Fused ring derivatives containing 1,4-oxazepane

Abstract

This relates to a series of fused cyclic derivatives containing 1,4-oxazazene-heptane and methods for their preparation, specifically to compounds represented by formula (II) and their pharmaceutically acceptable salts.

Description

[0001] This application claims the following priority:

[0002] CN202110164857.7, February 5, 2021;

[0003] CN202111138395.8, September 27, 2021. Technical Field

[0004] This invention relates to a series of fused cyclic derivatives containing 1,4-oxazacycloheptane and methods for their preparation, specifically to compounds of formula (II) and their pharmaceutically acceptable salts. Background Technology

[0005] 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 composed of a tetramer of four identical subunits, each consisting of a heavy chain, a light chain, and an exclusive domain (Turk, D. et al. EMBO J. 2001, 20, 6570-6582). The main physiological function of DPP1 is to activate pro-inflammatory neutrophil serine proteases (NSPs, including neutrophil elastase, protease 3, and cathepsin G) in the bone marrow by cleaving the N-terminal dipeptide. NSPs are closely related to inflammation regulation, can activate various cytokines, and play an important role in the clearance of pathogenic microorganisms. Studies have shown that persistent inflammatory responses and excessive activation of NSPs are prevalent in the airways of patients with chronic obstructive pulmonary disease (COPD) or bronchiectasis, leading to the degradation of pulmonary elastin and other proteins, further causing lung tissue damage and bronchial wall destruction (Christine T.N. Pham, Nat. Rev. Immunol. 2006, 6, 541-550). DPP1 inhibitors can inhibit the activation of pro-inflammatory neutrophil proteases at the source, thereby suppressing the inflammatory response and airway damage caused by neutrophils in the airways.

[0006] Currently, there are no DPP1 inhibitors on the market. Bresencatib (INS1007, also known as AZD7986) is the most advanced drug in clinical research, having met its primary endpoint in a Phase II clinical trial for bronchiectasis and currently undergoing Phase III clinical trials. Furthermore, AZD7986 is in Phase II clinical trials for the treatment of chronic obstructive pulmonary disease (COPD). Therefore, the development of DPP1 inhibitors has broad market prospects. Summary of the Invention

[0007] This invention provides compounds of formula (II) or pharmaceutically acceptable salts thereof.

[0008]

[0009] in,

[0010] Z is selected from N and C;

[0011] Structural unit Selected from The structural unit Selected from

[0012] They are selected independently from single and double bonds, respectively, where when When selected from a double bond, R2 does not exist;

[0013] T is independently selected from N and CR3, respectively;

[0014] Each R1 is independently selected from H, F, Cl, Br, I, -OH, -NH2, -CN, and C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. a Replaced;

[0015] R2 is selected from H, F, Cl, Br, I, =O, -OH, -NH2, -CN, C 1-3 Alkyl and 5-6 membered heterocyclic alkyl, wherein the C 1-3 Alkyl groups and 5-6 membered heterocyclic alkyl groups are each independently and optionally bound by 1, 2, or 3 R groups. b Replaced;

[0016] R3 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, and C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. c Replaced;

[0017] R4 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, and C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. d Replaced;

[0018] R5 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, and C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. e Replaced;

[0019] R6 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, and C.1-3 Alkyl, wherein the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. f Replaced;

[0020] R a They are independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN, respectively;

[0021] R b Each of the following is independently selected from F, Cl, Br, I, =O, -OH, -NH2, -CN, and C. 1-3 alkyl;

[0022] R c They are independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN, respectively;

[0023] R d They are independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN, respectively;

[0024] R e They are independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN, respectively;

[0025] R f They are independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN, respectively;

[0026] n is selected from 1, 2, 3, and 4;

[0027] The 5-6 membered heterocyclic alkyl group comprises 1, 2, 3 or 4 heteroatoms or heterogroups independently selected from -O-, -NH-, -S- and -N-.

[0028] This invention provides compounds of formula (I) or pharmaceutically acceptable salts thereof.

[0029]

[0030] in,

[0031] Selected from single and double bonds;

[0032] Structural unit Selected from

[0033] T is selected from N and CR3;

[0034] R1 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, and C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's.a Replaced;

[0035] R2 is selected from H and C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. b Replaced;

[0036] R3 is selected from H and C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. c Replaced;

[0037] R4 is selected from H and C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. d Replaced;

[0038] R5 is selected from H and C. 1-3 Alkyl, wherein the C 1-3 Alkyl groups may be optionally surrounded by 1, 2, or 3 R's. e Replaced;

[0039] R a They are independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN, respectively;

[0040] R b They are independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN, respectively;

[0041] R c They are independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN, respectively;

[0042] R d They are independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN, respectively;

[0043] R e They are independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN, respectively;

[0044] n is selected from 1, 2, 3, and 4.

[0045] In some embodiments of the present invention, the above-mentioned compound has the structure shown in formula (II′):

[0046]

[0047] Among them, structural units Z, R1, R2, R6 and n are as defined in this invention;

[0048] Carbon atoms marked with "*" and "#" are chiral carbon atoms, existing as a single enantiomer (R) or (S) or rich in one enantiomer.

[0049] In some embodiments of the present invention, the above-mentioned compound has the structure shown in formula (I′):

[0050]

[0051] Among them, structural units R1, R2, and n are as defined in this invention;

[0052] Carbon atoms marked with "*" and "#" are chiral carbon atoms, existing as a single enantiomer (R) or (S) or rich in one enantiomer.

[0053] In some embodiments of the present invention, the above-mentioned R a R c R d and R e The variables are independently selected from F, Cl, and Br, respectively, and other variables are as defined in this invention.

[0054] In some embodiments of the present invention, the above-mentioned R b The components are selected from F, Cl, Br and -CH3, and other variables are as defined in this invention.

[0055] In some embodiments of the present invention, R1 is selected from H, F, Cl and -CH3, and other variables are as defined in the present invention.

[0056] In some embodiments of the present invention, R1 is selected from H and F, and other variables are as defined in the present invention.

[0057] In some embodiments of the present invention, R2 is selected from H, -CH3, The -CH3, Each of the 1, 2, or 3 R's can be selected independently. b Replaced by, R b Other variables are as defined in this invention.

[0058] In some embodiments of the present invention, R2 is selected from H, -CH3, Other variables are as defined in this invention.

[0059] In some embodiments of the present invention, R2 is selected from H and -CH3, and other variables are as defined in the present invention.

[0060] In some embodiments of the present invention, R3 is selected from H, F, Cl, and Br, and other variables are as defined in the present invention. In some embodiments of the present invention, R3 is selected from H, and other variables are as defined in the present invention.

[0061] In some embodiments of the present invention, R4 is selected from H, and other variables are as defined in the present invention.

[0062] In some embodiments of the present invention, R5 is selected from H and -CH3, and other variables are as defined in the present invention.

[0063] In some embodiments of the present invention, R6 is selected from H, F, Cl and Br, and other variables are as defined in the present invention.

[0064] In some embodiments of the present invention, the above-mentioned structural unit Selected from R2, R3, R4, R5, and R6, and other variables are as defined in this invention.

[0065] In some embodiments of the present invention, the above-mentioned structural unit Selected from R2, R3, R4, R5, and R6, and other variables are as defined in this invention.

[0066] In some embodiments of the present invention, the above-mentioned structural unit Selected from Other variables are as defined in this invention.

[0067] In some embodiments of the present invention, the structure shown in the above compound formula (II-1) is:

[0068]

[0069] Among them, structural units R1, R2, R6 and n are as defined in this invention.

[0070] In some embodiments of the present invention, the structure shown in the above compound formula (II′-1) is:

[0071]

[0072] Among them, structural units R1, R2, R6 and n are as defined in this invention;

[0073] Carbon atoms marked with "*" and "#" are chiral carbon atoms, existing as a single enantiomer (R) or (S) or rich in one enantiomer.

[0074] In some embodiments of the present invention, the compound represented by the above-described compound formula (I) or a pharmaceutically acceptable salt thereof,

[0075]

[0076] in,

[0077] Structural unit Selected from

[0078] They are selected independently from single and double bonds, respectively, where when When selected from a double bond, R2 does not exist;

[0079] T, R1, R2, R4, R5 and n are as defined in this invention.

[0080] In some embodiments of the present invention, the above-mentioned compounds have the structures shown in (I-1), (I-2), or (I-3):

[0081]

[0082] Wherein, T, R1, R2, R4, R5 and n are as defined in this invention.

[0083] In some embodiments of the present invention, the above-mentioned compounds have the structures shown in formula (I-1A), (I-1B), (I-2A), (I-2B), or (I-3A):

[0084]

[0085] Wherein, T, R1, R2, R4 and R5 are as defined in this invention.

[0086] In some embodiments of the present invention, the above-mentioned compounds have the structures shown in formula (I′-1A), (I′-1B), (I′-2A), (I′-2B), or (I′-3A):

[0087]

[0088] Wherein, T, R1, R2, R4 and R5 are as defined in this invention;

[0089] Carbon atoms marked with "*" and "#" are chiral carbon atoms, existing as a single enantiomer (R) or (S) or rich in one enantiomer.

[0090] In some embodiments of the present invention, the above-mentioned compounds have structures shown in formula (I′-1A-1), (I′-1B-1), (I′-2A-1), (I′-2B-1), or (I′-3A-1):

[0091]

[0092]

[0093] Wherein, T, R1, R2, R4 and R5 are as defined in this invention;

[0094] Some solutions in this invention are derived from arbitrary combinations of the above-mentioned variables.

[0095] The present invention also provides compounds of the following formula or pharmaceutically acceptable salts thereof.

[0096]

[0097]

[0098] The present invention also provides compounds of the following formula or pharmaceutically acceptable salts thereof.

[0099]

[0100]

[0101]

[0102]

[0103]

[0104] Technical effect

[0105] The compounds provided by this invention have significant inhibitory activity against DPP1 at the enzyme and cellular levels; they have high oral exposure in mice and rats and exhibit good pharmacokinetic properties; they have strong distribution ability in bone marrow; and they can significantly inhibit the activity of elastase in rat bone marrow neutrophils.

[0106] Definitions and Explanations

[0107] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings. A particular term or phrase should not be considered uncertain or unclear unless specifically defined, but should be understood in its ordinary sense. When a trade name appears herein, it is intended to refer to the corresponding product or its active ingredient.

[0108] The term “pharmaceutically acceptable” as used herein refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0109] The term "pharmaceutically acceptable salt" refers to a salt of the compounds of this invention, prepared by reacting a compound with a relatively non-toxic acid or base, as discovered in this invention, with a specific substituent. When the compounds of this invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine, or magnesium salts, or similar salts. When the compounds of this invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts, such as hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, octanoic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; as well as salts of amino acids (such as arginine) and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups, and thus can be converted into either a base or an acid addition salt.

[0110] The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing acid radicals or bases by conventional chemical methods. Generally, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of a suitable base or acid in water or an organic solvent or a mixture thereof.

[0111] The compounds of this invention can exist in specific geometric or stereoisomeric forms. This invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)- enantiomers, (R)- and (S)- enantiomers, diastereomers, (D)- isomers, (L)- isomers, and racemic mixtures thereof, as well as other mixtures, such as mixtures enriched with enantiomers or diastereomers, all of which are within the scope of this invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are included within the scope of this invention.

[0112] Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.

[0113] Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise because the single bonds of double bonds or cyclic carbon atoms cannot rotate freely.

[0114] Unless otherwise stated, the term "diastereomer" refers to a stereoisomer of a molecule having two or more chiral centers and being in a non-mirror relationship with each other.

[0115] Unless otherwise stated, "(+)" indicates right-handed rotation, "(-)" indicates left-handed rotation, and "(±)" indicates racemic rotation.

[0116] Unless otherwise specified, use wedge-shaped solid line keys. and wedge-shaped dashed key The absolute configuration of the center of a solid is represented by a straight solid line key. and straight dashed key The relative configuration of the center of a solid is indicated by a wavy line. Indicates wedge-shaped solid line key or wedge-shaped dashed key Or use wavy lines Indicates a straight solid line key and straight dashed key

[0117] The compounds of this invention can exist in specific forms. Unless otherwise stated, the terms "tautomer" or "tautomer form" refer to isomers of different functional groups in dynamic equilibrium at room temperature, capable of rapidly interconverting. If tautomerization is possible (e.g., in solution), chemical equilibrium of the tautomer can be achieved. For example, proton tautomers (also called prototropic tautomers) involve interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers involve interconversions involving the rearrangement of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between the two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0118] Unless otherwise stated, the terms "rich in one isomer," "isomer enrichment," "rich in one enantiomer," or "enantiomer enrichment" mean that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.

[0119] Unless otherwise stated, the terms "isomer excess" or "enantiomer excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomer excess (ee value) is 80%.

[0120] Optically active (R)- and (S)- isomers, as well as D- and L- isomers, can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. To obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated, and the auxiliary group is cleaved to provide the desired enantiomer in pure form. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a salt of the diastereomeric isomer is formed with a suitable optically active acid or base, followed by diastereomeric resolution using conventional methods known in the art, and then the pure enantiomer is recovered. Furthermore, the separation of enantiomers and diastereomeric isomers is typically accomplished by using chromatography employing a chiral stationary phase, optionally combined with chemical derivatization (e.g., from amines to carbamates).

[0121] The compounds of this invention may contain atomic isotopes in non-natural proportions on one or more atoms constituting the compound. For example, the compounds may be labeled with radioactive isotopes, such as tritium. 3 H), Iodine-125 125 I) or C-14 14 C). For example, deuterium can be used to replace hydrogen to form deuterated drugs. The bond between deuterium and carbon is stronger than that between ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have advantages such as reduced toxicity, increased drug stability, enhanced efficacy, and prolonged drug biological half-life. All isotopic variations of the compounds of this invention, regardless of radioactivity, are included within the scope of this invention.

[0122] The terms “optional” or “optionally” refer to events or conditions that may occur but are not required to occur as described below, and the description includes both cases where said events or conditions occur and cases where said events or conditions do not occur.

