Condensed ring derivatives containing 1,4-oxazepane

Abstract

The present invention relates to a series of fused ring derivatives containing 1,4-oxazepane and a method for preparing the same, specifically to a compound represented by formula (II) and a pharma- ceutically acceptable salt thereof. [Formula 1] JPEG2024505715000141.jpg5299

Description

Technical Field

[0001] This application claims the following priorities: CN202110164857.7, February 5, 2021; CN202111138395.8, September 27, 2021.

[0002] The present invention relates to a fused-ring derivative containing a series of 1,4-oxazepanes and a method for producing the same, and specifically relates to a compound represented by formula (II) and a pharmaceutically acceptable salt thereof.

Background Art

[0003] Dipeptidyl peptidase 1 (DPP1), also known as cathepsin C, is highly expressed in tissues such as the lung, kidney, liver, and spleen. DPP1 is a type of lysosomal cysteine protease and is a tetramer composed of four identical subunits, and each subunit is composed of a heavy chain, a light chain, and an exclusive domain (Turk, D. et al. EMBO J. 2001, 20, 6570-6582.). The main physiological role of DPP1 is to activate pro-inflammatory neutrophil serine proteases (including NSPs, neutrophil elastase, proteinase 3, and cathepsin G) by cleaving the N-terminal dipeptide in the bone marrow. NSPs are closely related to inflammation regulation, can activate various cytokines, and play an important role in the elimination of pathogenic microorganisms. According to research, in the airways of patients with diseases such as chronic obstructive pulmonary disease (COPD) or bronchiectasis, a large amount of persistent inflammatory reaction and over-activation of NSPs are observed, which decomposes lung elastin and the like, and further causes damage to lung tissue and destruction of bronchial wall tissue (Christine T. N. Pham, Nat. Rev. Immunol. 2006, 6, 541-550). DPP1 inhibitors can inhibit the inflammatory reaction and airway damage caused by neutrophils in the airway by fundamentally inhibiting the activation of pro-inflammatory neutrophil proteases.

[0004] Currently, there are no drugs commercially available as DPP1 inhibitors. Brensocatib (INS1007, also known as AZD7986) is the drug with the most rapid progress in clinical research. The Phase II clinical trial for bronchiectasis has reached the primary evaluation items, and the current Phase III clinical trial is in progress. Furthermore, AZD7986 for the treatment of chronic obstructive pulmonary disease is in Phase II clinical research. Therefore, the development of DPP1 inhibitors has a broad market prospect.

Summary of the Invention

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

[0006]

Chemical formula

[0007] However, Z is selected from N and C,

[0008] structural unit

Chemical formula

[0009]

Chemical formula

[0010]

Chemical formula

[0011] are each independently selected from a single bond and a double bond, where

Chemical formula

[0012] T is independently selected from N and CR3,

[0013] Each R1 is independently selected from H, F, Cl, Br, I, -OH, -NH2, -CN, and C 1-3 alkyl, where the C 1-3 alkyl is optionally substituted by 1, 2, or 3 R a s,

[0014] R2 is selected from H, F, Cl, Br, I, =O, -OH, -NH2, -CN, C 1-3 alkyl, and 5- to 6-membered heterocycloalkyl, where the C 1-3 alkyl and 5- to 6-membered heterocycloalkyl are each independently optionally substituted by 1, 2, or 3 R b s,

[0015] R3 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, and C 1-3 alkyl, where the C 1-3 alkyl is optionally substituted by 1, 2, or 3 R c s,

[0016] R4 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, and C 1-3 alkyl, where the C 1-3 alkyl is optionally substituted by 1, 2, or 3 R d s,

[0017] R5 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, and C 1-3 alkyl, where the C 1-3 alkyl is optionally substituted by 1, 2, or 3 R e s,

[0018] R6 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN, and C 1-3Selected from alkyl, wherein said C 1-3 alkyl is optionally substituted by 1, 2 or 3 R f wherein,

[0019] R a is independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN respectively,

[0020] R b is independently selected from F, Cl, Br, I, =O, -OH, -NH2, -CN and C 1-3 alkyl respectively,

[0021] R c is independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN respectively,

[0022] R d is independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN respectively,

[0023] R e is independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN respectively,

[0024] R f is independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN respectively,

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

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

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

[0028]

Chemical formula

[0029] However, [Chemical formula] is selected from a single bond and a double bond,

[0030] structural unit [Chemical formula] is selected from,

[0031] T is selected from N and CR3,

[0032] R1 is selected from H, F, Cl, Br, I, -OH, -NH2, -CN and C 1-3 alkyl, where the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a s,

[0033] R2 is selected from H and C 1-3 alkyl, where the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R b s,

[0034] R3 is selected from H and C 1-3 alkyl, where the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R c s,

[0035] R4 is selected from H and C 1-3 alkyl, where the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R d s,

[0036] R5 is selected from H and C 1-3 alkyl, where the C 1-3 alkyl is optionally substituted by 1, 2 or 3 Re is optionally replaced by

[0037] R a is independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN,

[0038] R b is independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN,

[0039] R c is independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN,

[0040] R d is independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN,

[0041] R e is independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN,

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

[0043] In some embodiments of the present invention, the above compound has a structure represented by formula (II’).

[0044]

Chemical formula

[0045] However, the structural unit

Chemical formula

[0046] The carbon atoms with "*" and "#" are chiral carbon atoms and exist in the form of (R) or (S) single enantiomers or an enantiomer-rich form.

[0047] In some embodiments of the present invention, the above compound has a structure represented by formula (I').

[0048]

Chemical formula

[0049] However, for the structural unit

Chemical formula

[0050] The carbon atoms with "*" and "#" are chiral carbon atoms and exist in the form of (R) or (S) single enantiomers or an enantiomer-rich form.

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

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

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

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

[0055] In some embodiments of the present invention, the above R2 is H, -CH3,

Chemical formula

Chemical formula

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

Chemical formula

[0057] selected from, and other variables are as defined in the present invention.

