an aqueous solution containing 0.05% ammonia monohydrate, phase B is acetonitrile; gradient: phase B 18% to 48%, 9 min) to obtain compound 14. The ee value of compound 14 was measured by SFC (chromatographic column: Chiralcel OJ-3 50 mm × 4.6 mm ID, 3 μm; mobile phase: phase A was supercritical CO2, phase B was methanol solution containing 0.05% diethylamine; gradient: phase B 5% to 40%).

[0285] Compound 14: ee%=67%, RT=1.956 min. 1 H NMR (400 MHz, CD3OD) δ 8.89 - 8.76 (m, 1H), 7.93 (d, J = 1.3 Hz, 1H), 7.71 - 7.60 (m, 3H ), 7.57 - 7.44 (m, 3H), 5.25 - 5.11 (m, 1H), 4.30 - 4.21 (m, 1H), 4.11 - 4.00 (m, 1H), 3.88 - 3.77 (m, 1H), 3.41-3.35 (m, 1H), 3.29-3.23 (m, 2H), 3.17 - 2.95 (m, 2H), 2.88 - 2.74 (m, 1H), 2.11 - 1.87 (m, 2H). MS-ESI calculated value [M+H] + 408, actual value 408.

[0286] Example 15 Synthesis Route: [ka]

[0287] Step 1 Intermediate C (180 mg, 654 μmol), intermediate P (288 mg, 589 μmol), and potassium phosphate (347 mg, 1.64 mmol) were added to tetrahydrofuran (3 mL) and water (1 mL). Under nitrogen gas protection, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (85 mg, 131 μmol) was added to the reaction solution. The reaction solution was heated to 60°C under nitrogen gas protection and reacted for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was separated by silica gel column chromatography (dichloromethane / methanol, 10 / 1, V / V) to obtain compound 15-1. MS-ESI calculated value [M+H] + 557, actual value 557.

[0288] Step 2 Compound 15-1 (196 mg, 351 μmol) and methyl N-(triethylammoniosulfonyl)carbamate (206 mg, 862 μmol) were added to dichloromethane (3 mL). The reaction solution was reacted at 15° C. for 12 hours. The reaction solution was washed with water (20 mL×3) and saturated brine (20 mL×3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 15-2, which was used directly in the next step. MS-ESI calculated values ​​[M+H] + 539, actual value 539.

[0289] Step 3 Compound 15-2 (100 mg, 186 μmol) was added to formic acid (0.5 mL) and water (0.1 mL), and the reaction solution was reacted at 25 °C for 3 hours. The reaction solution was added to saturated sodium bicarbonate solution (25 mL) and extracted with dichloromethane (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (column: Phenomenex Synergi C18 150 mm × 25 mm × 10 μm; mobile phase: Phase A was an aqueous solution containing 0.225% formic acid, Phase B was acetonitrile; gradient: Phase B 10% to 40%, 10 min) to obtain the formate salt of compound 15. The formate salt of compound 15 was separated by SFC (chromatography column: Chiralpak AD-3 50 mm × 4.6 mm I.D., 3 μm; mobile phase: Phase A was a supercritical fluid). CO2, phase B is a methanol solution containing 0.05% diethylamine; gradient: phase B 40%).

[0290] Compound 15: ee%=82.26%, RT=0.879 min. 1 H NMR (400 MHz, CD3OD) δ 7.55 - 7.25 (m, 3H), 6.97 - 6.83 (m, 2H), 6.76 (d, J = 8.3 Hz, 1H), 5.24 - 5.04 (m, 1H), 4.32 - 4.26 (m, 2H), 4.24 - 4.14 (m, 1H), 4.05 - 3.96 (m, 1H), 3.85 - 3.77 (m, 1H), 3.32 - 3.19 (m, 5H), 3.08 - 2.97 (m, 1H), 2.95 (s, 3H), 2.94-2.88 (m, 1H), 2.82 - 2.69 (m, 1H), 2.09 - 1.80 (m, 2H). MS-ESI calculated value [M+H] + 439, actual value 439.

[0291] Example 16 Synthesis Route: [ka]

[0292] Step 1 Intermediate Q (239 mg, 491 μmol), compound 8-1 (87 mg, 491 μmol), and potassium phosphate (261 mg, 1.23 mmol) were added to tetrahydrofuran (3 mL) and water (1 mL). Under nitrogen gas protection, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (64 mg, 98 μmol) was added to the reaction solution. The reaction solution was heated to 70 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was extracted with ethyl acetate (10 mL x 3), washed with saturated brine (10 mL x 3), and the combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product obtained was separated by silica gel column chromatography (dichloromethane / methanol, 10 / 1, v / v) to obtain compound 16-1. MS-ESI calculated value [M -55]. + 482, actual value 482.

[0293] Step 2 Compound 16-1 (167 mg, 310 μmol) was added to formic acid (0.5 mL) and water (0.1 mL), and the reaction solution was stirred at 25° C. for 3 hours. The reaction solution was quenched with sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (20 mL×2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by preparative high-performance liquid chromatography (column: Waters Xbridge 150 mm × 25 mm × 5 μm; Mobile phase: Phase A is an aqueous solution containing 0.05% ammonia monohydrate, Phase B is acetonitrile; Gradient: Phase B 27% to 57%, The eluate was separated by SFC (chromatographic column: Chiralpak AD-3 50 mm × 4.6 mm ID, 3 μm; mobile phase: phase A was supercritical CO2, phase B was 0.05% diethylamine in methanol; gradient: phase B 40%) to obtain compound 16. The ee value of compound 16 was measured by SFC (chromatographic column: Chiralpak AD-3 50 mm × 4.6 mm ID, 3 μm; mobile phase: phase A was supercritical CO2, phase B was 0.05% diethylamine in methanol; gradient: phase B 40%).

[0294] Compound 16: ee%=100%, RT=0.790 min. 1 H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.81 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 1.5 Hz, 1H), 7.63 - 7.53 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.42-7.31 (m, 2H), 5.32 - 5.22 (m, 1H), 4.23-4.12 (s, 4H), 4.10 - 4.03 (m, 1H), 3.85 - 3.76 (m, 1H), 3.45 - 3.32 (m, 3H), 3.02 - 2.92 (m, 3H), 2.07-1.79 (m, 2H). MS-ESI calculated value [M+H] + 438, actual value 438.