[0123] The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which can include deuterium and hydrogen variants, provided that the valence state 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 on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, unless otherwise specified, and the type and number of substituents can be arbitrary on a chemically feasible basis.

[0124] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0125] When the number of a linking group is 0, such as -(CRR)0-, it indicates that the linking group is a single bond.

[0126] When one of the variables is selected as a single bond, it means that the two groups it connects to are directly connected. For example, when L in ALZ represents a single bond, it means that the structure is actually AZ.

[0127] When a substituent is vacant, it means that the substituent does not exist. For example, if X is vacant in AX, the structure is actually A. When the listed substituents do not specify which atom they are attached to the substituted group through, such substituents can be bonded to any of their atoms. For example, a pyridinium group as a substituent can be attached to the substituted group through any carbon atom on the pyridine ring.

[0128] When the listed linking groups do not specify their linking direction, the linking direction is arbitrary, for example, The linker group L is -MW-. In this case, -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form a ring. Alternatively, rings A and B can be connected in the opposite direction to the left-to-right reading order to form a ring. The combination of linking groups, substituents, and / or their variants is permitted only if such a combination produces a stable compound.

[0129] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups by chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with a corresponding valence. The chemical bonds connecting the site to other groups can be straight solid line bonds. Straight dashed key or wavy line For example, a straight solid line bond in -OCH3 indicates that the oxygen atom in that group is connected to other groups; The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the nitrogen atom in the group; The wavy lines in the diagram indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 2. This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... Even if H atoms are drawn on -N- in these four connection methods, Still includes In this type of linkage, when a chemical bond is attached, the number of hydrogen atoms at that site is reduced by one, resulting in a monovalent piperidinyl group.

[0130] When the chemical bond of a substituent intersects the chemical bonds of two atoms on the linking ring, it means that the substituent can bond with any atom on the ring. When the atom to which a substituent is attached is not specified, the substituent can bond with any atom. If the atom to which the substituent is attached is in a bicyclic or tricyclic system, it means that the substituent can bond with any atom in any ring of that system. Combinations of substituents and / or variables are only permitted if the combination produces a stable compound. For example, structural units. This indicates that it can be substituted at any position on the cyclohexyl or cyclopentyl group.

[0131] Unless otherwise specified, the term ring This refers to aromatic rings, including benzene rings and 5-6 membered heteroaromatic rings, such as cyclopentadienylene rings. Including but not limited to wait.

[0132] Unless otherwise specified, the terms "5-6 membered heteroaryl" and "5-6 membered heteroaryl" are used interchangeably in this invention. The term "5-6 membered heteroaryl" refers to a monocyclic group with a conjugated π-electron system consisting of 5 to 6 ring atoms, where 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO and S (=O)). p(where p is 1 or 2). The 5-6 membered heteroaryl group can be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl group includes both 5-membered and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrole (including N-pyrrole, 2-pyrrole, and 3-pyrrole), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl), imidazole (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl), and triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl). (and 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isooxazolyl, 4-isooxazolyl and 5-isooxazolyl, etc.), 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.).

[0133] Unless otherwise specified, the term "C" 1-3 "alkyl" is used to denote a straight-chain or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 Alkyl groups include C 1-2 and C 2-3 Alkyl groups, etc.; they can be monovalent (e.g., methyl), divalent (e.g., methylene), or polyvalent (e.g., methine). C 1-3 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.

[0134] Unless otherwise specified, the number of atoms in a ring is usually defined as the elemental number of the ring. For example, a "5-6 elemental ring" refers to a "ring" with 5-6 atoms arranged around it.

[0135] Unless otherwise specified, the term "5-6 membered heterocyclic alkyl" on its own or in combination with other terms refers to a saturated cyclic group consisting of 5 to 6 ring atoms, wherein 1, 2, 3, or 4 of the 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(where p is 1 or 2). It includes monocyclic and bicyclic systems, wherein bicyclic systems include spirocyclic, fused, and bridged rings. Furthermore, regarding the "5-6 membered heterocyclic alkyl", the heteroatom can occupy the connection position between the heterocyclic alkyl group and the rest of the molecule. The 5-6 membered heterocyclic alkyl group includes 5-membered and 6-membered heterocyclic alkyl groups. Examples of 5-6 membered heterocyclic alkyl groups include, but are not limited to, pyrrolidinyl, pyrazolyl, imidazoalkyl, tetrahydrothiopheneyl (including tetrahydrothiophene-2-yl and tetrahydrothiophene-3-yl), tetrahydrofuranyl (including tetrahydrofuran-2-yl), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl), piperazinyl (including 1-piperazinyl and 2-piperazinyl), morpholinyl (including 3-morpholinyl and 4-morpholinyl), dioxyl, dithiaalkyl, isoxazolyl, isothiazolyl, 1,2-oxazinyl, 1,2-thiaazinyl, hexahydropyridazinyl, etc. 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., nucleophilic substitution). For example, representative leaving groups include trifluoromethanesulfonates; chlorine, bromine, iodine; sulfonate groups, such as methanesulfonates, toluenesulfonates, p-bromobenzenesulfonates, p-toluenesulfonates, etc.; acyl groups, such as acetoxy groups, trifluoroacetoxy groups, etc.

[0136] Unless otherwise specified, C n-n+m Or C n -C n+m This includes any specific case with n to n+m carbons, such as C 1-12 Including C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 C 11 and C 12 It also includes any range from n to n+m, such as C 1-12 Including 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-membered to n+m-membered rings represent the number of atoms in the ring from n to n+m. For example, 3-12-membered rings include 3-membered, 4-membered, 5-membered, 6-membered, 7-membered, 8-membered, 9-membered, 10-membered, 11-membered, and 12-membered rings, and also any range from n to n+m. For example, 3-12-membered rings include 3-6-membered, 3-9-membered, 5-6-membered, 5-7-membered, 6-7-membered, 6-8-membered, and 6-10-membered rings, etc.

[0137] The term "protecting group" includes, but is not limited to, "amino protecting group," "hydroxy protecting group," or "thiol protecting group." The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen position of an amino group. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (e.g., acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), triphenylmethyl (Tr), 1,1-di-(4′-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxyl protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Representative hydroxyl protecting groups include, but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanolyl groups (e.g., acetyl); arylmethyl groups, such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl (diphenylmethyl, DPM); silyl groups, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc.

[0138] The compounds of the present invention can be prepared by a variety of synthetic methods known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention.

[0139] The structures of the compounds of this invention can be confirmed by conventional methods well known to those skilled in the art. If this invention relates to the absolute configuration of a compound, that absolute configuration can be confirmed by conventional techniques in the art. For example, single-crystal X-ray diffraction (SXRD) is used, where the cultured single crystal is used to collect diffraction intensity data using a Bruker D8 venture diffractometer with CuKα radiation as the light source. The scanning method is as follows: After scanning and collecting relevant data, the crystal structure can be further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.

[0140] The volume used in this invention is commercially available.

[0141] This invention uses the following abbreviations: Alloc represents allyloxycarbonyl; SEM represents trimethylsilylethoxymethyl; OTs represents 4-toluenesulfonyloxy; OMs represents methanesulfonyloxy; Boc represents tert-butyloxycarbonyl; 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 ditert-butyl dicarbonate; NH4Cl represents ammonium chloride; T3 P represents 1-propylphosphonic tricyclic anhydride; Pd / C represents palladium / carbon catalyst; TMSN3 represents azidotrimethylsilane; NCS represents N-chlorosuccinimide; HBr represents hydrobromic acid; AcOH represents acetic acid; HATU represents O-(7-azabenzotriazole)-N,N,N′,N′-tetramethylurea hexafluorophosphate; DBU represents 1,8-diazabicycloundec-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; SFC represents supercritical fluid chromatography. DMSO represents dimethyl sulfoxide; DMSO-d6 represents deuterated dimethyl sulfoxide; CD3OD represents deuterated methanol; CDCl3 represents deuterated chloroform; D2O represents deuterated water; Solutol represents polyethylene glycol (15)-hydroxystearate.

[0142] Compounds are named according to conventional naming principles in the field or using Software naming conventions are used; commercially available compounds use supplier catalog names. Attached Figure Description

[0143] Figure 1 These are the in vivo efficacy test results of the compound of this invention on the elastase activity of rat bone marrow neutrophils. Detailed Implementation

[0144] The present invention will be described in detail below with reference to examples, but this does not imply any adverse limitation on the invention. The compounds of the present invention can be prepared by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include, but are not limited to, the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention.

[0145] Intermediate A

[0146] Synthesis route:

[0147]

[0148] first step

[0149] Intermediate A-1 (12.5 g, 31.95 mmol) was dissolved in DMF (50 mL), followed by the addition of DIEA (6.19 g, 47.93 mmol) and O-benzotriazole-N,N,N′,N′-tetramethylurea tetrafluoroborate (10.26 g, 31.95 mmol). The mixture was stirred at 25 °C for 30 minutes, then ammonia (12 M, 4.79 mL, 57.52 mmol) was added, and the mixture was stirred at 25 °C for another 12 hours. After the reaction was complete, water (50 mL) was added to the reaction mixture, and the mixture was stirred for 15 minutes. The mixture was filtered, the filter cake was collected, and dried to obtain intermediate A-2, which was used directly in the next reaction. MS-ESI calculated value [M+Na] + 413, measured value 413.

[0150] Step 2

[0151] Intermediate A-2 (20.0 g, 50.11 mmol) was dissolved in dichloromethane (200 mL), and N-(triethylaminosulfonyl)carbamate (29.26 mg, 122.77 mmol) was added. The mixture was stirred at 25 °C for 12 hours. After the reaction was complete, water (200 mL) was added to the reaction solution, and extraction was performed. The organic phase was dried over anhydrous sodium sulfate, and the crude product obtained by vacuum concentration was separated into intermediates A-3 by silica gel column chromatography (petroleum ether / ethyl acetate, 15 / 1 to 1 / 1, V / V). MS-ESI calculated value [M+H] + 373, measured value 373.

[0152] Step 3

[0153] Intermediate A-3 (9.6 g, 25.79 mmol) was dissolved in THF (100 mL), and methanesulfonic acid (18.59 g, 193.44 mmol) was added. The mixture was stirred at 25 °C for 12 hours. After the reaction was complete, the pH was adjusted to >8 with saturated sodium bicarbonate solution, and the mixture was 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. MS-ESI calculated value [M+H] + 273, measured value 273.

[0154] Step 4

[0155] An ethyl acetate solution of T3P (14.03 g, 22.05 mmol) was added to DMF (100 mL), followed by intermediates A-4 (4.0 g, 14.7 mmol), A-5 (3.79 g, 15.44 mmol), and triethylamine (6.69 g, 66.2 mmol). The mixture was stirred at 25 °C for 12 hours. After the reaction was complete, saturated brine (300 mL) was added to the reaction solution, followed by extraction with ethyl acetate (250 mL × 3). The organic phases were combined, washed with saturated brine (500 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1 to 0 / 1, V / V) to obtain intermediate A. 1 ¹H NMR (400MHz, CDCl₃) δ 7.71 (d, J = 8.0Hz, 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, measured value 522.

[0156] Intermediate B

[0157] Synthesis route:

[0158]

[0159] Intermediate A (600 mg, 1200 μmol), potassium acetate (354 mg, 3600 μmol), and bis(phenylphosphino)boronic acid ester (397 mg, 1560 μmol) were added to dimethyl sulfoxide (6 mL), followed by the addition of [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloromethane dichloride complex (49 mg, 60 μmol). The reaction mixture was heated to 85 °C for 5 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1–0 / 1, V / V) to obtain intermediate B. 1 ¹H NMR (400MHz, CDCl₃) δ 7.82 (d, J = 7.8Hz, 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 values ​​[M+H]+ 500, measured value 500.

[0160] Intermediate C

[0161] Synthesis route:

[0162]

[0163] first step

[0164] Intermediate C-1a (15.0 g, 81.42 mmol) was dissolved in tetrahydrofuran (30 mL). Butyllithium (2.5 M, 40.71 mL, 102.8 mmol) was slowly added dropwise at -78 °C, and the reaction was allowed to proceed for half an hour. Then, 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), extracted with ethyl acetate (300 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. This crude product was then separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, V / V) to obtain intermediate C-1c. MS-ESI calculated value [M+H] + 371 and 373, actual measured values ​​are 371 and 373.

[0165] Step 2

[0166] 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 mixture was reacted at 25 °C for 12 hours. The reaction solution was washed with methyl tert-butyl ether (200 mL), the pH of the aqueous phase was adjusted to 8 with saturated sodium bicarbonate solution, and 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 reaction. MS-ESI calculated value [M+H] + 276 and 278, actual measured values ​​are 276 and 278.

[0167] Step 3

[0168] Hydrochloric acid (3M, 119 mL, 356 mmol) was slowly added to intermediate C-1d (6.56 g, 23.76 mmol), and the reaction was carried out at 60 °C for 12 hours. The reaction solution was cooled to room temperature, the pH was adjusted to 7 with aqueous sodium hydroxide solution, and the mixture was washed three times with water. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain intermediate C-1e, which was used directly in the next reaction. MS-ESI calculated value [M+H] + 262 and 264, actual measured values ​​are 262 and 264.

[0169] Step 4

[0170] 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 Boc₂O (3.27 g, 14.96 mmol) were added. The reaction mixture was reacted at 25 °C for 4 hours. The pH of the reaction solution was adjusted to 4-5 with saturated citric acid aqueous solution, and the solution 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 C-1f, which was used directly in the next reaction. MS-ESI calculated value [M-56+1] + 306 and 308, actual measured values ​​are 306 and 308.

[0171] Step 5

[0172] Intermediate C-1f (2.90 g, 8.01 mmol) was dissolved in DMF (50 mL), and N-methylmorphorline (1.21 g, 12.01 mmol) and O-benzotriazole-N,N,N′,N′-tetramethylurea tetrafluoroborate (2.57 g, 8.01 mmol) were added. The mixture was stirred at 25 °C for 30 min. Then, ammonium chloride aqueous solution (0.35 M, 45.75 mL, 16.01 mmol) was added, and the mixture was stirred at 25 °C for 12 h. Water (160 mL) was added to the reaction mixture, the mixture was filtered, the filter cake was collected, and dried to obtain intermediate C-1, which was used directly in the next reaction. MS-ESI calculated value [M-56+1] + 305 and 307, actual measured values ​​are 305 and 307.