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

[0059] In some embodiments of the present invention, the above 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, the above R3 is selected from H, and other variables are as defined in the present invention.

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

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

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

[0063] In some embodiments of the present invention, the above structural unit

Chemical formula

[0064] In some embodiments of the present invention, the above structural unit

Chemical formula

[0065] In some embodiments of the present invention, the above structural unit

Chemical formula

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

[0067]

Chemical formula

[0068] However, the structural unit

Chemical formula

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

[0070]

Chemical formula

[0071] However, the structural unit

Chemical formula

[0072] The carbon atoms with “*” and “#” are chiral carbon atoms and exist in the form of (R) or (S) single enantiomers or an enantiomer-rich form.

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

[0074]

Chemical formula

[0075] However, The structural unit

Chemical formula

Chemical formula

Chemical formula

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

[0077]

Chemical formula

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

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

[0080]

Chemical formula

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

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

[0083]

Chemical formula

[0084] However, T, R1, R2, R4 and R5 are as defined in the present invention, and

[0085] the carbon atoms marked with "*" and "#" are chiral carbon atoms and exist in the form of (R) or (S) single enantiomers or an enantiomer-rich form.

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

[0087]

Chemical formula

[0088]

Chemical formula

[0089] However, T, R1, R2, R4 and R5 are as defined in the present invention,

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

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

[0092]

Chemical formula

[0093]

Chemical formula

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

[0095]

Chemical formula

[0096]

Chemical formula

[0097] [Chemical formula]

[0098] [Chemical formula] [Advantages of the Invention]

[0099] The compound provided by the present invention has significant inhibitory activity against DPP1 at the enzyme level and cell level, has a high oral exposure in rats and mice, has good pharmacokinetic properties, has a strong distribution ability in the bone marrow, and can significantly inhibit the activity of neutrophil elastase in rat bone marrow.

[0100] Definitions and Explanations

[0101] Unless otherwise specified, the following terms and phrases used in this specification shall have the following meanings. Specific terms and phrases should not be considered uncertain or unclear when not specifically defined, but should be understood according to their ordinary meanings. When a trade name is described in this specification, it is intended to refer to the corresponding trade name or its active ingredient.

[0102] As used in this specification, the term "pharmaceutically acceptable" means, for those compounds, materials, compositions and / or dosage forms, within the scope of sound medical judgment, suitable for use in contact with human and animal tissues, with little excessive toxicity, irritation, allergic reaction or other problems or complications, and commensurate with a reasonable benefit / risk ratio.

[0103] The term "pharmaceutically acceptable salt" refers to salts of the compounds of the present invention produced from relatively non-toxic acids or bases with the specific substituents found in the present invention. When the compounds of the present invention contain relatively acidic functional groups, the base addition salts can be obtained by contacting such compounds in a pure solution or a suitable inert solvent with a sufficient amount of base. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When the compounds of the present invention contain relatively basic functional groups, the acid addition salts can be obtained by contacting such compounds in a pure solution or a suitable inert solvent with a sufficient amount of acid. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts and organic acid salts, as well as salts of amino acids (such as arginine, etc.) and salts of organic acids such as glucuronic acid. The inorganic acids include, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate ion, phosphoric acid, monohydrogen phosphate ion, dihydrogen phosphate ion, sulfuric acid, hydrogen sulfate ion, hydroiodic acid, phosphorous acid, etc. The organic acids include, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and similar acids. Some specific compounds of the present invention contain both basic and acidic functional groups and can therefore be converted into either base addition salts or acid addition salts.

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

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

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

[0107] Unless otherwise specified, the terms "cis-trans isomer" or "geometric isomer" are due to the fact that the single bonds of carbon atoms forming a double bond or a ring cannot rotate freely.

[0108] Unless otherwise specified, the term "diastereomer" refers to stereoisomers in which a molecule has two or more chiral centers and the molecules are non-mirror images of each other.

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

[0110]

Chemical formula

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

[0112] Unless otherwise stated, the terms "rich in one isomer", "isomer-rich", "rich in one enantiomer", or "enantiomer-rich" mean that the content of one isomer or enantiomer is less than 100%, and the content of this isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

[0113] Unless otherwise stated, the term "isomer excess" or "enantiomer excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, when the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80%.

[0114] The optically active (R)- and (S)-isomers, as well as the D and L isomers, can be produced by chiral synthesis or by chiral reagents or other conventional techniques. To obtain one enantiomer of a certain compound of the present invention, it can be produced by asymmetric synthesis or derivatization with a chiral auxiliary, where the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., an amino group) or an acidic functional group (e.g., a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereomers are resolved by conventional methods known in the art and recovered to obtain the pure enantiomer. Also, the separation of enantiomers and diastereomers is usually carried out using chromatography with a chiral stationary phase and optionally in combination with a chemical derivatization method (e.g., generating a carbamate from an amine).

[0115] The compounds of the present invention may contain an unnatural proportion of atomic isotopes in one or more of the atoms constituting the compound. For example, the compound can be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I), C-14 ( 14 C), etc. Or for example, deuterium can be substituted for hydrogen to form a deuterated drug, and the bond formed by deuterium and carbon is stronger than the bond formed by normal hydrogen and carbon. Compared with the non-deuterated drug, the deuterated drug has advantages such as reducing toxic side effects, enhancing the stability of the drug, enhancing the effectiveness, and extending the biological half-life of the drug. The conversion of the isotope composition of the compounds of the present invention is included within the scope of the present invention regardless of whether it is radioactive or not.

[0116] The terms "optionally" or "optionally selected" mean that the event or situation described thereafter may occur but does not necessarily occur, and the description includes both the case where the event or situation occurs and the case where the event or situation does not occur.

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

[0118] If any of the variables (e.g., R) appears one or more times in the composition or structure of the compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0 to 2 R's, the group may optionally be substituted by up to 2 R's, and in each case R has independent options. Also, combinations of substituents and / or their variants are permitted only if such combinations result in a stable compound.