[0295] Example 17 Synthesis Route: [ka]

[0296] Step 1 Intermediate R (100 mg, 214 μmol), compound 8-1 (75 mg, 428 μmol), and potassium phosphate (159 mg, 751 μmol) were added to tetrahydrofuran (6 mL) and water (3 mL). Under nitrogen gas protection, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (28 mg, 43 μmol) was added to the reaction solution. The reaction solution was heated to 70 °C under nitrogen gas protection and reacted for 5 hours. The reaction solution was added to water (30 mL) and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 2, v / v) to give compound 17-1. 1 H NMR (400 MHz, CDCl3) δ 7.98 (s, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.56 - 7.46 (m, 3H), 7.39 - 7.25 (m, 3H), 5.25-5.10 (m, 1H), 4.24-4.00 (m, 6H), 3.83-3.70 (m, 0.5H), 3.58-3.48 (m, 1H), 3.47 - 3.00 (m, 4.5H), 2.48 (s, 3H), 2.01-1.78 (m, 2H), 1.46 (s, 9H). MS-ESI calculated value [M+Na] + 540, actual value 540.

[0297] Step 2 Compound 17-1 (80 mg, 154 μmol) was added to formic acid (1.5 mL) and water (0.15 mL), and the reaction solution was stirred at 25 °C for 2 h. The reaction solution was quenched with sodium bicarbonate solution (50 mL) and extracted with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (column: Phenomenex C18 80 mm × 40 mm × 3 μm; mobile phase: phase A is an aqueous solution containing 0.05% ammonia monohydrate, phase B is acetonitrile; gradient: phase B 37% to 67%, 8 min) to obtain compound 17. Compound 17 was purified by SFC (chromatography column: Chiralpak AD-3 The ee value was measured using a 150 mm x 4.6 mm column with an ID of 3 μm; mobile phase: phase A was supercritical CO 2 , and phase B was an ethanol solution containing 0.05% diethylamine; gradient: phase B was 40% diethylamine.

[0298] Compound 17: ee%=100%, RT=2.581 min. 1 H NMR (400 MHz, MeOD-d4) δ 7.99 (s, 1H), 7.78 (d, J=8.5 Hz, 1H), 7.72 (s, 1H), 7.56 (s, 1H), 7.52 (d, J=7.8 Hz, 1H), 7.45-7.39 (m, 1H), 7.33 (d, J=7.8 Hz, 1H), 5.18-5.13 (m, 1H), 4.14-4.10 (m, 1H), 4.09 (s, 3H), 4.05-3.96 (m, 1H), 3.84-3.75 (m, 1H), 3.39-3.32 (m, 1H), 3.24-3.15 (m, 2H), 2.96-2.85 (m, 1H), 2.83-2.73 (m, 1H), 2.79-2.60 (m, 1H), 2.48 (s, 3H), 1.98-1.79 (m, 2H). MS-ESI calculated value [M+H] + 418, measured value 418.

[0299] Example 18 Synthesis Route: [ka]

[0300] Step 1 Intermediate D (50 mg, 106 μmol), intermediate S (33 mg, 117 μmol), and potassium phosphate (56 mg, 266 μmol) were added to THF (6 mL) and water (3 mL). Under nitrogen gas protection, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (14 mg, 22 μmol) was added to the reaction solution. The reaction solution was heated to 70 °C under nitrogen gas protection and reacted for 5 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, v / v) to obtain compound 18-1. 1 H NMR (400 MHz, CDCl3) δ 7.70 (d, J=8.3 Hz, 1H), 7.49-7.31 (m, 5H), 7.26 (d, J=7.5 Hz, 1H), 5.27-5.11 (m, 1H), 4.22-4.00 (m, 3.5H), 3. 96 (s, 3H), 3.81-3.70 (m, 0.5H), 3.61-3.42 (m, 1.5H), 3.32-3.05 (m, 3.5H), 2.04-1.85 (m, 2H), 1.45 (s, 9H). MS-ESI calculated value [M+Na] + 562, actual value 562.

[0301] Step 2 Compound 18-1 (84 mg, 155 μmol) was added to formic acid (1.5 mL) and water (0.15 mL), and the reaction solution was reacted at 25 °C for 2 h. The reaction solution was added to saturated sodium bicarbonate solution (20 mL), the pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (70 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (column: Phenomenex C18 80 mm × 40 mm × 3 μm; mobile phase: phase A is an aqueous solution containing 0.05% ammonia monohydrate, phase B is acetonitrile; gradient: phase B 42% to 72%, 8 min) to obtain compound 18. The ee value of compound 18 was measured by SFC (chromatographic column: Chiralcel OJ-3 50 mm × 4.6 mm ID, 3 μm; mobile phase: phase A was supercritical CO2, phase B was ethanol solution containing 0.05% diethylamine; gradient: phase B 5% to 40%).

[0302] Compound 18: ee%=100.00%, RT=3.989 min. 1 H NMR (400 MHz, CD3OD) δ 7.72 (d, J=11.0 Hz, 2H), 7.58-7.49 (m, 2H), 7.49-7.42 (m, 2H), 5.22-5.14 (m, 1H), 4.17-4.09 (m, 1H), 4.05-3.90 (m, 4H), 3.84-3.75 (m, 1H), 3.39-3.33 (m, 1H), 3.30-3.24 (m, 1H), 3.23-3.15 (m, 1H), 2.98-2.86 (m, 1H), 2.84-2.73 (m, 1H), 2.70-2.60 (m, 1H), 1.99-1.78 (m, 2H). MS-ESI calculated value [M+H] + 440, actual value 440.

[0303] Example 19 Synthesis Route: [ka]

[0304] Step 1 Intermediate D (50 mg, 106 μmol), Intermediate T (56 mg, 212 μmol), and potassium phosphate (68 mg, 319 μmol) were added to THF (6 mL) and water (3 mL). Under nitrogen gas protection, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (14 mg, 22 μmol) was added to the reaction solution. The reaction solution was heated to 70°C under nitrogen gas protection and reacted for 3 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 7, V / V) to obtain compound 19-1. 1 H NMR (400 MHz, CDCl3) δ 8.16 (s, 1H), 7.47-7.30 (m, 5H), 7.00 (d, J=10.8 Hz, 1H), 5.30-5.13 (m, 1H), 4.18-4.09 (m, 3H), 3.83-3.71 (m, 0.5H), 3.61-3.47 (m, 1.5H), 3.44-3.07 (m, 4H), 2.00-1.89 (m, 2H), 1.46 (s, 9H). MS-ESI calculated value [M+Na] + 548, actual value 548.