[0173] Step 6

[0174] Intermediate C-1 (1810 mg, 5010 μmol) was dissolved in tetrahydrofuran (25 mL), and methanesulfonic acid (4820 mg, 50100 μmol) was added. The mixture was reacted at 30 °C for 15 hours. The reaction solution was added to saturated sodium bicarbonate solution (25 mL), and the pH was adjusted to 8–9 with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (50 mL × 2), and the organic phases were combined. The mixture was dried over anhydrous sodium sulfate, and the crude product was concentrated under reduced pressure. Intermediate C-2 was obtained by silica gel column chromatography (dichloromethane / methanol, 10 / 1–5 / 1, V / V). 1 ¹H NMR (400MHz, 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 values ​​[M+H] +261 and 263, actual values ​​are 261 and 263.

[0175] Step 7

[0176] A 50% T3P ethyl acetate solution (1870 mg, 2940 μmol) was added to DMF (10 mL), followed by intermediate C-2 (591 mg, 2260 μmol), intermediate A-5 (610 mg, 2490 μmol), and triethylamine (916 mg, 9050 μmol). The reaction mixture was reacted at 25 °C for 4 hours. The reaction solution was then extracted with ethyl acetate (50 mL × 3), and the organic phases were combined and washed with saturated brine (100 mL × 3). The mixture was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was then separated by silica gel column chromatography (dichloromethane / methanol, 100 / 1~10 / 1, V / V) to obtain intermediate C. 1 ¹H NMR (400MHz, 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 measured values ​​are 510 and 512.

[0177] Intermediate D

[0178] Synthesis route:

[0179]

[0180] Intermediate C (52 mg, 106 μmol) was dissolved in dichloromethane (5 mL), and N-(triethylaminosulfonyl)carbamate (76 mg, 319 μmol) was added. The mixture was reacted at 25 °C for 18 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 crude product was then separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 1 / 3, V / V) to obtain intermediate D. 1¹H NMR (400MHz, 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 measured values ​​are 492 and 494.

[0181] Intermediate E

[0182] Synthesis route:

[0183]

[0184] Intermediate E-1 (300 mg, 1410 μmol), potassium phosphate (600 mg, 2830 μmol), and bis(diphenylphosphine)boronic acid ester (539 mg, 2120 μmol) were added to 1,4-dioxane (8 mL), followed by the addition of [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (104 mg, 141 μmol). The reaction mixture was heated to 110 °C for 12 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1–3 / 2, V / V) to obtain intermediate E. 1 ¹H NMR (400MHz, CDCl₃) δ 8.55 (s, 1H), 7.91 (d, J = 8.4Hz, 1H), 7.51 (d, J = 8.4Hz, 1H), 4.31 (s, 3H), 1.39 (s, 12H). MS-ESI calculated values ​​[M+H] + 260, measured value 260.

[0185] intermediate F

[0186] Synthesis route:

[0187]

[0188] Intermediate F-1 (300 mg, 1410 μmol), potassium acetate (277 mg, 2830 μmol), and bis(diphenylphosphine)boronic acid ester (539 mg, 2120 μmol) were added to 1,4-dioxane (8 mL), followed by the addition of [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (207 mg, 282 μmol). The reaction mixture was heated to 110 °C for 12 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1–10 / 3, V / V) to obtain intermediate F.1 ¹H NMR (400MHz, 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 values ​​[M+H] + 260, measured value 260.

[0189] intermediate G

[0190] Synthesis route:

[0191]

[0192] first step

[0193] Intermediate G-1 (20.0 g, 139.3 mmol) was dissolved in THF (100 mL), and carbonyl diimidazole (24.85 g, 153.23 mmol) was added. The reaction mixture was reacted at 80 °C for 1 hour. The pH of the reaction solution was adjusted to 6 with 1 M dilute hydrochloric acid, filtered, and the filter cake was collected, dried, and used directly in the next reaction. MS-ESI calculated value [M+H] + 170, measured value 170.

[0194] Step 2

[0195] 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 mixture, filtered, the filter cake was collected, and dried to obtain intermediate G-3, which was used directly in the next reaction. MS-ESI calculated value [M+H] + 184, measured value 184.

[0196] Step 3

[0197] Intermediate G-3 (1800 mg, 9800 μmol), potassium acetate (2890 mg, 29410 μmol), and bis(diphenyl ether) borate (4980 mg, 19610 μmol) were added to 1,4-dioxane (20 mL). Palladium acetate (132 mg, 588 μmol) and 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (280 mg, 588 μmol) were then added to the reaction mixture. The reaction mixture was heated to 80 °C for 3 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1–3 / 1, V / V) to obtain intermediate G. 1¹H NMR (400MHz, CDCl₃) δ 7.64 (d, J = 8.0Hz, 1H), 7.42 (s, 1H), 7.22 (d, J = 8.0Hz, 1H), 3.44 (s, 3H), 1.38 (s, 12H). MS-ESI calculated values ​​[M+H] + 276, measured value 276.

[0198] intermediate H

[0199] Synthesis route:

[0200]

[0201] Intermediate H-1 (995 mg, 4400 μmol), potassium acetate (1300 mg, 13200 μmol), and bis(diphenyl ether) borate (2240 ​​mg, 8800 μmol) were added to 1,4-dioxane (10 mL). Palladium acetate (60 mg, 264 μmol) and 2-dicyclohexylphosphine-2′,4′,6′-triisopropylbiphenyl (126 mg, 264 μmol) were then added to the reaction mixture. The reaction mixture was heated to 80 °C for 3 hours under nitrogen protection. The reaction mixture 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. 1 ¹H NMR (400MHz, CDCl₃) δ 7.96–7.86 (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 values ​​[M+H] + 274, measured value 274.

[0202] Intermediate I

[0203] Synthesis route:

[0204]

[0205] first step

[0206] Intermediates 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 mixture was heated to 120 °C and reacted for 14 hours. The reaction mixture was extracted with saturated brine (50 mL) and ethyl acetate (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 into intermediates I-3 and I-4 by thin-layer chromatography (developing solvent: petroleum ether / ethyl acetate, 3 / 1, V / V).

[0207] Intermediate I-3: 1 H NMR (400MHz, CDCl3) δ7.96 (s, 1H), 7.63 (s, 1H), 7.58 (d, J = 8.5Hz, 1H), 7.24 (d, J = 8.5Hz, 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).

[0208] Intermediate I-4: 1 H NMR (400MHz, CDCl3) δ7.85 (s, 1H), 7.80 (s, 1H), 7.44 (d, J = 8.8Hz, 1H), 7.08 (d, J = 8.8Hz, 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).

[0209] Step 2

[0210] Intermediate I-3 (50 mg, 131 μmol), potassium acetate (32 mg, 329 μmol), and bis(diphenylphosphine)boronic acid ester (67 mg, 263 μmol) were added to 1,4-dioxane (3 mL), followed by the addition of [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (19 mg, 26 μmol). The reaction mixture was heated to 110 °C for 12 hours under nitrogen protection. The reaction mixture 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 ¹H NMR (400MHz, CDCl₃) δ 8.02 (s, 1H), 7.94 (s, 1H), 7.74 (d, J = 8.1Hz, 1H), 7.57 (d, J = 8.1Hz, 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 values ​​[M⁻⁶+¹]. + 372, measured value 372.

[0211] Intermediate J

[0212] Synthesis route:

[0213]

[0214] Intermediate I-4 (50 mg, 131 μmol), potassium acetate (32 mg, 329 μmol), and bis(diphenylphosphine)boronic acid ester (67 mg, 263 μmol) were added to 1,4-dioxane (3 mL), followed by the addition of [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (19 mg, 26 μmol). The reaction mixture was heated to 110 °C for 12 hours under nitrogen protection. The reaction mixture 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 ¹H 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 values ​​[M+H] + 428, measured value 428.

[0215] intermediate K

[0216] Synthesis route:

[0217]

[0218] first step

[0219] Intermediate I-3 (500 mg, 1310 μmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (1540 mg, 13510 μmol) was added. The mixture was reacted at 25 °C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain a crude product containing intermediate K-1, which was used directly in the next reaction step. MS-ESI calculated value [M+H] + 280 and 282, actual measured values ​​are 280 and 282.

[0220] Step 2

[0221] 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 a saturated sodium bicarbonate solution (100 mL), extracted with ethyl acetate (100 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then separated by silica gel column chromatography (dichloromethane / methanol, 20 / 1~10 / 1, V / V) to obtain intermediate K-2. 1 ¹H NMR (400MHz, CDCl₃) δ 7.96 (s, 1H), 7.67 (s, 1H), 7.59 (d, J = 8.5Hz, 1H), 7.25 (d, J = 8.5Hz, 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 values ​​[M+H] + 294 and 296, actual values ​​are 294 and 296.

[0222] Step 3

[0223] Intermediate K-2 (320 mg, 1090 μmol), potassium acetate (267 mg, 2720 μmol), and bis(diphenylphosphine)boronic acid ester (414 mg, 1630 μmol) were added to 1,4-dioxane (3 mL), followed by the addition of [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (80 mg, 109 μmol). The reaction mixture was heated to 110 °C for 12 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane / methanol, 10 / 1–20 / 3, V / V) to obtain intermediate K. 1 ¹H NMR (400MHz, CDCl₃) δ 8.00 (s, 1H), 7.92 (s, 1H), 7.74 (d, J = 8.0Hz, 1H), 7.58 (d, J = 8.3Hz, 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 values ​​[M+H] + 342, measured value 342.

[0224] intermediate L

[0225] Synthesis route:

[0226]

[0227] first step

[0228] Intermediate I-1 (500 mg, 2.54 mmol) was dissolved in dimethyl sulfoxide (5 mL), and potassium carbonate (491 mg, 3.55 mmol) and 2-iodopropane (518 mg, 3.05 mmol) were slowly added. The reaction mixture was reacted at 15 °C for 12 hours. The reaction solution 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, concentrated under reduced pressure to obtain the crude product, and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, V / V) to obtain intermediate L-1. MS-ESI calculated value [M+H] + 239 and 241, actual values ​​are 239 and 241.

[0229] Step 2

[0230] Intermediate L-1 (233 mg, 974 μmol), potassium acetate (191 mg, 1.95 mmol), and bis(diphenylphosphine)boronic acid ester (371 mg, 1.46 mmol) were added to 1,4-dioxane (3 mL), followed by the addition of [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (143 mg, 195 μmol). The reaction mixture was heated to 110 °C for 12 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure to obtain intermediate L, which was directly used in the next reaction step. MS-ESI calculated value [M+H] + 287, measured value 287.

[0231] intermediate M

[0232] Synthesis route:

[0233]

[0234] first step

[0235] Intermediate I-1 (500 mg, 2.54 mmol) and intermediate M-1 (686 mg, 3.81 mmol) were dissolved in DMF (5 mL). Potassium carbonate (879 mg, 6.34 mmol) and tetrabutylammonium iodide (94 mg, 254 μmol) were slowly added, and the mixture was reacted at 120 °C for 14 hours under nitrogen protection. The reaction mixture was extracted with water (20 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain the crude product, and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, V / V) to obtain intermediate M-2. 1¹H NMR (400MHz, CDCl₃) δ 8.00 (s, 1H), 7.68 (s, 1H), 7.62 (d, J = 8.5Hz, 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 values ​​[M+H] + 281 and 283, actual measured values ​​are 281 and 283.

[0236] Step 2

[0237] Intermediate M-2 (237 mg, 843 μmol), potassium acetate (248 mg, 2.53 mmol), and bis(diphenylphosphine)boronic acid ester (321.09 mg, 1.26 mmol) were added to 1,4-dioxane (3 mL), followed by 1,1-bis(diphenylphosphine)ferrocene palladium chloride (62 mg, 84 μmol). The reaction mixture was heated to 110 °C for 12 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure to obtain intermediate M, which was directly used in the next reaction. MS-ESI calculated value [M+H] + 329, measured value 329.

[0238] intermediate N

[0239] Synthesis route:

[0240]

[0241] Intermediate N-1 (201 mg, 1.02 mmol), potassium acetate (298 mg, 3.04 mmol), and bis(diphenylphosphine)boronic acid ester (385 mg, 1.52 mmol) were added to 1,4-dioxane (2 mL), followed by the addition of 1,1-bis(diphenylphosphine)ferrocene palladium chloride (74 mg, 101 μmol). The reaction mixture was heated to 90 °C for 12 hours under nitrogen protection. The reaction mixture 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 reaction. MS-ESI calculated value [M+H] + 245, measured value 245.

[0242] Intermediate O

[0243] Synthesis route:

[0244]

[0245] Intermediate O-1 (200 mg, 1.02 mmol), potassium acetate (297 mg, 3.03 mmol), and bis(diphenylphosphine)boronic acid ester (385 mg, 1.52 mmol) were added to 1,4-dioxane (2 mL), followed by the addition of 1,1-bis(diphenylphosphine)ferrocene palladium chloride (74 mg, 101 μmol). The reaction mixture was heated to 90 °C for 12 hours under nitrogen protection. The reaction mixture 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 reaction. MS-ESI calculated value [M+H] + 245, measured value 245.

[0246] intermediate P

[0247] Synthesis route:

[0248]

[0249] first step

[0250] Intermediate P-1 (500 mg, 2.34 mmol) was dissolved in acetonitrile (5 mL), and potassium carbonate (516 mg, 3.74 mmol) and methyl iodoform (1.66 g, 3.05 mmol) were slowly added. The reaction mixture was reacted at 50 °C for 12 hours. The reaction solution was extracted with ethyl acetate (20 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain the crude product, and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1, V / V) to obtain intermediate P-2. MS-ESI calculated value [M+H] + 228 and 230, actual measured values ​​are 228 and 230.

[0251] Step 2

[0252] Intermediate P-2 (174 mg, 762.87 μmol), potassium acetate (225 mg, 2.29 mmol), and bis(diphenylphosphine)boronic acid ester (291 mg, 1.14 mmol) were added to 1,4-dioxane (2 mL), followed by the addition of [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (56 mg, 76.29 μmol). The reaction mixture was heated to 90 °C for 12 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure to obtain intermediate P, which was directly used in the next reaction. MS-ESI calculated value [M+H] + 276, measured value 276.