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

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

[0121] When the substituent is empty, it means that the substituent does not exist. For example, when X in A-X is empty, the structure actually means A. When it is not indicated through which atom the listed substituent is bonded to the substituted group, such a substituent can be bonded through any of its atoms. For example, pyridinyl as a substituent may be bonded to the substituted group through any carbon atom of the pyridine ring.

[0122] When the listed linking group does not indicate its linking direction, the linking direction is arbitrary. For example,

Chem.

[0123] the linking group L in is -M-W-, and at this time -M-W- links ring A and ring B in the same direction as the reading order from left to right to

Chem.

[0124] form, and can also link ring A and ring B in the direction opposite to the reading order from left to right to

Chem.

[0125] form. The combination of the linking group, substituent and / or its variant is only allowed when such a combination results in a stable compound.

[0126] Unless otherwise specified, when a group has one or more bondable sites, any one or more sites of the group can be bonded to other groups via chemical bonds. When the bonding mode of the chemical bond is delocalized and there are H atoms at the bondable sites, when the chemical bonds are bonded, the number of H atoms at the site decreases to a group with the corresponding valence according to the number of the bonded chemical bonds. The chemical bond by which the site is bonded to another group is

[0127]

Chem.

[0128] For example, the straight solid line bond of -OCH3 represents that it is bonded to another group through the oxygen atom in the group.

Chem.

Chem.

[0129]

Chem.

[0130] represents that any bondable site of the piperidinyl can be bonded to another group through one chemical bond, and at least

Chem.

Chem.

Chem.

[0131] When the chemical bond of a substituent intersects with the chemical bond between two atoms on the linking ring, it means that the substituent can form a bond with any atom on the ring. If the atom to which the substituent is bonded is not specified, the substituent may bond to any atom, and if the atom to which the substituent is bonded is a bicyclic or tricyclic system, it means that the substituent may bond to any atom on any ring within that system. Combinations of substituents and / or variables are only permitted if the combination results in a stable compound. For example, the structural unit

Chem.

Chem.

[0132] Unless otherwise specified, the ring

Chem.

Chem.

Chem.

[0133] Unless otherwise specified, in the present invention, the terms "5- to 6-membered heteroaryl ring" and "5- to 6-membered heteroaryl" can be used interchangeably. The term "5- to 6-membered heteroaryl" is a monocyclic group having a conjugated π-electron system composed of 5 to 6 ring atoms, and 1, 2, 3, or 4 of its ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms. Here, the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(=O) p, p is 1 or 2). The 5- to 6-membered heteroaryl can be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5- to 6-membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of the 5- to 6-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl, 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, etc.), triazolyl (such as 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), furanyl (including 2-furanyl, 3-furanyl, etc.), thienyl (including 2-thienyl, 3-thienyl, etc.), pyridyl (including 2-pyridyl, 3-pyridyl, 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl, 4-pyrimidinyl, etc.).

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

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

[0136] Unless otherwise indicated, the term "5- or 6-membered heterocycloalkyl" means, by itself or in combination with other terms, a saturated cyclic group consisting of 5 to 6 ring atoms each, where 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized, and the carbon, nitrogen, and sulfur heteroatoms may optionally be oxidized (i.e., C(=O), NO, and S(=O) p、 p is 1 or 2). It includes monocyclic and bicyclic ring systems, where the bicyclic ring systems include spiro rings, fused rings, and bridged rings. Also, with respect to said "5- or 6-membered heterocycloalkyl", the heteroatom can occupy the position where it is bonded to the heterocycloalkyl and other parts of the molecule. The 5- or 6-membered heterocycloalkyl includes 5-membered and 6-membered heterocycloalkyl. Examples of 5- or 6-membered heterocycloalkyl include pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, etc., but are not limited thereto. The term "leaving group" refers to a functional group or atom that may be substituted by another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction). For example, typical leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate, etc., and acyloxy groups such as acetoxy, trifluoroacetoxy, etc.

[0137] Unless otherwise indicated, Cn-n+m or C n -C n+m includes any one specific form of from n to n + m carbons. For example, C 1-12 is C1, C2, C3, C4, C5, C6, C7, C8, C9, C 10 , C 11 , and C 12 and includes any one range among n to n + m. For example, C 1-12 is C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 and so on. Similarly, n-membered to (n + m)-membered represents that the number of atoms in the ring is from n to n + m. For example, 3- to 12-membered rings include 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 7-membered rings, 8-membered rings, 9-membered rings, 10-membered rings, 11-membered rings, and 12-membered rings, and also includes any one range among n to n + m. For example, 3- to 12-membered rings include 3- to 6-membered rings, 3- to 9-membered rings, 5- to 6-membered rings, 5- to 7-membered rings, 6- to 7-membered rings, 6- to 8-membered rings, and 6- to 10-membered rings and so on.

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

[0139] 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 combination with other chemical synthesis methods, and equivalent alternative methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention.

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

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

[0142] The following abbreviations are used in the present invention: Alloc represents allyloxycarbonyl; SEM represents trimethylsilylethoxymethyl; OTs represents 4-toluenesulfonyloxy; OMs represents methanesulfonyloxy; Boc represents tert-butoxycarbonyl; DCM represents dichloromethane; DIEA represents N,N-diisopropylethylamine; MeI represents iodomethane; PE represents petroleum ether; EA represents ethyl acetate; THF represents tetrahydrofuran; EtOH represents ethanol; MeOH represents methanol; DMF represents N,N-dimethylformamide; Boc2O represents di-tert-butyl dicarbonate; NH4Cl represents ammonium chloride; T3P represents propylphosphonic anhydride; Pd / C represents palladium / carbon catalyst; TMSN3 represents trimethylsilyl azide; NCS represents N-chlorosuccinimide; HBr represents hydrobromic acid; AcOH represents acetic acid; HATU represents O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate; DBU represents 1,8-diazabicyclo[5.4.0]undec-7-ene; FA represents formic acid; ACN represents acetonitrile; TLC represents thin layer chromatography; HPLC represents high performance liquid chromatography; LCMS represents liquid chromatography mass spectrometry; 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 heavy water; Solutol represents polyethylene glycol (15)-hydroxystearate.