[0305] Step 2 Compound 19-1 (30 mg, 57 μmol) was added to formic acid (1.5 mL) and water (0.15 mL), and the reaction solution was reacted at 25 °C for 2 hours. The reaction solution was added to saturated sodium bicarbonate solution (20 mL), the pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (column: Phenomenex C18 80 × 40 mm × 3 μm; mobile phase: phase A is an aqueous solution containing 0.05% ammonia monohydrate, phase B is acetonitrile; gradient: phase B 36% to 66%, 8 min) to obtain compound 19. The ee value of compound 19 was measured by SFC (chromatographic column: Chiralcel OJ-3 100 mm × 4.6 mm ID, 3 μm; mobile phase: phase A was supercritical CO2, phase B was ethanol solution containing 0.05% diethylamine; gradient: phase B 5% to 40%).

[0306] Compound 19: ee%=100.00%, RT=3.563min. 1 H NMR (400 MHz, CD3OD) δ 8.13 (s, 1H), 7.59 (s, 1H), 7.54-7.42 (m, 3H), 7.14 (d, J=11.3 Hz, 1H), 5.23-5.13 (m, 1H), 4.16-4.08 (m, 1H), 4.04-3.94 (m, 1H), 3.84-3.74 (m, 1H), 3.39-3.33 (m, 1H), 3.29-3.22 (m, 1H), 3.21-3.15 (m, 1H), 2.97-2.86 (m, 1H), 2.84-2.74 (m, 1H), 2.68-2.60 (m, 1H), 1.98-1.79 (m, 2H). MS-ESI calculated value [M+H] + 426, actual value 426.

[0307] Example 20 Synthesis Route: [ka]

[0308] Step 1 Intermediate D (47 mg, 100 μmol), intermediate U (51 mg, 200 μmol), and potassium carbonate (35 mg, 250 μmol) were added to dioxane (6 mL) and water (3 mL). Under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (16 mg, 20 μmol) was added to the reaction solution. The reaction solution was heated to 80°C under nitrogen gas protection and reacted for 8 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 0 / 1, v / v) to obtain compound 20-1. MS-ESI calculated value [M+H] + 522, actual value 522.

[0309] Step 2 Compound 20-1 (31 mg, 59 μmol) was added to formic acid (1.5 mL) and water (0.15 mL), and the reaction solution was reacted at 25 °C for 5 h. The reaction solution was added to saturated sodium bicarbonate solution (20 mL), the pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (Phenomenex Gemini-NX 80 mm × 40 mm × 3 μm column; mobile phase: Phase A was an aqueous solution containing 0.05% ammonia monohydrate, Phase B was acetonitrile; gradient: Phase B 33% to 63%, 8 min) to obtain compound 20. The ee value of compound 20 was measured by SFC (chromatographic column: Chiralcel AD-3 50 mm × 4.6 mm ID, 3 μm; mobile phase: phase A was supercritical CO2, phase B was ethanol solution containing 0.05% diethylamine; gradient: phase B 40%).

[0310] Compound 20: ee%=99.46%, RT=0.598 min. 1H NMR (400 MHz, CD3OD) δ 8.60 (d, J=1.5 Hz, 1H), 8.15 (s, 1H), 7.63-7.42 (m, 4H), 6.62 (d, J=3.0 Hz, 1H), 5.16-5.08 (m, 1H), 4.13-3.99 (m, 2H), 3.93 (s, 3H), 3.83-3.74 (m, 1H), 3.38-3.32 (m, 1H), 3.30-3.23 (m, 2H), 3.01-2.91 (m, 1H), 2.91 - 2.79 (m, 2H), 1.98-1.79 (m, 2H). MS-ESI calculated value [M+H] + 422, actual value 422.

[0311] Example 21 Synthesis Route: [ka]

[0312] Step 1 Intermediate D (50 mg, 105 μmol), Intermediate V (49 mg, 200 μmol), and potassium carbonate (58 mg, 421 μmol) were added to dioxane (10 mL) and water (5 mL). Under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene] Palladium(II) dichloride dichloromethane adduct (17 mg, 21 μmol) was added to the reaction solution. The reaction solution was heated to 85°C under nitrogen gas protection and reacted for 12 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was separated by silica gel column chromatography (dichloromethane / methanol, 20 / 1 to 10 / 1, V / V) to obtain compound 21-1. MS-ESI calculated value [M+H] + 508, measured value 508.

[0313] Step 2 Compound 21-1 (180 mg, 354 μmol) was added to formic acid (1.5 mL) and water (0.15 mL), and the reaction solution was reacted at 25 °C for 2 hours. The reaction solution was added to saturated sodium bicarbonate solution (20 mL), the pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (Phenomenex Gemini-NX 80 mm × 40 mm × 3 μm column; mobile phase: Phase A was an aqueous solution containing 0.05% ammonia monohydrate, Phase B was acetonitrile; gradient: Phase B 32% to 62%, 8 min) to obtain compound 21. The ee value of compound 21 was measured by SFC (chromatography column: Chiralcel OJ-3 100 mm × 4.6 mm I.D., 3 μm; mobile phase: phase A was supercritical CO2, phase B was ethanol solution containing 0.05% diethylamine; gradient: phase B 5% to 40%).

[0314] Compound 21: ee%=98.58%, RT=3.576min. 1 H NMR (400 MHz, CD3OD) δ8.58 (d, J=1.8 Hz, 1H), 8.06 (d, J=1.0 Hz, 1H), 7.64 (d, J=3.3 Hz, 1H), 7.54-7.43 (m, 3H), 6.64 (d, J=3.3 Hz, 1H), 5.23-5.15 (m, 1H), 4.14-4.09 (m, 1H), 4.04 - 3.96 (m, 1H), 3.84-3.75 (m, 1H), 3.39-3.33 (m, 1H), 3.30-3.23 (m, 1H), 3.22-3.15 (m, 1H), 2.97-2.88 (m, 1H), 2.83-2.74 (m, 1H), 2.68-2.60 (m, 1H), 1.98-1.79 (m, 2H). MS-ESI calculated value [M+H] + 408, actual value 408.