[0253] intermediate Q

[0254] Synthesis route:

[0255]

[0256] first step

[0257] Intermediate C-1a (3 g, 16.28 mmol) was dissolved in tetrahydrofuran (30 mL), and n-butyllithium (2.5 M, 13.03 mL) was slowly added at -78 °C. The reaction was allowed to proceed for half an hour, followed by the slow addition of intermediate Q-1 (4.86 g, 17.1 mmol) dissolved in tetrahydrofuran (10 mL) at -78 °C. The reaction was allowed to proceed for 12 hours at 25 °C. The reaction mixture was quenched with ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL × 3), and the organic phases were combined. The mixture was washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. Intermediate Q-2 was then separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0-100 / 1, V / V). 1 ¹H NMR (400MHz, CDCl₃) δ 7.51 (d, J = 2.0Hz, 1H), 7.31–7.28 (m, 1H), 7.09 (d, J = 8.3Hz, 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 = 6.8Hz, 3H), 0.65 (d, J = 6.8Hz, 3H). MS-ESI calculated values ​​[M+H] + 387 and 389, actual measured values ​​are 387 and 389.

[0258] Step 2

[0259] 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. The reaction mixture was reacted 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 sodium bicarbonate solution. The solution was extracted with ethyl acetate (30 mL × 3), and 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 reaction step. 1 ¹H NMR (400MHz, 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 values ​​[M+H] + 292 and 294, actual values ​​are 292 and 294.

[0260] Step 3

[0261] Hydrochloric acid (3M, 55 mL) was slowly added to intermediate Q-3 (3.42 g, 11.69 mmol), and the reaction was carried out at 60 °C for 16 hours. The reaction solution was cooled to room temperature, the pH was adjusted to 7 with aqueous sodium hydroxide solution, and the mixture was washed three times with water. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain intermediate Q-4, which was used directly in the next reaction. MS-ESI calculated value [M+H] + 278 and 280, actual measured values ​​are 278 and 280.

[0262] Step 4

[0263] Intermediate Q-4 (4 g, 14.36 mmol) was dissolved in dioxane (40 mL), and sodium carbonate solution (2 M, 7.90 mL) and Boc₂O (3.64 g, 16.66 mmol) were added. The reaction mixture was reacted at 25 °C for 4 hours. The pH of the reaction solution was adjusted to 4-5 with saturated citric acid aqueous solution, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Heptane (15 mL) was added, and the mixture was stirred for 15 minutes. The mixture was filtered, the filter cake was collected, dried, and intermediate Q-5 was obtained, which was used directly in the next reaction. 1 ¹H NMR (400MHz, 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 values ​​[M+H] + 378 and 380, actual measured values ​​are 378 and 380.

[0264] Step 5

[0265] Intermediate Q-5 (1.06 g, 2.79 mmol) was dissolved in DMF (5 mL), and ammonia (12 M, 696.56 μL) and N-methylmorpholine (423 mg, 4.18 mmol) were slowly added. The mixture was stirred at 25 °C for 30 minutes. Then, HATU (1.06 g, 2.79 mmol) was added at 0 °C, and the reaction was carried out at 25 °C for 12 hours. Water (20 mL) was added to the reaction mixture, and the mixture was filtered. The filter cake was washed three times with water, collected, and dried to obtain intermediate Q-6, which was used directly in the next reaction step. 1¹H NMR (400MHz, DMSO-d⁶) δ 7.66 (d, J = 1.8Hz, 1H), 7.53–7.44 (m, 1H), 6.90 (d, J = 9.0Hz, 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 values ​​[M+Na] + 399 and 401, actual measured values ​​are 399 and 401.

[0266] Step 6

[0267] 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 reaction mixture was reacted at 25 °C for 12 hours. The pH of the reaction solution was adjusted to greater than 8 with saturated sodium bicarbonate aqueous solution, extracted with ethyl acetate (10 mL × 3), washed with saturated brine (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate Q-7, which was directly used in the next reaction. MS-ESI calculated value [M+H] + 277 and 279, actual measured values ​​are 277 and 279.

[0268] Step 7

[0269] T3P (50% ethyl acetate solution, 278.58 mg, 876 μmol) was dissolved in DMF (3 mL), and intermediates Q-7 (243 mg, 876 μmol) and A-5 (143 mg, 584 μmol) were added, followed by triethylamine (266 mg, 2.63 mmol). The reaction mixture was reacted 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 (10 mL × 3), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then separated by silica gel column chromatography (dichloromethane / methanol, 10 / 1, V / V) to obtain intermediate Q-8. MS-ESI calculated value [M+Na] + 526 and 528, actual measured values ​​are 526 and 528.

[0270] Step 8

[0271] Intermediate Q-8 (350 mg, 693 μmol) and methyl N-(triethylaminosulfonyl)carbamate (826 mg, 3.47 mmol) were added to dichloromethane (3 mL) and reacted at 25 °C for 12 hours. The reaction mixture was then added to water (20 mL), extracted with ethyl acetate (10 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate Q, which was used directly in the next reaction. MS-ESI calculated value [M + Na]+ 508 and 510, actual measured values ​​are 508 and 510.

[0272] intermediate R

[0273] Synthesis route:

[0274]

[0275] first step

[0276] Intermediate C-1a (2.0 g, 10.86 mmol) was dissolved in tetrahydrofuran (30 mL). Butyllithium (2.5 M, 6.08 mL, 15.20 mmol) was slowly added dropwise at -78 °C, and the reaction was allowed to proceed for half an hour. Then, intermediate R-1 (2.87 g, 10.86 mmol) dissolved in tetrahydrofuran (15 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 (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 obtain a crude product. This crude product was then separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0-10 / 1, V / V) to obtain intermediate R-2. 1 ¹H NMR (400MHz, CDCl₃) δ 7.27 (s, 1H), 7.21 (d, J = 8.0Hz, 1H), 6.97 (d, J = 8.3Hz, 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 = 6.8Hz, 3H), 0.64 (d, J = 6.8Hz, 3H). MS-ESI calculated values ​​[M+H] + 367 and 369, actual measured values ​​are 367 and 369.

[0277] Step 2

[0278] 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. The reaction mixture was reacted at 25 °C for 12 hours. The reaction solution was washed with methyl tert-butyl ether (20 mL), the pH of the aqueous phase was adjusted to 8 with saturated sodium bicarbonate solution, and 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 reaction. 1¹H NMR (400MHz, 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 values ​​[M+H] + 272 and 274, actual measured values ​​are 272 and 274.

[0279] Step 3

[0280] Hydrochloric acid (3M, 37 mL, 110 mmol) was slowly added to intermediate R-3 (2.0 g, 7.35 mmol), and the reaction was carried out at 60 °C for 16 hours. The reaction solution was cooled to room temperature, the pH was adjusted to 7 with aqueous sodium hydroxide solution, and the mixture was washed three times with water. The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain intermediate R-4, which was used directly in the next reaction. MS-ESI calculated value [M+H] + 258 and 260, actual measured values ​​are 258 and 260.

[0281] Step 4

[0282] 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 Boc₂O (1.71 g, 7.85 mmol) were added. The reaction mixture was reacted at 25 °C for 4 hours. The pH of the reaction solution was adjusted to 4-5 with saturated citric acid aqueous solution, and the solution was extracted with ethyl acetate (200 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain intermediate R-5, which was used directly in the next reaction. MS-ESI calculated value [MH] - 356 and 358, actual measured values ​​are 356 and 358.

[0283] Step 5

[0284] Intermediate R-5 (2.68 g, 7.48 mmol) was dissolved in DMF (15 mL), and N-methylmorpholine (1.14 g, 11.22 mmol) and HATU (2.84 g, 7.48 mmol) were added. The mixture was stirred at 0 °C for 30 min. Then, ammonia (865 μL, 22.44 mmol) was added, and the mixture was stirred at 25 °C for 12 h. Water (100 mL) was added to the reaction mixture, 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 / 4–1 / 3, V / V) to obtain intermediate R-6.1 ¹H NMR (400MHz, MeOD-d⁴) δ 7.31 (s, 1H), 7.23 (d, J = 8.0Hz, 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 values ​​[M-100] + 257 and 259, actual measured values ​​are 257 and 259.

[0285] Step 6

[0286] 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. The reaction mixture was reacted at 25 °C for 12 hours. The pH of the reaction solution was adjusted to greater than 8 with saturated sodium bicarbonate aqueous solution, and the mixture was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, 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 ¹H NMR (400MHz, 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 values ​​[M+H] + 257 and 259, actual measured values ​​are 257 and 259.

[0287] Step 7

[0288] T3P (389 mg, 612 μmol in 50% ethyl acetate solution) was dissolved in DMF (5 mL), and intermediates R-7 (115 mg, 448 μmol) and A-5 (100 mg, 407 μmol) were added, followed by triethylamine (187 mg, 1.83 mmol). The reaction mixture was reacted 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 organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 4, V / V) to obtain intermediate R-8. 1¹H NMR (400MHz, 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 values ​​[M+Na] + 506 and 508, actual measured values ​​are 506 and 508.

[0289] Step 8

[0290] Intermediate R-8 (190 mg, 393 μmol) and methyl N-(triethylaminosulfonyl)carbamate (280 mg, 1.18 mmol) were added to dichloromethane (5 mL) and reacted at 25 °C for 12 hours. 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 was then separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 3, V / V) to obtain intermediate R. 1 ¹H NMR (400MHz, 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 measured values ​​are 488 and 490.

[0291] intermediate S

[0292] Synthesis route:

[0293]

[0294] first step

[0295] Intermediate S-1 (200 mg, 948 μmol) was dissolved in acetonitrile (10 mL), and 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (419 mg, 1.18 mmol) was added. The reaction mixture was reacted at 90 °C for 2 hours. The reaction solution was poured into water (50 mL), extracted with ethyl acetate (30 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain crude product, and separated by thin-layer chromatography (petroleum ether / ethyl acetate, 20 / 3, V / V) to obtain intermediate S-2. 1 ¹H NMR (400MHz, CDCl₃) δ 7.53–7.47 (m, 2H), 7.24 (d, J = 8.8 Hz, 1H), 3.89 (s, 3H). MS-ESI calculated values ​​[M+H] + 229 and 231, actual values ​​are 229 and 231.

[0296] Step 2

[0297] Intermediate S-2 (33 mg, 144 μmol), potassium acetate (35 mg, 369 μmol), and bis(diphenylphosphine)boronic acid ester (55 mg, 216 μmol) were added to 1,4-dioxane (3 mL), followed by the addition of [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (21 mg, 29 μmol). The reaction mixture was heated to 90 °C under nitrogen protection for 12 hours. The reaction mixture 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 ¹H NMR (400MHz, CDCl₃) δ 7.73 (d, J = 1.8Hz, 1H), 7.56 (d, J = 8.0Hz, 1H), 7.49–7.43 (m, 1H), 3.87 (s, 3H), 1.31 (s, 12H). MS-ESI calculated values ​​[M+H] + 277, measured value 277.

[0298] intermediate T

[0299] Synthesis route:

[0300]

[0301] Intermediate T-1 (500 mg, 2.33 mmol), potassium acetate (571 mg, 5.81 mmol), and bis(diphenylphosphine)boronic acid ester (886 mg, 3.49 mmol) were added to 1,4-dioxane (6 mL), followed by the addition of [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (170 mg, 232 μmol). The reaction mixture was heated to 100 °C for 12 hours under nitrogen protection. The reaction mixture 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 values ​​[M+H] + 263, measured value 263.

[0302] intermediate U

[0303] Synthesis route:

[0304]

[0305] Intermediate U-1 (50 mg, 237 μmol), potassium acetate (58 mg, 593 μmol), and bis(diphenylphosphine)boronic acid ester (90 mg, 355 μmol) were added to 1,4-dioxane (3 mL), followed by the addition of [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (35 mg, 47 μmol). The reaction mixture was heated to 100 °C for 12 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure to obtain intermediate U, which was used directly in the next step. MS-ESI calculated value [M+H] + 177, measured value 177.

[0306] intermediate V

[0307] Synthesis route:

[0308]

[0309] Intermediate V-1 (100 mg, 507 μmol), potassium acetate (125 mg, 1.27 mmol), and bis(diphenylphosphine)boronic acid ester (193 mg, 761 μmol) were added to 1,4-dioxane (3 mL), followed by the addition of [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride (74 mg, 101 μmol). The reaction mixture was heated to 100 °C for 12 hours under nitrogen protection. The reaction mixture was concentrated under reduced pressure to obtain intermediate V, which was used directly in the next step. MS-ESI calculated value [M+Na] + 267, measured value 267.

[0310] Example 1

[0311] Synthesis route:

[0312]

[0313] first step

[0314] 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 protection, [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (20 mg, 24 μmol) was added to the reaction mixture. The reaction mixture was heated to 80 °C for 2 hours under nitrogen protection. The reaction mixture was added to water (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1–1 / 4, V / V) to obtain compound 1-1. MS-ESI calculated value [M+Na] + 527, measured value 527.

[0315] Step 2

[0316] 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 then added to a saturated sodium bicarbonate solution (30 mL), and the pH was adjusted to 8-9 with saturated sodium bicarbonate solution. Extraction was performed 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 (column: DAICL CHIRALPAK AD 250 mm × 30 mm × 10 μm; mobile phase: A phase was supercritical CO2, B phase was an ethanol solution containing 0.1% ammonia; gradient: B phase 50%-50%) to obtain compound 1. The ee value was then measured by SFC (column: Chiralcel AD-3 50 mm × 4.6 mm × 3 μm; mobile phase: A phase was supercritical CO2, B phase was an ethanol solution containing 0.05% diethylamine; gradient: B phase 5%-40%).

[0317] Compound 1: ee%=100.00%, RT=2.547min. 1H NMR (400MHz, CDCl3) δ8.23 (s, 1H), 7.77 (d, J=8.4Hz, 1H), 7.66 (d, J=8.0Hz, 2H), 7.60 (d , J=8.4Hz, 1H), 7.45 (d, J=8.0Hz, 2H), 7.22 (d, J=8.8Hz, 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 values ​​[M+H] + 405, measured value 405.