[0143] Compounds are named according to the normal naming principles in the art or using ChemDraw® software, and commercially available compounds are named in the supplier's product catalog.

Brief Description of the Drawings

[0144]

Figure 1

Mode for Carrying Out the Invention

[0145] Hereinafter, the present invention will be described in detail by way of examples, which should not be construed as limiting the present invention in any way. The compounds of the present invention can be produced by various synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combination with other chemical synthesis methods, and equivalent alternative methods well known to those skilled in the art. Preferred embodiments include, but are not limited to, the examples of the present invention. Various changes and modifications to specific embodiments of the present invention will be apparent to those skilled in the art without departing from the spirit and scope of the present invention.

[0146] Intermediate A Synthesis Route:

Chemical Formula

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

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

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

[0150] Step 4 A solution of T3P in ethyl acetate (14.03 g, 22.05 mmol) was added to DMF (100 mL), and Intermediate A-4 (4.0 g, 14.7 mmol), Intermediate A-5 (3.79 g, 15.44 mmol) and triethylamine (6.69 g, 66.2 mmol) were sequentially added. The mixture was stirred at 25 °C for 12 hours. After completion of the reaction, saturated brine (300 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (250 mL × 3). The combined organic phases were washed with saturated brine (500 mL × 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1 - 0 / 1, V / V) to obtain Intermediate A. 11H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.0 Hz, 2H), 7.12 - 6.93 (m, 3H), 5.20 - 5.12 (m, 1H), 4.25 - 3.95 (m, 3H), 3.82 - 3.68 (m, 0.5 H), 3.60 - 3.22 (m, 3H), 3.12 - 2.90 (m, 2.5 H), 2.12 - 1.82 (m, 2H), 1.48 (s, 9H). MS-ESI calculated value [M+Na] + 522, measured value 522.

[0151] Intermediate B Synthesis route:

Chem.

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

[0153] Intermediate C Synthesis Route:

Chem.

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

[0155] Step 2 Intermediate C-1c (24.85 g, 66.94 mmol) was dissolved in acetonitrile (200 mL), and hydrochloric acid (0.2 M, 840 mL, 167.34 mmol) was slowly added and 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 aqueous sodium hydrogen carbonate solution, extracted with ethyl acetate (1000 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain Intermediate C-1d, which was directly used in the reaction of the next step. MS-ESI calculated values [M+H] + 276 and 278, measured values 276 and 278.

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

[0157] Step 4 Intermediate C-1e (3.38 g, 12.9 mmol) was dissolved in dioxane (50 mL) and water (100 mL), sodium carbonate (1.50 g, 14.9 mmol) and Boc2O (3.27 g, 14.96 mmol) were added, and the mixture was reacted at 25 °C for 4 hours. The pH of the reaction solution was adjusted to 4 - 5 with a saturated aqueous citric acid solution, extracted with ethyl acetate (100 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain intermediate C-1f, which was directly used in the reaction of the next step. MS-ESI calculated value [M-56+1] + 306 and 308, measured value 306 and 308.

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

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

[0160] Step 7 50% solution of T3P in ethyl acetate (1870 mg, 2940 μmol) was added to DMF (10 mL), then Intermediate C-2 (591 mg, 2260 μmol), Intermediate A-5 (610 mg, 2490 μmol) and triethylamine (916 mg, 9050 μmol) were added sequentially, and the mixture was reacted at 25 °C for 4 hours. The reaction solution was added to saturated brine (50 mL), and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated brine (100 mL × 3), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained crude product was separated by silica gel column chromatography (dichloromethane / methanol, 100 / 1 - 10 / 1, V / V) to obtain Intermediate C. 11H NMR (400 MHz, CDCl3) δ 7.26 - 7.19 (m, 2H), 7.16 - 7.10 (m, 1H), 4.70 - 4.55 (m, 1H), 4.25 - 3.94 (m, 3H), 3.88 - 3.75 (m, 0.5H), 3.57 - 3.28 (m, 2H), 3.27 - 2.95 (m, 3.5H), 2.07 - 1.78 (m, 2H), 1.46 (s, 9H). MS-ESI calculated value [M+Na] + 510 and 512, measured values 510 and 512.

[0161] Intermediate D Synthesis route:

Chemical formula

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

[0163] Intermediate E Synthesis route:

Chemical formula

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

[0165] Intermediate F Synthesis route:

Chemical Structure

[0166] Intermediate F-1 (300 mg, 1410 μmol), potassium acetate (277 mg, 2830 μmol), and bis(pinacolato)diboron (539 mg, 2120 μmol) were added to 1,4-dioxane (8 mL). Next, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (207 mg, 282 μmol) was added to the reaction solution. The reaction solution was heated to 110 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 to 10 / 3, V / V) to obtain Intermediate F. 11H NMR (400 MHz, CDCl3) δ 8.06 - 8.02 (m, 2H), 7.83 - 7.77 (m, 1H), 4.33 (s, 3H), 1.40 (s, 12H). MS-ESI calculated value [M + H] + 260, measured value 260.

[0167] Intermediate G Synthesis route:

Chemical Structure

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

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

[0170] Step 3 Intermediate G-3 (1800 mg, 9800 μmol), potassium acetate (2890 mg, 29410 μmol), and bis(pinacolato)diboron (4980 mg, 19610 μmol) were added to 1,4-dioxane (20 mL). Next, palladium acetate (132 mg, 588 μmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (280 mg, 588 μmol) were added to the reaction solution. The reaction solution was heated to 80 °C under nitrogen gas protection and reacted for 3 hours. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 20 / 1 - 3 / 1, V / V) to obtain Intermediate G. 1 H NMR (400 MHz, CDCl3) δ7.64 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.22 (d, J = 8.0 Hz, 1H), 3.44 (s, 3H), 1.38 (s, 12H). MS-ESI calculated value [M + H] + 276, measured value 276.