[0315] Example 22 Synthesis Route: [ka]

[0316] Step 1 Intermediate D (70 mg, 149 μmol), Intermediate I (95 mg, 223 μmol), and potassium phosphate (95 mg, 447 μmol) were added to THF (5 mL) and water (2 mL). Under nitrogen gas protection, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (19 mg, 30 μmol) was added to the reaction solution. The reaction solution was heated to 70 °C under nitrogen gas protection and reacted for 2 hours. The reaction solution was concentrated under reduced pressure, and the obtained crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 7, V / V) to obtain compound 22-1. 1 H NMR (400 MHz, CDCl3) δ 8.03 (s, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.58 (s, 1H), 7.50-7.43 (m, 1H), 7.43-7.33 (m, 3H), 7.23 (d, J=8.5 Hz, 1H), 5.27-5.13 (m, 1H), 4.69-4.58 (m, 1H), 4.43-4.21 (m, 2H), 4.21-4.13 (m, 1H), 4.09-4.01 (m, 1H), 3.78-3.69 (m, 0.5H), 3.60-3.44 (m, 1.5H), 3.42-3.19 (m, 3.5H), 3.17-3.08 (m, 0.5H), 3.06-2.90 (m, 2H), 2.35-2.19 (m, 2H), 2.09-2.04 (m, 2H), 2.03-1.99 (m, 1H), 1.99 - 1.87 (m, 2H), 1.49 (s, 9H), 1.45 (s, 9H). MS-ESI calculated value [M+Na] + 713, measured value 713.

[0317] Step 2 Compound 22-1 (70 mg, 101 μmol) was added to formic acid (1.5 mL) and water (0.3 mL), and the reaction mixture was allowed to react at 25 °C for 2 h. The reaction mixture was added to saturated sodium bicarbonate solution (50 mL), the pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane / methanol (4 / 1, v / v, 50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (Phenomenex Gemini-NX C18 75 mm x 30 mm x 3 μm column; mobile phase: Phase A was an aqueous solution containing 0.025% formic acid, Phase B was acetonitrile; gradient: Phase B 0% to 30%, 7 min) to obtain the formate salt of compound 22. The formate salt of compound 22 was analyzed by SFC (chromatography column: Chiralcel AD-3 50 mm × 4.6 mm ID, 3 μm; mobile phase: phase A was supercritical CO2, phase B was ethanol solution containing 0.05% diethylamine; gradient: phase B 5% to 40%).

[0318] Compound 22: ee%=75.40%, RT=2.230min. 1 H NMR (400 MHz, CD3OD) δ 8.09 (s, 1H), 7.92 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.62-7.52 (m, 2H), 7.52-7.42 (m, 2H), 5.19-5.13 (m, 1H), 5.13-5.02 (m, 1H), 4.44-4.34 (m, 1H), 4.16-4.03 (m, 1H), 3.88-3.80 (m, 1H), 3.67-3.58 (m, 2H), 3.57-3.48 (m, 1H), 3.40-3.32 (m, 2H), 3.30-3.13 (m, 4H), 3.07-2.97 (m, 1H), 2.54-2.39 (m, 2H), 2.35-2.24 (m, 2H), 2.17-1.98 (m, 2H). MS-ESI calculated value [M+H] + 491, actual value 491.

[0319] Example 23 Synthesis Route: [ka]

[0320] Step 1 Intermediate D (50 mg, 106 μmol), intermediate J (91 mg, 212 μmol), and potassium phosphate (68 mg, 319 μmol) were added to THF (5 mL) and water (2 mL). Under nitrogen gas protection, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (14 mg, 21 μmol) was added to the reaction solution. The reaction solution was heated to 70 °C under nitrogen gas protection and reacted for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 3, V / V) to obtain compound 23-1. 1 H NMR (400 MHz, CDCl3) δ 8.05-7.93 (m, 1H), 7.88 (s, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.50-7.15 (m, 6H), 5.25-5.13 (m, 1H), 4.66-4.53 (m, 1H), 4.43-4.25 (m, 2H), 4.21-3.98 (m, 3H), 3.83-3.73 (m, 0.5H), 3.61-3.49 (m, 1H), 3.44-3.15 m, 3.5H), 3.13-2.87 (m, 3H), 2.33-2.21 (m, 2H), 2.20-2.07 (m, 2H), 2.00-1.85 (m, 2H), 1.50 (s, 9H), 1.46 (s, 9H). MS-ESI calculated value [M+Na] + 713, measured value 713.

[0321] Step 2 Compound 23-1 (60 mg, 87 μmol) was added to formic acid (1.5 mL) and water (0.15 mL), and the reaction mixture was allowed to react at 25 °C for 2 h. The reaction mixture was added to saturated sodium bicarbonate solution (50 mL), adjusted to pH > 8 with saturated sodium bicarbonate solution, and extracted with dichloromethane / methanol (4 / 1, v / v, 50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (Phenomenex Gemini-NX C18 75 mm x 30 mm x 3 μm column; mobile phase: Phase A was aqueous solution containing 0.025% formic acid, Phase B was acetonitrile; gradient: Phase B 0% to 20%, 7 min) to obtain the formate salt of compound 23. The formate salt of compound 23 was analyzed by SFC (chromatographic column: Chiralcel IA 100 mm × 4.6 mm ID, 3 μm; mobile phase: phase A was n-hexane containing 0.1% diethylamine, phase B was ethanol solution containing 0.1% diethylamine; gradient: phase B 80%).

[0322] Compound 23: ee%=90.87%, RT=6.608 min. 1 H NMR (400 MHz, CD3OD) δ 8.41-8.29 (m, 1H), 7.90-7.75 (m, 2H), 7.56-7.38 (m, 4H), 5.25-5.10 (m, 1H), 4.45-4.35 (m, 1H), 4.15-4.02 (m, 1H), 3.92-3.78 (m, 1H), 3.70-3.47 (m, 3H), 3.44-3.36 (m, 1H), 3.28-3.10 (m, 5H), 3.08-2.95 (m, 1H), 2.52-2.38 (m, 4H), 2.15-1.97 (m, 2H). MS-ESI calculated value [M+H] + 491, actual value 491.