[0318] Example 2

[0319] Synthesis route:

[0320]

[0321] first step

[0322] 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 protection, [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (26 mg, 32 μmol) was added to the reaction mixture. The reaction mixture was heated to 80 °C for 2 hours under nitrogen protection. The reaction mixture was added to water (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1–3 / 7, V / V) to obtain compound 2-2. MS-ESI calculated value [M+Na] + 526, measured value 526.

[0323] Step 2

[0324] 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 then added to a saturated sodium bicarbonate solution (30 mL), and the pH was adjusted to 8–9 with the saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (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 an SFC (separation column: DAICEL CHIRALPAK AD 250 mm × 30 mm × 10 μm; mobile phase: A phase was supercritical CO2, B phase was an ethanol solution containing 0.1% ammonia; gradient: B phase 60%–60%) to obtain compound 2. The ee value was then measured by SFC (column: Chiralcel IG-3 50mm×4.6mm×3μm; mobile phase: phase A is supercritical CO2, phase B is an ethanol solution containing 0.05% diethylamine; gradient: phase B 5%-40%).

[0325] Compound 2: ee%=100.00%, RT=2.759min. 1 ¹H NMR (400MHz, CD₃OD) δ 8.00 (s, 1H), 7.81 (d, J = 8.4Hz, 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 values ​​[M+H] + 404, measured value 404.

[0326] Example 3

[0327] Synthesis route:

[0328]

[0329] first step

[0330] 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 protection, [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (26 mg, 32 μmol) was added to the reaction solution. The reaction solution was heated to 80 °C for 2 hours under nitrogen protection. The reaction solution was added to water (20 mL), 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 was then separated by silica gel column chromatography (dichloromethane / methanol, 100 / 1–20 / 1, V / V) to obtain compound 3-2. MS-ESI calculated value [M+Na] + 526, measured value 526.

[0331] Step 2

[0332] 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 then added to a saturated sodium bicarbonate solution (30 mL), and the pH was adjusted to 8–9 with the saturated sodium bicarbonate solution. Extraction was performed 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: A phase was supercritical CO2, B phase was an ethanol solution containing 0.1% ammonia; gradient: B phase 50%–50%) to obtain compound 3. The ee value was then measured by SFC (chromatographic column: Chiralcel AD-3 50mm×4.6mm×3μm; mobile phase: A phase is supercritical CO2, B phase is ethanol solution containing 0.05% diethylamine; gradient: B phase 5%-40%).

[0333] Compound 3: ee%=100.00%, RT=2.456min. 1H NMR (400MHz, CD3OD) δ8.05 (s, 1H), 7.97 (s, 1H), 7.74-7.69 (m, 1H), 7.68-7.60 (m, 3H), 7.39 (d, J=8.0Hz, 2H), 5.14-5.08 (m, 1H), 4.14-4.10 (m, 1H), 4.09 (s, 3 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 values ​​[M+H] + 404, measured value 404.

[0334] Example 4

[0335] Synthesis route:

[0336]

[0337] first step

[0338] 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 protection, [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (20 mg, 24 μmol) was added to the reaction solution. The reaction solution was heated to 80 °C for 2 hours under nitrogen protection. The reaction solution was added to water (20 mL), 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 was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1–1 / 3, V / V) to obtain compound 4-1. MS-ESI calculated value [M+Na] + 527, measured value 527.

[0339] Step 2

[0340] 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 then added to a saturated sodium bicarbonate solution (30 mL), and the pH was adjusted to 8–9 with the saturated sodium bicarbonate solution. Extraction was performed 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: A phase was supercritical CO2, B phase was an ethanol solution containing 0.1% ammonia; gradient: B phase 50%–50%) to obtain compound 4. The ee value was then measured by SFC (chromatographic column: Chiralcel AD-3 50mm×4.6mm×3μm; mobile phase: A phase is supercritical CO2, B phase is ethanol solution containing 0.05% diethylamine; gradient: B phase 5%-40%).

[0341] Compound 4: ee%=100.00%, RT=2.247min. 1 H NMR (400MHz, CDCl3) δ8.12 (d, J=8.8Hz, 1H), 7.73-7.65 (m, 3H), 7.62 (d, J=8.8Hz, 1 H), 7.46 (d, J=8.0Hz, 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 values ​​[M+H] + 405, measured value 405.

[0342] Example 5

[0343] Synthesis route:

[0344]

[0345]

[0346] first step

[0347] 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 protection, [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (32 mg, 40 μmol) was added to the reaction solution. The reaction solution was heated to 80 °C for 3 hours under nitrogen protection. The reaction solution was added to water (20 mL), 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 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, measured value 541.

[0348] Step 2

[0349] Compound 5-1 (56 mg, 108 μmol) was added to formic acid (1.0 mL) and water (0.1 mL), and the reaction mixture was reacted at 25 °C for 2 hours. The reaction mixture was then added to a saturated sodium bicarbonate solution (30 mL), and the pH was adjusted to 8–9 with the saturated sodium bicarbonate solution. Extraction was performed 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 (HPLC) (column: Waters Xbridge 150 mm × 25 mm × 5 μm; mobile phase: phase A was an aqueous solution containing 0.05% ammonia monohydrate, phase B was acetonitrile; gradient: phase B 16%–46%, 10 min) to obtain compound 5. The ee value was then measured by SFC (column: Chiralcel AD-3 50mm×4.6mm×3μm; mobile phase: phase A is supercritical CO2, phase B is isopropanol solution containing 0.05% diethylamine; gradient: phase B 40%).

[0350] Compound 5: ee%=100.00%, RT=0.747min. 1H NMR (400MHz, CDCl3) δ7.91 (d, J=8.0Hz, 1H), 7.70-7.65 (m, 1H), 7.65-7.60 (m, 3H ), 7.43 (d, J=8.0Hz, 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 values ​​[M+H] + 419, measured value 419.

[0351] Example 6

[0352] Synthesis route:

[0353]

[0354] first step

[0355] 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 protection, [1,1-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (21 mg, 32 μmol) was added to the reaction mixture. The reaction mixture was heated to 60 °C for 6 hours under nitrogen protection. The reaction mixture was added to water (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then 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, measured value 557.

[0356] Step 2

[0357] Compound 6-1 (104 mg, 187 μmol) was dissolved in dichloromethane (10 mL), and methyl N-(triethylaminosulfonyl)carbamate (67 mg, 280 μmol) was added. The reaction mixture was reacted 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. The crude product containing compound 6-2 was used directly in the next reaction step. MS-ESI calculated value [M + Na] + 561, measured value 561.

[0358] Step 3

[0359] 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 then added to a saturated sodium bicarbonate solution (30 mL), and the pH was adjusted to 8–9 with the saturated sodium bicarbonate solution. Extraction was performed 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 (HPLC) (column: Waters Xbridge 150 mm × 25 mm × 5 μm; mobile phase: phase A was an aqueous solution containing 0.05% ammonia monohydrate, phase B was acetonitrile; gradient: phase B 22%–52%, 10 min) to obtain compound 6. The ee value was then measured by SFC (chromatographic column: Chiralcel OJ-3 50mm×4.6mm×3μm; mobile phase: A phase is supercritical CO2, B phase is ethanol solution containing 0.05% diethylamine; gradient: B phase 5%-40%).

[0360] Compound 6: ee% = 100.00%, RT = 2.123 min. 1 ¹H NMR (400MHz, CD₃OD) δ 7.51–7.39 (m, 5H), 7.32 (d, J = 8.2Hz, 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 values ​​[M+H] + 439, measured value 439.

[0361] Example 7

[0362] Synthesis route:

[0363]

[0364] first step

[0365] 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 protection, [1,1-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (27 mg, 41 μmol) was added to the reaction mixture. The reaction mixture was heated to 70 °C for 5 hours under nitrogen protection. The reaction mixture was added to water (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then separated by silica gel column chromatography (dichloromethane / methanol, 100 / 1–20 / 1, V / V) to obtain compound 7-1. MS-ESI calculated value [M+Na] + 563, measured value 563.

[0366] Step 2

[0367] Compound 7-1 (110 mg, 203 μmol) was dissolved in dichloromethane (5 mL), and methyl N-(triethylaminosulfonyl)carbamate (122 mg, 512 μmol) was added. The reaction mixture was reacted at 25 °C for 22 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 crude product was then 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 value [M+Na] + 545, measured value 545.

[0368] Step 3

[0369] Compound 7-2 (101 mg, 193 μmol) was added to formic acid (1.5 mL) and water (0.3 mL), and the reaction mixture was reacted at 25 °C for 2 hours. The reaction mixture was then added to a saturated sodium bicarbonate solution (30 mL), and the pH was adjusted to 8–9 with the saturated sodium bicarbonate solution. Extraction was performed 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 (HPLC) (column: Phenomenex Gemini-NX 80 mm × 40 mm × 3 μm; mobile phase: phase A was an aqueous solution containing 0.05% ammonia monohydrate, phase B was acetonitrile; gradient: phase B 26%–56%, 8 min) to obtain compound 7. The ee value was then measured by SFC (column: Chiralcel AD-3 150mm×4.6mm×3μm; mobile phase: phase A is supercritical CO2, phase B is an ethanol solution containing 0.05% diethylamine; gradient: phase B 5%-40%).

[0370] Compound 7: ee%=91.78%, RT=6.090min. 1 H NMR (400MHz, CD3OD) δ8.10-7.98(m, 2H), 7.74(d, J=8.8Hz, 1H), 7.63-7.53(m , 2H), 7.48 (t, J=8.0Hz, 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 values ​​[M+H] + 423, measured value 423.

[0371] Example 8

[0372] Synthesis route:

[0373]

[0374] first step

[0375] 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 protection, [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (33 mg, 41 μmol) was added to the reaction mixture. The reaction mixture was heated to 80 °C for 12 hours under nitrogen protection. The reaction mixture was added to water (20 mL), extracted with ethyl acetate (20 mL × 2), and the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then 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, measured value 540.

[0376] Step 2

[0377] Compound 8-2 (100 mg, 185 μmol) was dissolved in dichloromethane (6 mL), and methyl N-(triethylaminosulfonyl)carbamate (66 mg, 278 μmol) was added. The reaction mixture was reacted 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 crude product was then separated by silica gel column chromatography (eluent: dichloromethane / methanol, 20 / 1, V / V) to obtain compound 8-3. MS-ESI calculated value [M-56+H] + 466, measured value 466.

[0378] Step 3

[0379] 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 hours. The reaction solution was then added to a saturated sodium bicarbonate solution (30 mL), and the pH was adjusted to 8–9 with the saturated sodium bicarbonate solution. Extraction was performed 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 (HPLC) (column: Phenomenex Gemini-NX C18 75 mm × 30 mm × 3 μm; mobile phase: phase A was an aqueous solution containing 0.05% ammonia monohydrate, phase B was acetonitrile; gradient: phase B 23%–53%, 7 min) to obtain compound 8. The ee value was then measured by SFC (chromatographic column: Chiralcel AD-3 50mm×4.6mm×3μm; mobile phase: A phase is supercritical CO2, B phase is ethanol solution containing 0.05% diethylamine; gradient: B phase 5%-40%).

[0380] Compound 8: ee%=84.21%, RT=2.200min. 1 ¹H NMR (400MHz, CD₃OD) δ 8.00 (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 values ​​[M+H] + 422, measured value 422.

[0381] Example 9

[0382] Synthesis route:

[0383]

[0384] first step

[0385] Intermediate A (250 mg, 874 μmol), intermediate L (392.6 mg, 786 μmol), and potassium carbonate (241 mg, 1.75 mmol) were added to acetonitrile (2 mL) and water (0.5 mL). Under nitrogen protection, a [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (143 mg, 175 μmol) was added to the reaction mixture. The reaction mixture was heated to 80 °C for 3 hours under nitrogen protection. The crude product obtained by concentration under reduced pressure was separated into compound 9-1 by silica gel column chromatography (dichloromethane / methanol, 10 / 1, V / V). MS-ESI calculated value [M+H] + 532, measured value 532.

[0386] Step 2

[0387] Compound 9-1 (169 mg, 318 μmol) was added to formic acid (2.0 mL) and water (0.2 mL), and the reaction mixture was reacted at 25 °C for 3 hours. The reaction mixture was then added to a saturated sodium bicarbonate solution (20 mL), and the pH was adjusted to 8–9 with the saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate (10 mL × 3), and the organic phases were combined. The mixture was 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 (HPLC) (column: Welch Ultimate XB-CN 250 mm × 50 mm × 10 μm; mobile phase: phase A was n-hexane, phase B was a solution containing 0.1% ammonia ethanol monohydrate; gradient: phase B 25%–65%, 15 min) to obtain compound 9. Compound 9 was analyzed for its ee value using SFC (column: Chiralcel OJ-3 50mm×4.6mm ID, 3μm; mobile phase: A phase was supercritical CO2, B phase was methanol solution containing 0.05% diethylamine; gradient: B phase 5%-40%).

[0388] Compound 9: ee%=93.00%, RT=1.896min. 1H NMR (400MHz, CD3OD) δ8.05 (s, 1H), 7.85-7.77 (m, 2H), 7.73 (d, J=8.3Hz, 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 values ​​[M+H] + 432, measured value 432.

[0389] Example 10

[0390] Synthesis route:

[0391]

[0392] first step

[0393] 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 protection, a [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (143 mg, 175 μmol) was added to the reaction mixture. The reaction mixture was heated to 80 °C for 3 hours under nitrogen protection. The crude product obtained by concentration under reduced pressure was separated into compound 10⁻¹ by silica gel column chromatography (dichloromethane / methanol, 10 / 1, V / V). MS-ESI calculated value [M⁻⁵⁶ + 1]. + 512, measured value 512.