[0171] Intermediate H Synthesis route:

Chemical Structure

[0172] Intermediate H-1 (995 mg, 4400 μmol), potassium acetate (1300 mg, 13200 μmol), and bis(pinacolato)diboron (2240 mg, 8800 μmol) were added to 1,4-dioxane (10 mL). Next, palladium acetate (60 mg, 264 μmol) and 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (126 mg, 264 μmol) were added to the reaction solution. The reaction solution was heated to 80 °C under nitrogen gas protection and reacted for 3 hours. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1 - 1 / 1, V / V) to obtain Intermediate H. 11H NMR (400 MHz, 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 value [M + H] + 274, measured value 274.

[0173] Intermediate I Synthesis route:

Chemical formula

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

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

[0176] Intermediate I-4: 11H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.80 (s, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.08 (d, J = 8.8 Hz, 1H), 4.52 - 4.40 (m, 1H), 4.35 - 4.14 (m, 2H), 2.94 - 2.76 (m, 2H), 2.20 - 2.12 (m, 2H), 2.09 - 1.92 (m, 2H), 1.41 (m, 9H).

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

[0178] Intermediate J Synthetic route:

Chemical Structure

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

[0180] Intermediate K Synthetic route:

Chemical formula

[0181] Step 1 Intermediate I-3 (500 mg, 1310 μmol) was dissolved in dichloromethane (5 mL), trifluoroacetic acid (1540 mg, 13510 μmol) was added, and then 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 directly used in the reaction of the next step. MS-ESI calculated value [M+H] + 280 and 282, measured values 280 and 282.

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

[0183] Step 3 Intermediate K-2 (320 mg, 1090 μmol), potassium acetate (267 mg, 2720 μmol) and bis(pinacolato)diboron (414 mg, 1630 μmol) were added to 1,4-dioxane (3 mL), and then [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (80 mg, 109 μmol) was added to the reaction solution. The reaction solution was heated to 110 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (dichloromethane / methanol, 10 / 1 to 20 / 3, V / V) to obtain Intermediate K. 11H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.92 (s, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 4.80 - 4.71 (m, 1H), 3.46 - 3.36 (m, 2H), 2.90 - 2.76 (m, 2H), 2.62 (s, 3H), 2.52 - 2.28 (m, 4H), 1.39 (m, 12H). MS-ESI calculated value [M + H] + 342, measured value 342.

[0184] Intermediate L Synthesis route:

Chem.

[0185] Step 1 Intermediate I-1 (500 mg, 2.54 mmol) was dissolved in dimethyl sulfoxide (5 mL), potassium carbonate (491 mg, 3.55 mmol) and 2-iodopropane (518 mg, 3.05 mmol) were slowly added, and the reaction was carried out 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, and concentrated under reduced pressure. The obtained crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 1, V / V) to obtain Intermediate L-1. MS-ESI calculated value [M + H] + 239 and 241, measured value 239 and 241.

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

[0187] Intermediate M Synthetic route:

Chemical formula

[0188] Step 1 Intermediate I-1 (500 mg, 2.54 mmol) and Intermediate M-1 (686 mg, 3.81 mmol) were dissolved in DMF (5 mL). Potassium carbonate (879 mg, 6.34 mmol) and tetrabutylammonium iodide (94 mg, 254 μmol) were slowly added, and the reaction was carried out at 120 °C for 14 hours under nitrogen gas protection. The reaction solution was extracted with water (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. The obtained crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 2 / 1, V / V) to obtain Intermediate M-2. 1 H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.68 (s, 1H), 7.62 (d, J = 8.5 Hz, 1H), 7.34 - 7.21 (m, 1H), 4.67 - 4.54 (m, 1H), 4.27 - 4.13 (m, 2H), 3.72 - 3.57 (m, 2H), 2.51 - 2.28 (m, 2H), 2.09 - 1.92 (m, 2H). MS-ESI calculated value [M+H] + 281 and 283, found 281 and 283.

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

[0190] Intermediate N Synthesis route:

Chemical formula

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

[0192] Intermediate O Synthesis route:

Chemical formula

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

[0194] Intermediate P Synthetic route:

Chemical formula

[0195] Step 1 Intermediate P-1 (500 mg, 2.34 mmol) was dissolved in acetonitrile (5 mL), potassium carbonate (516 mg, 3.74 mmol) and iodomethane (1.66 g, 3.05 mmol) were slowly added, and the mixture was 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, and the crude product obtained by concentration under reduced pressure was 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, measured values 228 and 230.

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

[0197] Intermediate Q Synthesis route:

Chemical formula

[0198] Step 1 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 and reacted for 30 minutes. Intermediate Q-1 (4.86 g, 17.1 mmol) dissolved in tetrahydrofuran (10 mL) was slowly added at -78 °C and reacted at 25 °C for 12 hours. The reaction solution was quenched with ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and the crude product obtained by concentration under reduced pressure was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 0 to 100 / 1, V / V) to obtain Intermediate Q-2. 11H NMR (400 MHz, CDCl3) δ 7.51 (d, J = 2.0 Hz, 1H), 7.31 - 7.28 (m, 1H), 7.09 (d, J = 8.3 Hz, 1H), 4.26 - 4.33 (m, 1H), 3.74 (s, 3H), 3.68 - 3.60 (m, 4H), 3.45 - 3.37 (m, 1H), 2.94 - 2.86 (m, 1H), 2.25 - 2.17 (m, 1H), 1.01 (m, J = 6.8 Hz, 3H), 0.65 (d, J = 6.8 Hz, 3H). MS-ESI calculated value [M+H] + 387 and 389, measured values 387 and 389.

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

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

[0201] Step 4 Intermediate Q-4 (4 g, 14.36 mmol) was dissolved in dioxane (40 mL), sodium carbonate solution (2 M, 7.90 mL) and Boc2O (3.64 g, 16.66 mmol) were added, and the reaction was carried out at 25 °C for 4 h. The pH of the reaction solution was adjusted to 4 - 5 with a saturated aqueous citric acid solution, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, washed with saturated brine (50 mL × 2), dried over anhydrous sodium sulfate, then concentrated under reduced pressure, n-heptane (15 mL) was added and stirred for 15 min, filtered, the cake was collected and dried to obtain intermediate Q-5, which was directly used in the reaction of the next step. 1 H NMR (400 MHz, MeOD-d4) δ 7.68 - 7.54 (m, 1H), 7.48 - 7.37 (m, 1H), 7.24 (d, J = 8.2 Hz, 1H), 4.59 - 4.40 (m, 1H), 3.43 - 3.36 (m, 1H), 3.02 - 2.83 (m, 1H), 1.37 (s, 9H). MS-ESI calculated value [M+H] + 378 and 380, found 378 and 380.