[0323] Example 24 Synthesis Route: [ka]

[0324] Step 1 Intermediate D (70 mg, 149 μmol), intermediate K (101 mg, 298 μmol), and potassium phosphate (95 mg, 447 μmol) were added to THF (5 mL) and water (2 mL). Under nitrogen gas protection, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (19 mg, 30 μmol) was added to the reaction solution. The reaction solution was heated to 70 °C under nitrogen gas protection and reacted for 2 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was separated by silica gel column chromatography (dichloromethane / methanol, 20 / 1 to 10 / 1, V / V) to obtain compound 24-1. 1 H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.78 (d, J=8.3 Hz, 1H), 7.60 (s, 1H), 7.51-7.23 (m, 5H), 5.28-5.10 (m, 1H), 4.58-4.42 (m, 1H), 4.25-3.98 (m, 3H), 3.81-3.68 (m, 0.5H), 3.60-3.46 (m, 1H), 3.41-2.80 (m, 7H), 2.58-2.39 (m, 1.5H), 2.38 (s, 3H), 2.34-2.22 (m, 2H), 2.14-2.02 (m, 2H), 2.00-1.81 (m, 2H), 1.45 (s, 9H). MS-ESI calculated value [M+H] + 605, actual value 605.

[0325] Step 2 Compound 24-1 (110 mg, 182 μmol) was added to formic acid (1.5 mL) and water (0.15 mL), and the reaction mixture was allowed to react at 25 °C for 2 h. The reaction mixture was added to saturated sodium bicarbonate solution (50 mL), the pH was adjusted to 8 with saturated sodium bicarbonate solution, and the mixture was extracted with dichloromethane / methanol (4 / 1, V / V, 50 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. The crude product was separated by preparative high-performance liquid chromatography (Phenomenex Gemini-NX 80 mm x 40 mm x 3 μm column; mobile phase: Phase A was an aqueous solution containing 0.05% ammonia monohydrate, Phase B was acetonitrile; gradient: Phase B 36% to 66%, 8 min) to obtain compound 24. Compound 24 was purified by SFC (chromatographic column: Chiralcel IG-3 100 mm × 4.6 mm ID, 3 μm; mobile phase: supercritical CO2 for phase A, and supercritical CO2 for phase B). The ee value was measured using an ethanol solution containing 0.05% diethylamine; gradient: phase B 40%).

[0326] Compound 24: ee%=84.10%, RT=3.362 min. 1 H NMR (400 MHz, CD3OD) δ 8.04 (s, 1H), 7.91 (s, 1H), 7.83 (d, J=8.5 Hz, 1H), 7.62-7.52 (m, 2H), 7.51-7.41 (m, 2H), 5.24-5.17 (m, 1H), 4.82-4.74 (m, 1H), 4.21-4.13 (m, 1H), 4.07-3.99 (m, 1H), 3.86-3.77 (m, 1H), 3.41-3.41 (m, 1H), 3.39-3.35 (m, 1H), 3.31-3.23 (m, 2H), 3.18-3.11 (m, 2H), 3.03-2.94 (m, 1H), 2.91-2.83 (m, 1H), 2.77-2.68 (m, 1H), 2.54 - 2.47 (m, 2H), 2.45 (s, 3H), 2.45-2.37 (m, 2H), 2.12-2.04 (m, 2H), 2.02-1.85 (m, 2H). MS-ESI calculated value [M+H] + 505, actual value 505.

[0327] Biological activity assessment: Experimental Example 1: DPP1 enzyme activity inhibitory effect test

[0328] Test materials: Recombinant human cathepsin C / DPP1 was purchased from R&D Systems. Recombinant human cathepsin L (rhCathepsin L) was purchased from R&D Systems. Gly-Arg-AMC (hydrochloride) was purchased from CAYMAN CHEMICAL COMPANY.

[0329] Experimental Method: 1× Activation Buffer: 5 mM DTT, 0.01% (V / V) Triton X-100 (prepared when used); 1× Experimental Buffer: 50 mM NaCl, 5 mM DTT, 0.01% (V / V) Triton X-100 (prepared when used); Using 1x activation buffer, recombinant human cathepsin C / DPP1 enzyme and recombinant human cathepsin L (rhCathepsin L) enzyme were diluted to concentrations of 2 ng / μL and 0.4 ng / μL, respectively. Equal volumes of the working solutions of the two enzymes were taken, mixed uniformly, and then incubated at 25°C for 60 minutes.

[0330] Test compounds were diluted 5-fold using a multichannel pipette to eight concentrations, from 1 mM to 12.8 nM. Next, using 1x experimental buffer, each gradient of test compound was diluted to a working solution of 4% DMSO, and 5 μL was added to the corresponding wells. The experiment was set up in duplicate and centrifuged at 1000 rpm for 1 minute.

[0331] After incubation, 5 μL of the enzyme mixture was added to each well of the white microwell plate. At this point, the amount of DPP1 enzyme in each well was 5 ng. 5 μL of 1× experimental buffer solution was added to blank control wells.

[0332] Gly-Arg-AMC (hydrochloride) was diluted to 25 μM with 1× experimental buffer, and 10 μL / well was added to a white microwell plate. At this point, the substrate concentration was 12.5 μM. The microplate was centrifuged at 1000 rpm for 1 minute in a centrifuge. At this point, the compound concentration changed from 10 μM to 0.128 nM. After centrifugation, the microplate The tray was covered with a membrane and incubated at 25°C for 60 minutes.

[0333] After the incubation, fluorescence detection was carried out using a multilabel analyzer at an excitation wavelength of 360 nm and an emission wavelength of 460 nm.

[0334] Data Analysis: Converting raw data to enzyme activity using the equation (Sample-Min) / (Max-Min) × 100% yields IC 50 The values ​​of were obtained by curve fitting using four parameters (obtained from log(inhibitor) vs. response -- Variable slope mode in GraphPad Prism).

[0335] Max: Contains recombinant human cathepsin C / DPP1, recombinant human cathepsin L (rhCathepsin L), and Gly-Arg-AMC (hydrochloride).

[0336] Min: Contains no recombinant human cathepsin C / DPP1 or recombinant human cathepsin L (rhCathepsin L).

[0337] Table 1 provides the inhibitory activity of compounds of the present invention against the DPP1 enzyme.