[0394] Step 2

[0395] Compound 10⁻¹ (300 mg, 528 μmol) and methyl N-(triethylaminosulfonyl)carbamate (309 mg, 1.29 mmol) were added to dichloromethane (3 mL). The reaction mixture was reacted at 25 °C for 12 hours. The reaction mixture was washed with water (10 × 3 mL) and saturated brine (10 × 3 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 10⁻², which was used directly in the next reaction. MS-ESI calculated value [M + H] + 550, measured value 550.

[0396] Step 3

[0397] 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 (HPLC) (column: Unisil 3-100 C18 Ultra 150 mm × 50 mm × 3 μm; mobile phase: phase A was aqueous solution containing 0.225% formic acid, phase B was acetonitrile; gradient: phase B 15%-45%, 10 min) to obtain the formate salt of compound 10. The formate of compound 10 was measured for ee value by SFC (column: Chiralpak AD-3 50mm×4.6mm ID, 3μm; mobile phase: A phase is supercritical CO2, B phase is methanol solution containing 0.05% diethylamine; gradient: B phase 5%-40%).

[0398] Compound 10: ee%=83.46%, RT=1.879min. 1 H NMR (400MHz, CD3OD) δ8.10-8.03 (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 values ​​[M+H] + 450, measured value 450.

[0399] Example 11

[0400] Synthesis route:

[0401]

[0402] first step

[0403] 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 protection, [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (124 mg, 152 μmol) was added to the reaction solution. The reaction solution was heated to 80 °C for 3 hours under nitrogen protection. The crude product obtained by concentration under reduced pressure 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, measured value 574.

[0404] Step 2

[0405] 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), 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 (HPLC) (column: Waters Xbridge 150 mm × 25 mm × 5 μm; mobile phase: phase A was aqueous solution containing 0.05% ammonia, phase B was acetonitrile; gradient: phase B 25%-55%, 9 min) to obtain compound 11. Compound 11 was measured for its ee value using SFC (column: Chiralcel OD-3 50mm×4.6mm ID, 3μm; mobile phase: phase A was supercritical CO2, phase B was methanol solution containing 0.05% diethylamine; gradient: phase B 5%-40%).

[0406] Compound 11: ee%=95.846%, RT=2.026min. 1 ¹H NMR (400MHz, CD₃OD) δ 8.06 (s, 1H), 7.91–7.79 (m, 2H), 7.75 (d, J = 7.2Hz, 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 values ​​[M+H] + 474, measured value 474.

[0407] Example 12

[0408] Synthesis route:

[0409]

[0410] first step

[0411] 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 protection, [1,1-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (79 mg, 122 μmol) was added to the reaction mixture. The reaction mixture was heated to 60 °C for 12 hours under nitrogen protection. The crude product obtained by concentration under reduced pressure was separated into compound 12-1 by silica gel column chromatography (petroleum ether / ethyl acetate, 5 / 1-0 / 1, V / V). MS-ESI calculated value [M+H] + 610, measured value 610.

[0412] Step 2

[0413] Compound 12-1 (107 mg, 176 μmol) and methyl N-(triethylaminosulfonyl)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 obtain compound 12-2, which was used directly in the next reaction. MS-ESI calculated value [M+H] + 592, measured value 592.

[0414] Step 3

[0415] 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), 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 was n-hexane, phase B was an ethanol solution containing 0.1% ammonia monohydrate; gradient: phase B 25%-65%, 15 min) to obtain compound 12. Compound 12 was analyzed for its ee value using SFC (column: Chiralcel OJ-3 50mm×4.6mm ID, 3μm; mobile phase: phase A was supercritical CO2, phase B was methanol solution containing 0.05% diethylamine; gradient: phase B 5%-40%).

[0416] Compound 12: ee% = 96.59%, RT = 2.110 min. 1 H NMR (400MHz, CD3OD) δ8.07 (s, 1H), 7.92 (s, 1H), 7.84 (d, J=8.4Hz, 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 values ​​[M+H] + 492, measured value 492.

[0417] Example 13

[0418] Synthesis route:

[0419]

[0420] first step

[0421] 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 protection, [1,1-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (31 mg, 47 μmol) was added to the reaction mixture. The reaction mixture was heated to 60 °C for 12 hours under nitrogen protection. The reaction mixture was extracted with ethyl acetate (10 mL × 3), washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude product obtained by reduced pressure concentration was separated by silica gel column chromatography (dichloromethane / methanol, 10 / 1, V / V) to obtain compound 13-1. MS-ESI calculated value [M+H] + 508, measured value 508.

[0422] Step 2

[0423] 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), 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 (HPLC) (column: Waters Xbridge 150 mm × 25 mm × 5 μm; mobile phase: phase A containing 0.05% ammonia monohydrate, phase B acetonitrile; gradient: phase B 18%–48%, 9 min) to obtain compound 13. Compound 13 was determined by SFC (column: Chiralcel OJ-350 mm × 4.6 mm ID, 3 μm; mobile phase: phase A supercritical CO2, phase B 0.05% diethylamine in methanol; gradient: phase B 5%–40%).

[0424] Compound 13: ee% = 88.24%, RT = 1.769 min. 1 H NMR (400MHz, CD3OD) δ8.58-8.48 (m, 1H), 7.90 (s, 1H), 7.83 (s, 1H), 7.66-7 .55(m, 3H), 7.50(t, J=8.0Hz, 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, measured value 408.

[0425] Example 14

[0426] Synthesis route:

[0427]

[0428] first step

[0429] 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 protection, [1,1-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (31 mg, 47.25 μmol) was added to the reaction mixture. The reaction mixture was heated to 60 °C for 12 hours under nitrogen protection. The reaction mixture was extracted with ethyl acetate (10 mL × 3), washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude product obtained by reduced pressure 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.

[0430] Step 2

[0431] Compound 14-1 (100 mg, 197 μmol) was added to formic acid (0.5 mL) and water (0.1 mL), and the reaction mixture was reacted at 25 °C for 3 hours. The reaction mixture was quenched with sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL × 3), washed with saturated brine (20 mL × 2), and the combined organic phases were 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 (HPLC) (column: Waters Xbridge 150 mm × 25 mm × 5 μm; mobile phase: phase A was aqueous solution containing 0.05% ammonia monohydrate, phase B was acetonitrile; gradient: phase B 18%-48%, 9 min) to obtain compound 14. Compound 14 was analyzed for its ee value using SFC (column: Chiralcel OJ-3 50mm×4.6mm ID, 3μm; mobile phase: A phase was supercritical CO2, B phase was methanol solution containing 0.05% diethylamine; gradient: B phase 5%-40%).

[0432] Compound 14: ee%=67%, RT=1.956min. 1 ¹H NMR (400MHz, CD₃OD) δ 8.89–8.76 (m, 1H), 7.93 (d, J = 1.3Hz, 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 values ​​[M+H]+ 408, measured value 408.

[0433] Example 15

[0434] Synthesis route:

[0435]

[0436] first step

[0437] 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 protection, [1,1-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (85 mg, 131 μmol) was added to the reaction mixture. The reaction mixture was heated to 60 °C for 12 hours under nitrogen protection. The crude product obtained by concentration under reduced pressure was separated into compound 15-1 by silica gel column chromatography (dichloromethane / methanol, 10 / 1, V / V). MS-ESI calculated value [M+H] + 557, measured value 557.

[0438] Step 2

[0439] Compound 15-1 (196 mg, 351 μmol) and methyl N-(triethylaminosulfonyl)carbamate (206 mg, 862 μmol) were added to dichloromethane (3 mL). The reaction mixture was reacted at 15 °C for 12 hours. The reaction mixture was washed with water (20 mL × 3) and saturated brine (20 mL × 3), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 15-2, which was used directly in the next reaction. MS-ESI calculated value [M+H] + 539, measured value 539.

[0440] Step 3

[0441] 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 then added to a saturated sodium bicarbonate solution (25 mL), extracted with dichloromethane (20 mL × 3), 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 into formate salts of compound 15 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%-40%, 10 min). The formate of compound 15 was measured for ee value by SFC (column: Chiralpak AD-3 50mm×4.6mm ID, 3μm; mobile phase: A phase is supercritical CO2, B phase is methanol solution containing 0.05% diethylamine; gradient: B phase 40%).

[0442] Compound 15: ee%=82.26%, RT=0.879min. 1 ¹H NMR (400MHz, CD₃OD) δ 7.55–7.25 (m, 3H), 6.97–6.83 (m, 2H), 6.76 (d, J = 8.3Hz, 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 values ​​[M+H] + 439, measured value 439.

[0443] Example 16

[0444] Synthesis route:

[0445]

[0446] first step

[0447] 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 protection, [1,1-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (64 mg, 98 μmol) was added to the reaction mixture. The reaction mixture was heated to 70 °C for 12 hours under nitrogen protection. The reaction mixture was extracted with ethyl acetate (10 mL × 3), washed with saturated brine (10 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was then separated by silica gel column chromatography (dichloromethane / methanol, 10 / 1, V / V) to obtain compound 16-1. MS-ESI calculated value [M-55] + 482, measured value 482.

[0448] Step 2

[0449] Compound 16-1 (167 mg, 310 μmol) was added to formic acid (0.5 mL) and water (0.1 mL), and the reaction mixture was stirred at 25 °C for 3 hours. The reaction mixture was quenched with sodium bicarbonate solution (10 mL), 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 (HPLC) (column: Waters Xbridge 150 mm × 25 mm × 5 μm; mobile phase: phase A was aqueous solution containing 0.05% ammonia monohydrate, phase B was acetonitrile; gradient: phase B 27%-57%, 9 min) to obtain compound 16. Compound 16 was analyzed for its ee value using SFC (column: Chiralpak AD-3 50mm×4.6mm ID, 3μm; mobile phase: A phase was supercritical CO2, B phase was 0.05% diethylamine in methanol; gradient: B phase 40%).

[0450] Compound 16: ee%=100%, RT=0.790min. 1 ¹H NMR (400MHz, CDCl₃) δ 8.03 (s, 1H), 7.81 (d, J = 8.4Hz, 1H), 7.74 (d, J = 1.5Hz, 1H), 7.63–7.53 (m, 2H), 7.47 (d, J = 8.0Hz, 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 values ​​[M+H]+ 438, measured value 438.

[0451] Example 17

[0452] Synthesis route:

[0453]

[0454] first step

[0455] 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 protection, [1,1-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (28 mg, 43 μmol) was added to the reaction mixture. The reaction mixture was heated to 70 °C for 5 hours under nitrogen protection. The reaction mixture was then 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 crude product was then separated by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 2, V / V) to obtain compound 17-1. 1 ¹H 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, measured value 540.

[0456] Step 2

[0457] Compound 17-1 (80 mg, 154 μmol) was added to formic acid (1.5 mL) and water (0.15 mL), and the reaction mixture was stirred at 25 °C for 2 hours. The reaction mixture was quenched with sodium bicarbonate solution (50 mL), extracted with dichloromethane (50 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 (HPLC) (column: Phenomenex C18 80 mm × 40 mm × 3 μm; mobile phase: phase A was aqueous solution containing 0.05% ammonia monohydrate, phase B was acetonitrile; gradient: phase B 37%-67%, 8 min) to obtain compound 17. Compound 17 was analyzed for its ee value using SFC (column: Chiralpak AD-3150mm×4.6mm ID, 3μm; mobile phase: A phase was supercritical CO2, B phase was an ethanol solution containing 0.05% diethylamine; gradient: B phase 40%).

[0458] Compound 17: ee%=100%, RT=2.581 min. 1 H NMR (400MHz, MeOD-d4) δ7.99 (s, 1H), 7.78 (d, J=8.5Hz, 1H), 7.72 (s, 1H), 7.56 (s, 1H), 7.52 (d, J=7.8Hz, 1H), 7.45-7.39 (m, 1H), 7.33 (d, J= 7.8Hz, 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 values ​​[M+H] + 418, measured value 418.

[0459] Example 18

[0460] Synthesis route:

[0461]

[0462] first step

[0463] 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 protection, [1,1-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (14 mg, 22 μmol) was added to the reaction mixture. The reaction mixture was heated to 70 °C for 5 hours under nitrogen protection. The crude product obtained by concentration under reduced pressure was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, V / V) to give compound 18-1. 1 ¹H NMR (400MHz, CDCl₃) δ 7.70 (d, J = 8.3Hz, 1H), 7.49–7.31 (m, 5H), 7.26 (d, J = 7.5Hz, 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 values ​​[M+Na] + 562, measured value 562.

[0464] Step 2

[0465] Compound 18-1 (84 mg, 155 μmol) was added to formic acid (1.5 mL) and water (0.15 mL), and the reaction mixture was reacted at 25 °C for 2 hours. The reaction mixture was then added to a saturated sodium bicarbonate solution (20 mL), and the pH was adjusted to 8 with the saturated sodium bicarbonate solution. Extraction was performed 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 (HPLC) (column: Phenomenex C18 80 mm × 40 mm × 3 μm; mobile phase: phase A was an aqueous solution containing 0.05% ammonia monohydrate, phase B was acetonitrile; gradient: phase B 42%-72%, 8 min) to obtain compound 18. Compound 18 was analyzed for its ee value using SFC (column: Chiralcel OJ-3 50mm×4.6mm ID, 3μm; mobile phase: A phase is supercritical CO2, B phase is an ethanol solution containing 0.05% diethylamine; gradient: B phase 5%-40%).

[0466] Compound 18: ee%=100.00%, RT=3.989min. 1H NMR (400MHz, CD3OD) δ7.72 (d, J=11.0Hz, 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, measured value 440.

[0467] Example 19

[0468] Synthesis route:

[0469]

[0470] first step

[0471] 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 protection, [1,1-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (14 mg, 22 μmol) was added to the reaction mixture. The reaction mixture was heated to 70 °C for 3 hours under nitrogen protection. The crude product obtained by concentration under reduced pressure was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 7, V / V) to obtain compound 19-1. 1 ¹H NMR (400MHz, 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, measured value 548.

[0472] Step 2

[0473] 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 then added to a saturated sodium bicarbonate solution (20 mL), and the pH was adjusted to 8 with the saturated sodium bicarbonate solution. Extraction was performed 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 (HPLC) (column: Phenomenex C18 80 × 40 mm × 3 μm; mobile phase: phase A was an aqueous solution containing 0.05% ammonia monohydrate, phase B was acetonitrile; gradient: phase B 36%-66%, 8 min) to obtain compound 19. Compound 19 was analyzed for its ee value using SFC (column: Chiralcel OJ-3 100mm×4.6mm ID, 3μm; mobile phase: A phase was supercritical CO2, B phase was an ethanol solution containing 0.05% diethylamine; gradient: B phase 5%-40%).