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

[0203] Step 6 Intermediate Q-6 (1 g, 2.65 mmol) was dissolved in dichloromethane (10 mL), and trifluoroacetic acid (12.13 g, 106.35 mmol) was slowly added, followed by reaction at 25 °C for 12 hours. The reaction solution was adjusted to pH > 8 with saturated aqueous sodium bicarbonate solution, 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 to obtain Intermediate Q-7, which was directly used in the next-step reaction. MS-ESI calculated values [M+H] + 277 and 279, found 277 and 279.

[0204] Step 7 T3P (50% ethyl acetate solution, 278.58 mg, 876 μmol) was dissolved in DMF (3 mL), intermediate Q-7 (243 mg, 876 μmol) and intermediate A-5 (143 mg, 584 μmol) were added, then triethylamine (266 mg, 2.63 mmol) was added, and the reaction was carried out 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), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crude product was 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, measured values 526 and 528.

[0205] Step 8 Intermediate Q-8 (350 mg, 693 μmol) and methyl N-(triethylammonio sulfonyl) carbamate (826 mg, 3.47 mmol) were added to dichloromethane (3 mL), and the reaction was carried out at 25 °C for 12 hours. The reaction solution was 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 directly used in the reaction of the next step. MS-ESI calculated value [M+Na] + 508 and 510, measured values 508 and 510.

[0206] Intermediate R Synthesis route:

Chemical formula

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

[0208] Step 2 Intermediate R-2 (2.7 g, 7.35 mmol) was dissolved in acetonitrile (9 mL), hydrochloric acid (0.2 M, 77 mL, 15.44 mmol) was slowly added, and the reaction was carried out 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 aqueous sodium bicarbonate solution, extracted with ethyl acetate (100 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure to obtain Intermediate R-3, which was directly used in the reaction of the next step. 11H NMR (400 MHz, CDCl3) δ 7.33 (s, 1H), 7.29 - 7.27 (m, 1H), 7.02 (d, J = 8.0 Hz, 1H), 3.71 (s, 3H), 3.70 - 3.66 (m, 1H), 3.12 - 3.03 (m, 1H), 2.81 - 2.72 (m, 1H), 2.33 (s, 3H). MS-ESI calculated value [M + H] + 272 and 274, measured values 272 and 274.

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

[0210] Step 4 Intermediate R-4 (1.93 g, 7.48 mmol) was dissolved in dioxane (20 mL) and water (80 mL), sodium carbonate (1.59 g, 14.95 mmol) and Boc2O (1.71 g, 7.85 mmol) were added, and the mixture was reacted at 25 °C for 4 h. The pH of the reaction solution was adjusted to 4 - 5 with a saturated aqueous citric acid solution, extracted with ethyl acetate (200 mL × 3), the organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure to obtain intermediate R-5, which was directly used in the next step reaction. MS-ESI calculated value [M - H] - 356 and 358, measured values 356 and 358.

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

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

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

[0214] Step 8 Intermediate R-8 (190 mg, 393 μmol) and methyl N-(triethylammonio sulfonyl)carbamate (280 mg, 1.18 mmol) were added to dichloromethane (5 mL), and the reaction was carried out 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, concentrated under reduced pressure, and the obtained crude product was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 10 / 3, V / V) to obtain intermediate R. 11H NMR (400 MHz, CDCl3) δ 7.37-7.34 (s, 1H), 7.33-7.28 (m, 1H), 7.23-7.12 (m, 1H), 7.11-7.05 (m, 1H), 5.13-4.98 (m, 1H), 4.25-3.97 (m, 3H), 3.82-3.70 (m, 0.5H), 3.56-3.17 (m, 3H), 3.15-2.94 (m, 2.5H), 2.36 (s, 3H), 2.01-1.80 (m, 2H), 1.45 (m, 9H). MS-ESI calculated value [M+Na] + 488 and 490, measured values 488 and 490.

[0215] Intermediate S Synthesis route:

Chemical formula

[0216] Step 1 Intermediate S-1 (200 mg, 948 μmol) was dissolved in acetonitrile (10 mL), 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (419 mg, 1.18 mmol) was added, and the 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, and concentrated under reduced pressure. The obtained crude product was separated by thin-layer chromatography (petroleum ether / ethyl acetate, 20 / 3, V / V) to obtain Intermediate S-2. 1 1H NMR (400 MHz, CDCl3) δ 7.53-7.47 (m, 2H), 7.24 (d, J = 8.8 Hz, 1H), 3.89 (s, 3H). MS-ESI calculated value [M+H] + 229 and 231, measured values 229 and 231.

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

[0218] Intermediate T Synthesis route:

Chemical formula

[0219] Intermediate T-1 (500 mg, 2.33 mmol), potassium acetate (571 mg, 5.81 mmol), and bis(pinacolato)diboron (886 mg, 3.49 mmol) were added to 1,4-dioxane (6 mL). Next, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (170 mg, 232 μmol) was added to the reaction solution. The reaction solution was heated to 100 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was concentrated under reduced pressure and separated by silica gel column chromatography (petroleum ether / ethyl acetate, 3 / 2, V / V) to obtain Intermediate T. 1 H NMR (400 MHz, CDCl3) δ 8.28 - 8.10 (m, 1H), 7.79 (s, 1H), 7.24 - 7.18 (m, 1H), 1.38 (s, 12H). MS-ESI calculated value [M+H] + 263, measured value 263.

[0220] Intermediate U Synthesis route:

Chem.

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

[0222] Intermediate V Synthesis route:

Chem.