[0338] [Table 1]

[0339] Conclusion: The compounds of the present invention have significant inhibitory activity against the DPP1 enzyme.

[0340] Experimental Example 2: DPP1 activity inhibition test using U937 cells Test materials: 1) Experimental reagents and consumables

[0341] [Table 2]

[0342] 2) Experimental equipment

[0343] [Table 3]

[0344] Experimental Method: 1) Cell inoculation (1) Cell culture medium: 89% RPMI1640, 10% fetal bovine serum and 1% penicillin-streptomycin. (2) The medium was preheated in a water bath at 37°C. (3) The cell suspension in the cell culture flask was removed, placed in a 15 mL centrifuge tube, and centrifuged at 1000 rpm / min for 5 minutes. (4) After centrifugation, the supernatant was discarded, 2 mL of medium was added to resuspend the cells, an appropriate amount of the cell suspension was taken and mixed uniformly with trypan blue, and approximately 0.01 mL of the cell suspension was taken and counted. (5) The cell suspension was diluted with medium to the cell density required for plating (6.67 x 10^5 cells / ml). (6) 30 μL of the cell suspension was added to each well of the cell plate, and the plate was cultured in an incubator at 37°C containing 5% CO for use. (7) The required amount of cells and medium was taken and culture was continued in a new T75 culture flask.

[0345] 2) Medication (1) The test compound was prepared as a 10 mM solution in DMSO. (2) The compounds were diluted 5-fold in eight concentration gradients, from 2 mM to 0.0256 μM. A double-well experiment was set up, with 78 μL of medium added to the middle plate. 2 μL of the diluted compounds were then transferred per well to the corresponding positions on the middle plate. After uniform mixing, 10 μL was transferred per well to the cell plate, resulting in a final compound concentration ranging from 10 μM to 0.128 nM. The cell plate was placed in a CO2 incubator and incubated for 1 hour. (3) After 1 hour of incubation, a 100 μM Gly-Phe-AFC probe solution, i.e., a 60 mM Gly-Phe-AFC probe stock solution, was diluted with culture medium to a 500 μM working solution, and 10 μL was transferred per well to the cell plate. The cell plate was then incubated in a CO2 incubator. The plate was placed in a microwave oven and incubated for 1 hour.

[0346] 3) The plates were read and the data analyzed. (1) Plate reading: After the cell culture was completed, the cell plate was taken out and the plate was read on Victor Nivo.

[0347] Data Analysis: Converting raw data to percent inhibition using the equation (Sample-Min) / (Max-Min) × 100% yields IC 50The values ​​of were obtained by curve fitting using four parameters (obtained from the "log(inhibitor) vs. response -- Variable slope" mode in GraphPad Prism). Table 2 provides the inhibitory activity of the compounds of the present invention against U937 cell DPP1.

[0348] [Table 4]

[0349] Conclusion: The compounds of the present invention have good inhibitory activity against U937 cell DPP1.

[0350] Experimental Example 3: Pharmacokinetic evaluation of compounds of the present invention in mice Experimental objective: To test the pharmacokinetics of the compound in CD-1 mice.

[0351] Experimental materials: CD-1 mice (male, 20-40 g, 4-6 weeks old, Beijing Vital River Laboratory Animal Technology Co., Ltd.)

[0352] Experimental Procedure: The pharmacokinetic properties of compounds in rodents after intravenous and oral administration were tested according to standard protocols. In the experiment, candidate compounds were prepared into clear solutions and administered intravenously and orally in a single dose to two mice, respectively. The solvent for intravenous and oral administration was DMSO / Solutol / water in a ratio of 1:1:8. Whole blood samples collected within 24 hours were collected in commercially available EDTA2K anticoagulation tubes and centrifuged at 6000 g for 3 minutes. The supernatant was separated to obtain plasma samples. A 20-fold volume of acetonitrile solution containing an internal standard was added to precipitate proteins. After centrifugation, the supernatant was removed, and the same volume of water was added. After centrifugation, the supernatant was sampled and analyzed by LC-MS / MS. The blood drug concentration was quantitatively analyzed using the method, and pharmacokinetic parameters such as apparent volume of distribution, clearance, half-life, and area under the drug concentration-time curve were calculated. The experimental results are shown in Table 3.

[0353] [Table 5]

[0354] Conclusion: The compounds of the present invention show better bioavailability, higher area under the drug concentration-time curve, and lower clearance and tissue distribution in pharmacokinetics in CD-1 mice.

[0355] Experimental Example 4: Pharmacokinetic evaluation of the compounds of the present invention in rats Experimental objective: To study the pharmacokinetics of the compound in SD rats.

[0356] Experimental materials: SD rats (male, 200-300 g, 6-10 weeks old, Beijing Vital River Laboratory Animal Technology Co., Ltd.)

[0357] Experimental Procedure: The pharmacokinetic properties of compounds after intravenous and oral administration in rodents were tested according to standard protocols. Candidate compounds were prepared into clear solutions and administered intravenously and orally in a single dose to two rats, respectively. The solvent for intravenous and oral administration was a 5:95 mixture of DMSO and 10% hydroxypropyl-β-cyclodextrin in water. Whole blood samples collected within 24 hours were collected in commercially available EDTA2K anticoagulant tubes and centrifuged at 6000 g for 3 minutes. The supernatant was separated to obtain plasma samples. Proteins were precipitated by adding 20 volumes of acetonitrile containing an internal standard. After centrifugation, the supernatant was collected, and an equal volume of water was added. The supernatant was then centrifuged and sampled. Blood drug concentrations were quantitatively analyzed using LC-MS / MS analysis. Pharmacokinetic parameters, such as apparent volume of distribution, clearance, half-life, and area under the drug concentration-time curve, were calculated.

[0358] The experimental results are shown in Table 4.

[0359] [Table 6]

[0360] Conclusion: The compounds of the present invention show better bioavailability, higher area under the drug concentration-time curve, and lower clearance and tissue distribution in pharmacokinetics in SD rats.

[0361] Experimental Example 5: Evaluation of distribution of the compound of the present invention in mouse tissues (bone marrow) Experimental objective: To study the distribution of the compounds of the present invention in the bone marrow and plasma of CD-1 mice.