[0474] Compound 19: ee% = 100.00%, RT = 3.563 min. 1 H NMR (400MHz, CD3OD) δ8.13 (s, 1H), 7.59 (s, 1H), 7.54-7.42 (m, 3H), 7.14 (d, J=11.3Hz, 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, measured value 426.

[0475] Example 20

[0476] Synthesis route:

[0477]

[0478] first step

[0479] 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 protection, a [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloromethane dichloride complex (16 mg, 20 μmol) was added to the reaction mixture. The reaction mixture was heated to 80 °C for 8 hours under nitrogen protection. The crude product obtained by concentration under reduced pressure was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 0 / 1, V / V) to give compound 20-1. MS-ESI calculated value [M+H] + 522, measured value 522.

[0480] Step 2

[0481] 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 hours. The reaction solution was then added to a saturated sodium bicarbonate solution (20 mL), and the pH was adjusted to 8 with the saturated sodium bicarbonate solution. Extraction was performed 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 (HPLC) (column: Phenomenex Gemini-NX 80 mm × 40 mm × 3 μm; mobile phase: phase A was an aqueous solution containing 0.05% ammonia monohydrate, phase B was acetonitrile; gradient: phase B 33%-63%, 8 min) to obtain compound 20. Compound 20 was analyzed for its ee value using SFC (column: Chiralcel AD-3 50mm×4.6mm ID, 3μm; mobile phase: phase A was supercritical CO2, phase B was an ethanol solution containing 0.05% diethylamine; gradient: phase B 40%).

[0482] Compound 20: ee%=99.46%, RT=0.598min. 1 ¹H NMR (400MHz, CD₃OD) δ 8.60 (d, J = 1.5Hz, 1H), 8.15 (s, 1H), 7.63–7.42 (m, 4H), 6.62 (d, J = 3.0Hz, 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 values ​​[M+H] + 422, measured value 422.

[0483] Example 21

[0484] Synthesis route:

[0485]

[0486] first step

[0487] 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 protection, a [1,1′-bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex (17 mg, 21 μmol) was added to the reaction mixture. The reaction mixture was heated to 85 °C for 12 hours under nitrogen protection. The crude product obtained by concentration under reduced pressure was separated by silica gel column chromatography (dichloromethane / methanol, 20 / 1–10 / 1, V / V) to obtain compound 21-1. MS-ESI calculated value [M+H] + 508, measured value 508.

[0488] Step 2

[0489] 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 then added to a saturated sodium bicarbonate solution (20 mL), and the pH was adjusted to 8 with the saturated sodium bicarbonate solution. Extraction was performed 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 (HPLC) (column: Phenomenex Gemini-NX 80 mm × 40 mm × 3 μm; mobile phase: A phase was 0.05% ammonia monohydrate, B phase was acetonitrile; gradient: B phase 32%-62%, 8 min) to obtain compound 21. Compound 21 was measured for its ee value using SFC (column: Chiralcel OJ-3 100mm×4.6mm ID, 3μm; mobile phase: A phase was supercritical CO2, B phase was an ethanol solution containing 0.05% diethylamine; gradient: B phase 5%-40%).

[0490] Compound 21: ee% = 98.58%, RT = 3.576 min. 1H NMR (400MHz, CD3OD) δ8.58 (d, J=1.8Hz, 1H), 8.06 (d, J=1.0Hz, 1H), 7.64 (d, J=3.3Hz, 1H), 7.54-7.43 (m, 3H), 6.64 (d, J=3.3Hz, 1H), 5.23-5.15 (m, 1H), 4.14-4.09 (m, 1H), 4 0.04-3.96 (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 values ​​[M+H] + 408, measured value 408.

[0491] Example 22

[0492] Synthesis route:

[0493]

[0494] first step

[0495] 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 protection, [1,1-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (19 mg, 30 μmol) was added to the reaction mixture. The reaction mixture was heated to 70 °C for 2 hours under nitrogen protection. The crude product obtained by concentration under reduced pressure was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 7, V / V) to give compound 22-1. 1H NMR (400MHz, CDCl3) δ8.03 (s, 1H), 7.79 (d, J=8.3Hz, 1H), 7.58 (s, 1H), 7.50-7.4 3(m, 1H), 7.43-7.33(m, 3H), 7.23(d, J=8.5Hz, 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.

[0496] Step 2

[0497] 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 reacted at 25 °C for 2 hours. The reaction mixture was then added to a saturated sodium bicarbonate solution (50 mL), and the pH was adjusted to 8 with saturated sodium bicarbonate solution. Extraction was performed using dichloromethane / methanol (4 / 1, V / V, 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 into formate salts by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75 mm × 30 mm × 3 μm; mobile phase: phase A was an aqueous solution containing 0.025% formic acid, phase B was acetonitrile; gradient: phase B 0%-30%, 7 min) to obtain the formate salt of compound 22. The formate of compound 22 was measured for ee value by SFC (column: Chiralcel AD-3 50mm×4.6mm I.D., 3μm; mobile phase: A phase is supercritical CO2, B phase is ethanol solution containing 0.05% diethylamine; gradient: B phase 5%-40%).

[0498] Compound 22: ee% = 75.40%, RT = 2.230 min. 1H NMR (400MHz, CD3OD) δ8.09 (s, 1H), 7.92 (s, 1H), 7.84 (d, J=8.4Hz, 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( 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 values ​​[M+H] + 491, measured value 491.

[0499] Example 23

[0500] Synthesis route:

[0501]

[0502] first step

[0503] 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 protection, [1,1-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (14 mg, 21 μmol) was added to the reaction mixture. The reaction mixture was heated to 70 °C for 2 hours under nitrogen protection. The crude product obtained by concentration under reduced pressure was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 3, V / V) to give compound 23-1. 1H NMR (400MHz, CDCl3) δ8.05-7.93 (m, 1H), 7.88 (s, 1H), 7.73 (d, J=8.8Hz, 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.

[0504] Step 2

[0505] Compound 23-1 (60 mg, 87 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 then added to a saturated sodium bicarbonate solution (50 mL), and the pH was adjusted to >8 with saturated sodium bicarbonate solution. Extraction was performed using dichloromethane / methanol (4 / 1, V / V, 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 into formate salts by preparative high-performance liquid chromatography (HPLC) (column: Phenomenex Gemini-NX C18 75 mm × 30 mm × 3 μm; mobile phase: phase A was an aqueous solution containing 0.025% formic acid, phase B was acetonitrile; gradient: phase B 0%-20%, 7 min) to obtain the formate salt of compound 23. The formate of compound 23 was measured for ee value by SFC (column: Chiralcel IA 100mm×4.6mm I.D., 3μm; mobile phase: phase A is n-hexane containing 0.1% diethylamine, phase B is ethanol solution containing 0.1% diethylamine; gradient: phase B 80%).

[0506] Compound 23: ee%=90.87%, RT=6.608min. 1¹H NMR (400MHz, 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 values ​​[M+H] + 491, measured value 491.

[0507] Example 24

[0508] Synthesis route:

[0509]

[0510] first step

[0511] 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 protection, [1,1-bis(di-tert-butylphosphine)ferrocene]palladium dichloride (19 mg, 30 μmol) was added to the reaction mixture. The reaction mixture was heated to 70 °C for 2 hours under nitrogen protection. The crude product obtained by concentration under reduced pressure was separated by silica gel column chromatography (dichloromethane / methanol, 20 / 1–10 / 1, V / V) to obtain compound 24-1. 1 H NMR (400MHz, CDCl3) δ8.01 (s, 1H), 7.78 (d, J=8.3Hz, 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 values ​​[M+H] + 605, measured value 605.

[0512] Step 2

[0513] Compound 24-1 (110 mg, 182 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 then added to a saturated sodium bicarbonate solution (50 mL), and the pH was adjusted to 8 with saturated sodium bicarbonate solution. Extraction was performed using dichloromethane / methanol (4 / 1, V / V, 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 (HPLC) (column: Phenomenex Gemini-NX 80 mm × 40 mm × 3 μm; mobile phase: phase A was an aqueous solution containing 0.05% ammonia monohydrate, phase B was acetonitrile; gradient: phase B 36%-66%, 8 min) to obtain compound 24. Compound 24 was analyzed for its ee value using SFC (column: Chiralcel IG-3 100mm×4.6mm ID, 3μm; mobile phase: A phase was supercritical CO2, B phase was an ethanol solution containing 0.05% diethylamine; gradient: B phase 40%).

[0514] Compound 24: ee%=84.10%, RT=3.362min. 1 H NMR (400MHz, CD3OD) δ8.04 (s, 1H), 7.91 (s, 1H), 7.83 (d, J=8.5Hz, 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), 3.41-3.4 1 (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 values ​​[M+H] + 505, measured value 505.

[0515] Biological activity assessment:

[0516] Experimental Example 1: Test of the inhibitory effect of DPP1 enzyme activity

[0517] Experimental materials:

[0518] Recombinant human cathepsin C / DPP1 was purchased from R&D Systems;

[0519] Recombinant human cathepsin L (rhCathepsin L) was purchased from R&D Systems;

[0520] Gly-Arg-AMC (hydrochloride) was purchased from CAYMAN CHEMICAL COMPANY.

[0521] Experimental methods:

[0522] 1X Activation Buffer: 5mM DTT 0.01% (V / V) Triton X-100 (prepare fresh before use);

[0523] 1X experimental buffer: 50mM NaCl, 5mM DTT, 0.01% (V / V) Triton X-100 (prepare fresh before use);

[0524] The recombinant human cathepsin C / DPP1 enzyme and the recombinant human cathepsin L (rhCathepsin L) enzyme were diluted to concentrations of 2 ng / μL and 0.4 ng / μL, respectively, using 1X activation buffer; equal volumes of the two enzyme working solutions were mixed and incubated at 25°C for 60 minutes.

[0525] The test compound was diluted 5-fold to the 8th concentration using a multi-channel pipette, i.e., from 1 mM to 12.8 nM. Then, each gradient of the test compound was diluted with 1X experimental buffer to prepare a working solution of 4% DMSO. 5 μL / well was added to the corresponding well for a double-duplicate experiment. Centrifuge at 1000 rpm for 1 minute.

[0526] Add 5 μL of the enzyme mixture per well after incubation to a white microplate. At this point, the amount of DPP1 enzyme in each well is 5 ng. Add 5 μL of 1X experimental buffer per well to the blank control wells.

[0527] Dilute Gly-Arg-AMC (hydrochloride) to 25 μM with 1X experimental buffer, and add 10 μL / well to a white microplate. The substrate concentration is 12.5 μM. Centrifuge the microplate at 1000 rpm for 1 minute. The compound concentration will decrease from 10 μM to 0.128 nM. After centrifugation, attach the microplate to a membrane and incubate at 25°C for 60 minutes.

[0528] After incubation, fluorescence was detected using a multi-label analyzer with an excitation wavelength of 360 nm and an emission wavelength of 460 nm.

[0529] Data Analysis:

[0530] The raw data were converted into enzyme activity (IC50) using the equation (Sample-Min) / (Max-Min)×100%. 50The value can be obtained by curve fitting using four parameters (obtained in GraphPad Prism using log(inhibitor) vs. response -- Variable slope mode).

[0531] Max: Contains recombinant human cathepsin C / DPP1, recombinant human cathepsin L (rhCathepsin L), and Gly-Arg-AMC (hydrochloride).

[0532] Min: Does not contain recombinant human cathepsin C / DPP1 and recombinant human cathepsin L (rhCathepsin L).

[0533] Table 1 provides the inhibitory activity of the compounds of the present invention against DPP1 enzyme.

[0534] Table 1. Results of the inhibitory activity test of the compounds of the present invention against DPP1 enzyme.

[0535] compound <![CDATA[IC 50 (nM)]]> Compound 2 26.78 Compound 4 10.83 Compound 5 28.27 Compound 6 0.84 Compound 7 2.52 Compound 8 3.57 Compound 9 14.03 Compound 10 4.39 Compound 12 2.38 Compound 13 20.36 Compound 14 28.09 Compound 15 3.65 Compound 16 9.18 Compound 17 22.52 Compound 18 1.23 Compound 19 4.55 Compound 20 11.46 Compound 21 17.34 Compound 22 0.76 Compound 24 1.00

[0536] Conclusion: The compounds of this invention have significant inhibitory activity against DPP1 enzyme.

[0537] Experimental Example 2: Assay for DPP1 Inhibition Activity in U937 Cells

[0538] Experimental materials:

[0539] 1) Experimental reagents and consumables

[0540] name Brand item number U937 Punosai-CL-0239 RPMI1640 medium BI-01-100-1ACS fetal bovine serum Gibco-10099-141 Double antibiotics (penicillin, streptomycin) Procell-PB180120 Cell plate COSTAR-3603

[0541] 2) Experimental apparatus

[0542] name Brand item number Cell counting chamber Seeking excellence Victor Nivo PerkinElmer

[0543] Experimental methods:

[0544] 1) Cell inoculation

[0545] (1) Cell culture medium: 89% RPMI 1640, 10% fetal bovine serum and 1% penicillin-streptomycin;

[0546] (2) The culture medium was preheated in a 37°C water bath.

[0547] (3) Take the cell suspension from the cell culture flask and put it into a 15mL centrifuge tube. Centrifuge at 1000rpm / min for 5 minutes.

[0548] (4) After centrifugation, discard the supernatant, add 2 mL of culture medium to resuspend the cells, take out an appropriate amount of cell suspension, mix it with trypan blue, and take out about 0.01 mL of cell suspension for counting.

[0549] (5) Dilute the cell suspension with culture medium to the required cell density of 6.67 × 10^5 cells per milliliter for plating;

[0550] (6) Add 30 μL of cell suspension to each well of the cell plate and incubate in a 37°C incubator containing 5% CO2 for later use.

[0551] (7) Take the required amount of cells and continue culturing them in a new T75 culture flask.