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

[0224] Example 1 Synthesis route:

Chem.

[0225] Step 1 Intermediate A (60 mg, 120 μmol), Intermediate E (41 mg, 156 μmol) and potassium carbonate (50 mg, 360 μmol) were added to acetonitrile (8 mL) and water (2 mL). Under the protection of nitrogen gas, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (20 mg, 24 μmol) was added to the reaction solution. The reaction solution was heated to 80 °C under the protection of nitrogen gas and reacted for 2 hours. 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, concentrated under reduced pressure, and the obtained crude product was 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.

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

[0227] Compound 1: e.e.% = 100.00%, RT = 2.547 min. 11H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.8 Hz, 1H), 5.27-5.19 (m, 1H), 4.35 (s, 3H), 4.13-4.10 (m, 1H), 4.03-3.96 (m, 1H), 3.79-3.71 (m, 1H), 3.34-3.26 (m, 1H), 3.22-3.15 (m, 2H), 3.10-3.03 (m, 1H), 3.02-2.93 (m, 1H), 2.92-2.84 (m, 1H), 1.93-1.77 (m, 2H). MS-ESI calculated value [M+H] + 405, measured value 405.

[0228] Example 2 Synthesis route:

Chemical formula

[0229] Step 1 Intermediate A (80 mg, 160 μmol), Compound 2-1 (42 mg, 240 μmol) and potassium carbonate (66 mg, 480 μmol) were added to acetonitrile (6 mL) and water (2 mL). Under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (26 mg, 32 μmol) was added to the reaction solution. The reaction solution was heated to 80 °C under nitrogen gas protection and reacted for 2 hours. The reaction solution was added to water (20 mL), extracted with ethyl acetate (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained crude product was 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.

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

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

[0232] Example 3 Synthesis route:

Chemical formula

[0233] Step 1 Intermediate A (80 mg, 160 μmol), Compound 3-1 (42 mg, 240 μmol) and potassium carbonate (66 mg, 480 μmol) were added to acetonitrile (8 mL) and water (2 mL). Under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (26 mg, 32 μmol) was added to the reaction solution. The reaction solution was heated to 80 °C under nitrogen gas protection and reacted for 2 hours. 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, concentrated under reduced pressure, and the obtained crude product was 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.

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

[0235] Compound 3: e.e.% = 100.00%, RT = 2.456 min. 11H NMR (400 MHz, CD3OD) δ 8.05 (s, 1H), 7.97 (s, 1H), 7.74 - 7.69 (m, 1H), 7.68 - 7.60 (m, 3H), 7.39 (d, J = 8.0 Hz, 2H), 5.14 - 5.08 (m, 1H), 4.14 - 4.10 (m, 1H), 4.09 (s, 3H), 4.02 - 3.93 (m, 1H), 3.82 - 3.74 (m, 1H), 3.31 - 3.26 (m, 1H), 3.23 - 3.15 (m, 2H), 2.93 - 2.85 (m, 1H), 2.82 - 2.72 (m, 1H), 2.68 - 2.61 (m, 1H), 1.95 - 1.77 (m, 2H). MS-ESI calculated value [M+H] + 404, measured value 404.

[0236] Example 4 Synthesis route:

Chemical formula

[0237] Step 1 Intermediate A (60 mg, 120 μmol), Intermediate F (47 mg, 180 μmol) and potassium carbonate (33 mg, 240 μmol) were added to acetonitrile (8 mL) and water (2 mL). Under the protection of nitrogen gas, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (20 mg, 24 μmol) was added to the reaction solution. The reaction solution was heated to 80 °C under the protection of nitrogen gas and reacted for 2 hours. 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, concentrated under reduced pressure, and the obtained 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.

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

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

[0240] Example 5 Synthesis route:

Chemical Structure

[0241]

Chem.

[0242] Step 1 Intermediate A (100 mg, 200 μmol), Intermediate H (76 mg, 280 μmol) and potassium carbonate (55 mg, 400 μmol) were added to acetonitrile (8 mL) and water (2 mL). Under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (32 mg, 40 μmol) was added to the reaction solution. The reaction solution was heated to 80 °C under nitrogen gas protection and reacted for 3 hours. The reaction solution was added to water (20 mL), extracted with ethyl acetate (20 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the obtained 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.

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

[0244] Compound 5: e.e.% = 100.00%, RT = 0.747 min. 1 H NMR (400 MHz, CDCl3) δ 7.91 (d, J = 8.0 Hz, 1H), 7.70 - 7.65 (m, 1H), 7.65 - 7.60 (m, 3H), 7.43 (d, J = 8.0 Hz, 2H), 7.24 - 7.17 (m, 1H), 5.28 - 5.16 (m, 1H), 4.45 (s, 2H), 4.14 - 4.08 (m, 1H), 4.04 - 3.96 (m, 1H), 3.82 - 3.71 (m, 1H), 3.37 - 3.28 (m, 1H), 3.24 (s, 3H), 3.19 - 3.14 (m, 2H), 3.09 - 3.03 (m, 1H), 3.01 - 2.85 (m, 2H), 1.95 - 1.79 (m, 2H). MS-ESI calculated value [M + H] + 419, measured value 419.

[0245] Example 6 Synthesis route:

Chemical Structure

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

[0247] Step 2 Compound 6-1 (104 mg, 187 μmol) was dissolved in dichloromethane (10 mL), methyl N-(triethylammonio sulfonyl)carbamate (67 mg, 280 μmol) was added, and the 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), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product containing Compound 6-2, which was used directly in the reaction of the next step. MS-ESI calculated value [M+Na] + 561, found 561.

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

[0249] Compound 6: e.e.% = 100.00%, RT = 2.123 min. 11H NMR (400 MHz, CD3OD) δ 7.51 - 7.39 (m, 5H), 7.32 (d, J = 8.2 Hz, 1H), 5.19 - 5.14 (m, 1H), 4.15 - 4.08 (m, 1H), 4.05 - 3.95 (m, 1H), 3.84 - 3.74 (m, 1H), 3.46 (s, 3H), 3.29 - 3.16 (m, 3H), 2.97 - 2.88 (m, 1H), 2.85 - 2.75 (m, 1H), 2.70 - 2.62 (m, 1H), 1.98 - 1.79 (m, 2H). MS-ESI calculated value [M + H] + 439, measured value 439.