[0362] Experimental materials: CD-1 mice (male, 20-40 g, 4-6 weeks old, Beijing Vital River Laboratory Animal Technology Co., Ltd.)

[0363] Experimental Procedure: Using standard protocols, we tested the compound content in mouse bone marrow and plasma after oral administration. In the experiment, candidate compounds were prepared into clear solutions in a 5:95 mixture of DMSO and 10% hydroxypropyl-β-cyclodextrin aqueous solution and administered orally to mice at a single dose of 5 mg / kg. Whole blood and bone marrow samples were collected at 0.25, 0.5, 1, 2, 4, 6, and 24 hours. Whole blood samples were collected in commercially available EDTA2K anticoagulant tubes and centrifuged at 6000 g for 3 minutes. The supernatant was separated to obtain plasma samples. An acetonitrile solution containing an internal standard was added to precipitate proteins, and the supernatant was centrifuged and collected. An equal volume of water was added and mixed thoroughly. Blood drug concentrations were then quantified using LC-MS / MS analysis, and the area under the drug concentration-time curve was calculated. The femurs and tibias of each mouse were removed, muscle removed, one end cut off, and placed face down in a centrifuge tube. The tube was centrifuged at 8000 rpm for 1 minute. The precipitate was the bone marrow. The bone marrow was mixed with 50% methanol and homogenized. An acetonitrile solution containing an internal standard was added to precipitate proteins. The homogenate was centrifuged and the supernatant was collected. An equal volume of water was added and the mixture was mixed evenly. The drug concentration in the bone marrow was then quantitatively analyzed using LC-MS / MS analysis, and the area under the drug concentration-time curve was calculated.

[0364] The formula for calculating the bone marrow / plasma partition coefficient is bone marrow / plasma ratio = bone marrow AUC 0-last / plasma AUC 0-last The experimental results are shown in Table 5.

[0365] [Table 7]

[0366] Conclusion: The compounds of the present invention have a higher distribution in the bone marrow of CD-1 mice.

[0367] Experimental Example 6: Evaluation of distribution of the compound of the present invention in rat tissues (bone marrow) Experimental purpose: To examine the distribution of the test compound in the bone marrow and plasma of SD rats.

[0368] Experimental materials: SD rats (male, 200-300 g, 6-10 weeks old, Beijing Vital River Laboratory Animal Technology Co., Ltd.)

[0369] Experimental Procedure: Using standard protocols, the content of test compounds in rat bone marrow and plasma after oral administration was examined. In the experiment, candidate compounds were prepared into clear solutions in a 5:95 mixture of DMSO and 10% hydroxypropyl-β-cyclodextrin aqueous solution and administered orally to rats at a single dose of 5 mg / kg. Whole blood and bone marrow samples were collected at 0.25, 0.5, 1, 2, 4, 6, and 24 hours. Whole blood samples were collected in commercially available EDTA2K anticoagulant tubes and centrifuged at 6000 g for 3 minutes. The supernatant was separated to obtain plasma samples. An acetonitrile solution containing an internal standard was added to precipitate proteins, and the supernatant was centrifuged and collected. An equal volume of water was added and mixed uniformly. Blood drug concentrations were then quantified using LC-MS / MS analysis, and the area under the drug concentration-time curve was calculated. The left femur of a rat was removed, muscle removed, one end cut off, placed face down in a centrifuge tube, and centrifuged at 8000 rpm for 1 minute. The precipitate was bone marrow. The bone marrow was mixed with 50% methanol and homogenized. An acetonitrile solution containing an internal standard was added to precipitate proteins, and the homogenate was centrifuged to remove the supernatant. An equal volume of water was added and mixed uniformly. The drug concentration in the bone marrow was then quantitatively analyzed using LC-MS / MS analysis, and the area under the drug concentration-time curve was calculated.

[0370] The formula for calculating the bone marrow / plasma partition coefficient is bone marrow / plasma ratio = bone marrow AUC 0-last / plasma AUC 0-last The experimental results are shown in Table 6.

[0371] [Table 8]

[0372] Conclusion: The compounds of the present invention have higher distribution in the bone marrow of SD rats.

[0373] Experimental Example 7: Evaluation of in vivo efficacy of the compounds of the present invention on the activity of neutrophil elastase in rat bone marrow Experimental objective: To evaluate the effect of the compounds of the present invention on the activity of neutrophil elastase in bone marrow of SD rats.

[0374] Experimental materials: SD rats (male, 200-300 g, 6-10 weeks old, Beijing Vital River Laboratory Animal Technology Co., Ltd.)

[0375] Experimental Procedure: The experimental animals were divided into groups and administered the drugs according to Table 7. Two hours after the final administration, the bone marrow samples were collected from the animals. The red blood cells were first lysed with an erythrocyte lysing solution to preserve the lymphocytes, and then the lymphocytes were lysed with a lymphocyte lysing solution. The supernatant was collected for protein quantification and neutrophil elastase enzyme activity measurement, and the neutrophil elastase activity in the sample was calculated. The administration protocol is shown in Table 7.

[0376] [Table 9]

[0377] Experimental indicators: The activity of neutrophil elastase in the bone marrow samples was calculated, and the experimental results are shown in Figure 1.

[0378] Conclusion: The compounds of the present invention significantly inhibit the activity of neutrophil elastase in rats. It is possible.