[0552] 2) Adding medicine

[0553] (1) Prepare a 10 mM solution of the compound to be tested using DMSO;

[0554] (2) The compound was subjected to eight concentration gradients and five-fold dilutions, i.e., from 2 mM to 0.0256 μM, in a double-duplicate assay. 78 μL of culture medium was added to the intermediate plate, and then 2 μL of the gradient diluted compound was transferred to each well of the intermediate plate according to the corresponding position. After mixing, 10 μL of the compound was transferred to each well of the cell plate, resulting in a final concentration of the compound transferred to the cell plate ranging from 10 μM to 0.128 nM. The cell plate was incubated in a CO2 incubator for 1 hour.

[0555] (3) After incubation for 1 hour, add 100 μM of Gly-Phe-AFC probe solution, that is, take 60 mM of Gly-Phe-AFC probe storage solution, dilute it with culture medium to 500 μM working solution, transfer 10 μL to each well into the cell plate, and place the cell plate in a carbon dioxide incubator for 1 hour.

[0556] 3) Reading and analyzing the data:

[0557] (1) Reading the plate: After the cells are incubated, remove the cell plate and read the plate on a Victor Nivo.

[0558] Data Analysis:

[0559] The original data were converted into inhibition rate using the equation (Sample-Min) / (Max-Min)×100%, IC 50 The values ​​can be obtained by curve fitting using four parameters (obtained in GraphPad Prism in the "log(inhibitor) vs. response--Variable slope" mode). Table 2 provides the inhibitory activity of the compounds of this invention on DPP1 in U937 cells.

[0560] Table 2. Results of the test on the inhibitory activity of the compounds of the present invention against DPP1 in U937 cells.

[0561] compound <![CDATA[IC 50 (nM)]]> Compound 2 8.95 Compound 4 1.32 Compound 5 9.32 Compound 6 0.64 Compound 7 2.49 Compound 8 2.40 Compound 10 8.53 Compound 12 1.81 Compound 13 6.33 Compound 14 2.79 Compound 18 5.43 Compound 19 8.70 Compound 20 9.58 Compound 21 9.27 Compound 24 3.12

[0562] Conclusion: The compound of this invention has good inhibitory activity against DPP1 in U937 cells.

[0563] Experimental Example 3: Pharmacokinetic Evaluation of the Compounds of the Invention in Mice

[0564] Experimental objective: To test the pharmacokinetics of the compound in CD-1 mice.

[0565] Experimental materials: CD-1 mice (male, 20-40g, 4-6 weeks old, Vital River Pharmaceuticals, Beijing)

[0566] Experimental procedure:

[0567] The pharmacokinetic characteristics of the compound after intravenous and oral administration were tested in rodents using a standard protocol. In the experiment, the candidate compound was prepared into a clear solution and administered to two mice via single intravenous injection and oral administration, respectively. The solvent for intravenous and oral administration was DMSO / Solutol / water in a 1:1:8 ratio. Whole blood samples were collected within 24 hours into commercially available EDTA2K anticoagulant tubes, centrifuged at 6000g for 3 minutes, and the supernatant was separated to obtain plasma samples. Twenty volumes of acetonitrile solution containing internal standard were added to precipitate proteins. After centrifugation, the supernatant was collected, and an equal volume of water was added. The supernatant was then injected, and the plasma concentration was quantitatively analyzed using LC-MS / MS. Pharmacokinetic parameters, such as apparent volume of distribution, clearance, half-life, and area under the curve (AUC), were calculated. The experimental results are shown in Table 3.

[0568] Table 3. Results of pharmacokinetic tests of the compounds of this invention in mice.

[0569]

[0570] Conclusion: The compounds of this invention exhibit good bioavailability, high area under the curve and low clearance and tissue distribution in CD-1 mice pharmacokinetics.

[0571] Experimental Example 4: Pharmacokinetic Evaluation of the Compounds of the Invention in Rats

[0572] Experimental objective: To test the pharmacokinetics of the compound in SD rats.

[0573] Experimental materials: Male SD rats (200-300g, 6-10 weeks old, from Vital River Pharmaceuticals, Beijing)

[0574] Experimental procedure:

[0575] The pharmacokinetic characteristics of the compound after intravenous and oral administration were tested in rodents using a standard protocol. In the experiment, the candidate compound was prepared into a clear solution and administered to two rats via single intravenous injection and oral administration, respectively. The solvents for intravenous and oral administration were a 5:95 mixture of DMSO and 10% hydroxypropyl β-cyclodextrin aqueous solution. Whole blood samples were collected within 24 hours into commercially available EDTA2K anticoagulant tubes, centrifuged at 6000g for 3 minutes, and the supernatant was separated to obtain plasma samples. Twenty volumes of acetonitrile solution containing internal standard were added to precipitate proteins. After centrifugation, the supernatant was collected, and an equal volume of water was added. The supernatant was then injected, and the plasma concentration was quantitatively analyzed using LC-MS / MS. Pharmacokinetic parameters, such as apparent volume of distribution, clearance, half-life, and area under the curve (AUC), were calculated. The experimental results are shown in Table 4.

[0576] Table 4. Results of pharmacokinetic tests of the compounds of this invention in rats.

[0577]

[0578] Conclusion: The compounds of this invention exhibit good bioavailability, high area under the curve, and low clearance and tissue distribution in SD rat pharmacokinetic studies.

[0579] Experimental Example 5: Evaluation of the distribution of the compounds of the present invention in mouse tissues (bone marrow)

[0580] Experimental objective: To test the distribution of the compounds of this invention in the bone marrow and plasma of CD-1 mice.

[0581] Experimental materials: CD-1 mice (male, 20-40g, 4-6 weeks old, Vital River Pharmaceuticals, Beijing)

[0582] Experimental procedure:

[0583] The concentrations of the compound in mouse bone marrow and plasma after oral administration were tested using a standard protocol. In this experiment, the candidate compound was prepared into a clear solution using a solvent consisting of 5:95 DMSO and 10% hydroxypropyl β-cyclodextrin aqueous solution. Mice were administered a single oral 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 into commercially available EDTA2K anticoagulant tubes, centrifuged at 6000g for 3 minutes, and the supernatant was separated to obtain plasma samples. Acetonitrile solution containing an internal standard was added to precipitate proteins, and the supernatant was collected after centrifugation. An equal volume of water was added, and the mixture was stirred. The plasma drug concentration was quantitatively analyzed by LC-MS / MS, and the area under the curve (AUC) was calculated. The femurs and tibias of mice were harvested from both sides, the muscles were removed, one end was cut open, and the tubes were placed face down in centrifuge tubes. The tubes were centrifuged at 8000 rpm for 1 minute, and the precipitate was the bone marrow. The bone marrow was mixed with 50% methanol and water and ground into a homogenate. Acetonitrile solution containing internal standard was added to the homogenate to precipitate the protein. The supernatant was collected by centrifugation, and an equal volume of water was added. After mixing, the drug concentration in the bone marrow was quantitatively analyzed by LC-MS / MS, and the area under the curve was calculated.

[0584] The formula for calculating the bone marrow / plasma distribution coefficient is: Bone marrow / Plasma Ratio = Bone marrow AUC 0-last / Plasma AUC 0-last The experimental results are shown in Table 5.

[0585] Table 5 Results of mouse bone marrow / plasma distribution test of the compounds of this invention.

[0586]

[0587] Conclusion: The compounds of this invention are highly distributed in the bone marrow of CD-1 mice.

[0588] Experimental Example 6: Evaluation of the distribution of the compounds of the present invention in rat tissues (bone marrow)

[0589] Experimental objective: To test the distribution of the compound in the bone marrow and plasma of SD rats.

[0590] Experimental materials: Male SD rats (200-300g, 6-10 weeks old, from Vital River Pharmaceuticals, Beijing)

[0591] Experimental procedure:

[0592] The concentrations of the compound in rat bone marrow and plasma after oral administration were tested using a standard protocol. In this experiment, the candidate compound was prepared into a clear solution using a solvent consisting of 5:95 DMSO and 10% hydroxypropyl β-cyclodextrin aqueous solution. Rats were administered a single oral 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 into commercially available EDTA2K anticoagulant tubes, centrifuged at 6000g for 3 minutes, and the supernatant was separated to obtain plasma samples. Acetonitrile solution containing an internal standard was added to precipitate proteins, and the supernatant was collected after centrifugation. An equal volume of water was added, and the mixture was thoroughly mixed. The plasma drug concentration was quantitatively analyzed using LC-MS / MS, and the area under the curve (AUC) was calculated. The left femur of a rat was removed, the muscle was removed, one end was cut open, and the femur was placed face down in a centrifuge tube. The tube was centrifuged at 8000 rpm for 1 minute, and the precipitate was the bone marrow. The bone marrow was mixed with 50% methanol and water and ground into a homogenate. Acetonitrile solution containing internal standard was added to the homogenate to precipitate the protein. The supernatant was collected by centrifugation, and an equal volume of water was added. After mixing, the drug concentration in the bone marrow was quantitatively analyzed by LC-MS / MS, and the area under the curve was calculated.

[0593] The formula for calculating the bone marrow / plasma distribution coefficient is: Bone marrow / Plasma Ratio = Bone marrow AUC 0-last / Plasma AUC 0-last The experimental results are shown in Table 6.

[0594] Table 6 Results of rat bone marrow / plasma distribution test of the compounds of the present invention.

[0595]

[0596]

[0597] Conclusion: The compounds of this invention are highly distributed in the bone marrow of SD rats.

[0598] Experimental Example 7: In vivo efficacy evaluation of the effect of the compound of the present invention on elastase activity in rat bone marrow neutrophils

[0599] Experimental objective: To evaluate the effect of the compound of this invention on the elastase activity of bone marrow neutrophils in SD rats.

[0600] Experimental materials: Male SD rats (200-300g, 6-10 weeks old, from Vital River Pharmaceuticals, Beijing)

[0601] Experimental procedure:

[0602] Experimental animals were grouped and administered drugs according to Table 7. Two hours after the last administration, bone marrow was collected from the animals. Red blood cells were first lysed with red blood cell lysis buffer while lymphocytes were preserved. Lymphocytes were then lysed with lymphocyte lysis buffer. The supernatant was used for protein quantification and neutrophil elastase activity assay to further calculate the neutrophil elastase activity in the sample. The administration regimen is shown in Table 7.

[0603] Table 7 Grouping and Dosing Regimens of Experimental Animals

[0604]

[0605] Experimental indicators:

[0606] The elastase activity of neutrophils in bone marrow samples was calculated. The experimental results are shown below. Figure 1 .

[0607] Conclusion: The compounds of this invention can significantly inhibit the activity of neutrophil elastase in rats.

Claims

1. A compound of Formula (II) or a pharmaceutically acceptable salt thereof, wherein, Z is C; T is independently selected from N and CR3; R1 is F; R3 is selected from H, F, Cl, Br and I; n is 1; and the 5-6 membered heterocycloalkyl group comprises 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -0-, -NH-, -S- and -N-. ， 2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has a structure represented by Formula (II'): ###0002### (II') wherein, R3 is selected from H, F, Cl and Br; and R6 is selected from H, F, Cl and Br.

9. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound has a structure represented by Formula (I) or a pharmaceutically acceptable salt thereof, ###0004### (I) wherein, T is independently selected from N and CR3; R3 is selected from H, F, Cl, Br and I; R1, R2 and n are as defined in claim 1. Structural unit selected from and ; 10. The compound or a pharmaceutically acceptable salt thereof according to claim 9, wherein the compound has a structure represented by Formula (I-1): ###0005### (I-1) wherein, T, R1, R2 and n are as defined in claim 9.

11. The compound or a pharmaceutically acceptable salt thereof according to claim 10, wherein the compound has a structure represented by Formula (I-1A): ###0006### (I-1A) wherein, T, R1 and R2 are as defined in claim 10. R2is selected from the group consisting of H, F, CI, Br, I, -OH, -NH2, -CN, C 1-3 alkyl and 5-6 membered heterocycloalkyl, wherein the C 1-3 alkyl and 5-6 membered heterocycloalkyl are each independently optionally substituted with 1, 2, or 3 R b substituents; 12. The compound or a pharmaceutically acceptable salt thereof according to claim 11, wherein the compound has a structure represented by Formula (I'-1A): ###0007### (I'-1A) wherein, T, R1 and R2 are as defined in claim 11. R6is selected from the group consisting of H, F, Cl, Br, I, -OH, -NH2, -CN, and C 1-3 alkyl, wherein the C 1-3 alkyl is optionally substituted with 1, 2, or 3 R f substituents; R b are each independently selected from the group consisting of F, Cl, Br, I, =0, -OH, -NH2, -CN, and C 1-3 alkyl; R f are each independently selected from the group consisting of F, Cl, Br, I, =0, -OH, -NH2, and -CN; 13. A compound of the following formula: ###0008### or a pharmaceutically acceptable salt thereof. ​ ​ ， wherein, Structural unit Z, R1, R2, R6and n are as defined in claim 1 ; bring" The carbon atoms in “ and “ are chiral carbon atoms, existing as a single enantiomer (R) or (S) or rich in one enantiomer.

3. The compound or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein, R b is selected from F, CI, Br and -CH3.

4. The compound or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein, R2is selected from H, -CH3, , and wherein said -CH3, , and are each independently optionally substituted with 1, 2, or 3 R b .

5. The compound of claim 4, or a pharmaceutically acceptable salt thereof, wherein, R2is selected from H, -CH3, , , and .

6. The compound or pharmaceutically acceptable salt thereof of claim 1 or 2, wherein, ​ 7. The compound of claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein, ​ 8. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein, Structural unit selected from , , , , , , , and . ​ ， ​ structural unit selected from and ; ​ ​ ​ ​ ， wherein ​ ​ ， wherein, ​ ​ ， wherein ​ bring" The carbon atoms in “ and “ are chiral carbon atoms, existing as a single enantiomer (R) or (S) or rich in one enantiomer. ​ 、 、 、 、 、 、 。 14. A compound of the formula: ###0007### or a pharmaceutically acceptable salt thereof, wherein the compound is: ###0008### , , , , , , , , , , , , , , , , , .

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