Claims

1. A compound of formula (II) or a pharmaceutically acceptable salt thereof: 【Chemical 1】 (however, Z is selected from N and C; Structural Unit 【Chemistry 2】 wherein the structural unit is selected from 【Chemistry 3】 is selected from 【Chemistry 4】 are each independently selected from a single bond and a double bond, 【Chemistry 5】 When is selected from a double bond, R ２ does not exist, T is independently N or CR ３ is selected from Each R １ are each independently H, F, Cl, Br, I, —OH, or —NH ２ , -CN and C １－３ alkyl, wherein said C １－３ Alkyl is one, two or three R ａ is optionally replaced by R ２ is H, F, Cl, Br, I, =O, -OH, -NH ２ , -CN,C １－３ alkyl and 5- to 6-membered heterocycloalkyl, wherein said C １－３ Alkyl and 5- to 6-membered heterocycloalkyl each independently have 1, 2, or 3 R ｂ is optionally replaced by R ３ is H, F, Cl, Br, I, -OH, -NH ２ , -CN and C １－３ alkyl, wherein said C １－３ Alkyl is one, two or three R ｃ is optionally replaced by R ４ is H, F, Cl, Br, I, -OH, -NH ２ , -CN and C １－３ alkyl, wherein said C １－３ Alkyl is one, two or three R ｄ is optionally replaced by R ５ is H, F, Cl, Br, I, -OH, -NH ２ , -CN and C １－３ alkyl, wherein said C １－３ Alkyl is one, two or three R ｅ is optionally replaced by R ６ is H, F, Cl, Br, I, -OH, -NH ２ , -CN and C １－３ alkyl, wherein said C １－３ Alkyl is one, two or three R ｆ is optionally replaced by R ａ are each independently F, Cl, Br, I, ═O, —OH, or —NH ２ and -CN; R ｂ are each independently F, Cl, Br, I, ═O, —OH, or —NH ２ , -CN and C １－３ alkyl, R ｃ are each independently F, Cl, Br, I, ═O, —OH, or —NH ２ and -CN; R ｄ are each independently F, Cl, Br, I, ═O, —OH, or —NH ２ and -CN; R ｅ are each independently F, Cl, Br, I, ═O, —OH, or —NH ２ and -CN; R ｆ are each independently F, Cl, Br, I, ═O, —OH, or —NH ２ and -CN; n is selected from 1, 2, 3 and 4; The 5- to 6-membered heterocycloalkyl contains 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from —O—, —NH—, —S—, and —N—.

2. 2. The compound of claim 1, wherein the compound has a structure represented by formula (II'): or a pharmaceutically acceptable salt thereof. 【Chemistry 6】 (However, structural units 【Chemistry 7】 , Z, R １ , R ２ , R ６ and n is as defined in claim 1; Carbon atoms marked with "*" and "#" are chiral carbon atoms and exist in the form of either the (R) or (S) single enantiomer or in a form enriched in one enantiomer.

3. R ｂ is F, Cl, Br and -CH ３ 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, selected from:

4. R １ is H, F, Cl and -CH ３ 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, selected from:

5. R ２ is H, -CH ３ , 【Chemistry 8】 wherein said —CH ３ , 【Chemistry 9】 each independently represents 1, 2 or 3 R ｂ 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, optionally substituted by:

6. R ２ is H, -CH ３ , 【Chemistry 10】 6. The compound of claim 5, or a pharmaceutically acceptable salt thereof, selected from:

7. R ３ 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein is selected from H, F, Cl and Br.

8. R ４ 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein:

9. R ５ is H and -CH ３ 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, selected from:

10. R ６ 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein is selected from H, F, Cl and Br.

11. Structural Unit 【Chemistry 11】 3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, selected from:

12. Structural Unit 【Chemistry 12】 12. The compound of claim 11, or a pharmaceutically acceptable salt thereof, selected from:

13. Structural Unit 【Chemistry 13】 13. The compound of claim 12, or a pharmaceutically acceptable salt thereof, selected from:

14. The compound of claim 1, wherein the compound has a structure represented by formula (II-1): or a pharmaceutically acceptable salt thereof. 【Chemistry 14】 (However, structural units 【Chemistry 15】 , R １ , R ２ , R ６ and n is as defined in claim 1.

15. The compound of claim 14, wherein the compound has a structure represented by formula (II'-1): or a pharmaceutically acceptable salt thereof. 【Chemistry 16】 (However, structural units 【Chemistry 17】 , R １ , R ２ , R ６ and n is as defined in claim 14; Carbon atoms marked with "*" and "#" are chiral carbon atoms and exist in the form of either the (R) or (S) single enantiomer or in a form enriched in one enantiomer.

16. 15. The compound of claim 14, wherein the compound has the formula (I) or a pharmaceutically acceptable salt thereof: 【Chemistry 18】 (however, Structural Unit 【Chemistry 19】 is selected from 【Chemistry 20】 are each independently selected from a single bond and a double bond, 【Chemical 21】 When is selected from a double bond, R ２ does not exist, T is independently N or CR ３ is selected from R ３ is H, F, Cl, Br, I, -OH, -NH ２ , -CN and C １－３ alkyl, wherein said C １－３ Alkyl is one, two or three R ｃ is optionally replaced by R ４ is H, F, Cl, Br, I, -OH, -NH ２ , -CN and C １－３ alkyl, wherein said C １－３ Alkyl is one, two or three R ｄ is optionally replaced by R ５ is H, F, Cl, Br, I, -OH, -NH ２ , -CN and C １－３ alkyl, wherein said C １－３ Alkyl is one, two or three R ｅ is optionally replaced by R ｃ are each independently F, Cl, Br, I, ═O, —OH, or —NH ２ and -CN; R ｄ are each independently F, Cl, Br, I, ═O, —OH, or —NH ２ and -CN; R ｅ are each independently F, Cl, Br, I, ═O, —OH, or —NH ２ and -CN; R １ , R ２ and n is as defined in claim 14.

17. 17. The compound of claim 16, wherein the compound has a structure represented by formula (I-1), (I-2), or (I-3), or a pharmaceutically acceptable salt thereof. 【Chemical 22】 (However, T, R １ , R ２ , R ４ , R ５ and n is as defined in claim 16.

18. 18. The compound of claim 17, wherein the compound has a structure represented by formula (I-1A), (I-1B), (I-2A), (I-2B), or (I-3A), or a pharmaceutically acceptable salt thereof. 【Chemical 23】 (However, T, R １ , R ２ , R ４ and R ５ is as defined in claim 17.

19. 19. The compound of claim 18, wherein the compound has a structure represented by formula (I'-1A), (I'-1B), (I'-2A), (I'-2B), or (I'-3A), or a pharmaceutically acceptable salt thereof. 【Chemistry 24】 (However, T, R １ , R ２ , R ４ and R ５ is as defined in claim 18, Carbon atoms marked with "*" and "#" are chiral carbon atoms and exist in the form of either the (R) or (S) single enantiomer or in a form enriched in one enantiomer.

20. A compound of the formula: or a pharmaceutically acceptable salt thereof: 【Chemistry 25】 【Chemical 26】

21. 21. The compound of claim 20, wherein the compound is a compound of the formula: or a pharmaceutically acceptable salt thereof. 【Chemical 27】 ​ 【Chemical formula 29】 【Chemistry 30】

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