[0250] Example 7 Synthesis route:

Chemical formula

[0251] Step 1 Intermediate C (100 mg, 205 μmol), Intermediate F (69 mg, 266 μmol) and potassium phosphate (130 mg, 614 μmol) were added to tetrahydrofuran (8 mL) and water (3 mL). Under nitrogen gas protection, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (27 mg, 41 μmol) was added to the reaction solution. The reaction solution was heated to 70 °C under nitrogen gas protection and reacted for 5 hours. 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, concentrated under reduced pressure, and the obtained crude product was 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.

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

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

[0254] Compound 7: e.e.% = 91.78%, RT = 6.090 min. 11H NMR (400 MHz, CD3OD) δ 8.10 - 7.98 (m, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.63 - 7.53 (m, 2H), 7.48 (t, J = 8.0 Hz, 1H), 5.21 - 5.16 (m, 1H), 4.38 (s, 3H), 4.16 - 4.09 (m, 1H), 4.06 - 3.97 (m, 1H), 3.84 - 3.74 (m, 1H), 3.40 - 3.24 (m, 2H), 3.23 - 3.16 (m, 1H), 2.99 - 2.88 (m, 1H), 2.85 - 2.74 (m, 1H), 2.70 - 2.62 (m, 1H), 1.99 - 1.78 (m, 2H). MS-ESI calculated value [M+H] + 423, measured value 423.

[0255] Example 8 Synthesis route:

Chemical formula

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

[0257] Step 2 Compound 8-2 (100 mg, 185 μmol) was dissolved in dichloromethane (6 mL), methyl N-(triethylammoniosulfonyl)carbamate (66 mg, 278 μmol) was added, and the 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), the organic phases were combined, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the resulting crude product was separated by silica gel column chromatography (developing solvent: dichloromethane / methanol, 20 / 1, V / V) to obtain Compound 8-3. MS-ESI calculated value [M-56+H] + 466, found 466.

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

[0259] Compound 8: e.e.% = 84.21%, RT = 2.200 min. 11H NMR (400 MHz, 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 value [M+H] + 422, measured value 422.

[0260] Example 9 Synthesis route:

Chemical formula

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

[0262] Step 2 Compound 9-1 (169 mg, 318 μmol) was added to formic acid (2.0 mL) and water (0.2 mL), and the reaction solution was reacted at 25 °C for 3 hours. The reaction solution was added to saturated sodium bicarbonate solution (20 mL), the pH was adjusted to 8 - 9 with saturated sodium bicarbonate solution, and it was extracted with ethyl acetate (10 mL × 3). The organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a 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 9. The e.e. value of compound 9 was measured by SFC (chromatography column: Chiralcel OJ-3 50 mm × 4.6 mm I.D., 3 μm; mobile phase: phase A was supercritical CO2, phase B was a methanol solution containing 0.05% diethylamine; gradient: phase B 5% - 40%).

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

[0264] Example 10 Synthesis route: [Chem.]

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

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

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

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

[0269] Example 11 Synthesis route:

Chemical Structure

[0270] Step 1 Intermediate A (250 mg, 762 μmol), Intermediate M (342 mg, 685 μmol), and potassium carbonate (210 mg, 1.52 mmol) were added to acetonitrile (2 mL) and water (0.5 mL). Under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (124 mg, 152 μmol) was added to the reaction solution. The reaction solution was heated to 80 °C under nitrogen gas protection and reacted for 3 hours. The crude product obtained by concentrating the reaction solution 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.

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

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

[0273] Example 12 Synthesis route:

Chemical formula

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

[0275] Step 2 Compound 12-1 (107 mg, 176 μmol) and methyl N-(triethylammonio sulfonyl)carbamate (102 mg, 430 μmol) were added to dichloromethane (3 mL). The reaction solution was reacted at 25 °C for 12 h. 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 step reaction. MS-ESI calculated value [M+H] + 592, found 592.

[0276] Step 3 Compound 12-2 (90 mg, 152 μmol) was added to formic acid (2.0 mL) and water (0.2 mL), and the reaction solution was reacted at 25 °C for 3 h. 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 a 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. The e.e. value of Compound 12 was measured by SFC (chromatographic column: Chiralcel OJ-3 50 mm × 4.6 mm I.D., 3 μm; mobile phase: phase A was supercritical CO2, phase B was a methanol solution containing 0.05% diethylamine; gradient: phase B 5% - 40%).

[0277] Compound 12: e.e.% = 96.59%, RT = 2.110 min. 11H NMR (400 MHz, CD3OD) δ 8.07 (s, 1H), 7.92 (s, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.62 - 7.52 (m, 2H), 7.50 - 7.44 (m, 2H), 5.23 - 5.17 (m, 1H), 5.02 - 4.92 (m, 1H), 4.20 - 4.10 (m, 3H), 4.07 - 3.96 (m, 1H), 3.86 - 3.68 (m, 3H), 3.41 - 3.35 (m, 1H), 3.30 - 3.18 (m, 2H), 2.98 - 2.89 (m, 1H), 2.86 - 2.77 (m, 1H), 2.72 - 2.63 (m, 1H), 2.42 - 2.27 (m, 2H), 2.03 - 1.81 (m, 4H). MS-ESI calculated value [M+H] + 492, measured value 492.

[0278] Example 13 Synthesis route:

Chemical formula

[0279] Step 1 Intermediate D (58 mg, 236 μmol), Intermediate N (100 mg, 213 μmol) and potassium phosphate (125 mg, 591 μmol) were added to tetrahydrofuran (3 mL) and water (1 mL). Under nitrogen gas protection, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (31 mg, 47 μmol) was added to the reaction solution. The reaction solution was heated to 60 °C under nitrogen gas protection and reacted for 12 hours. The reaction solution was extracted with ethyl acetate (10 mL × 3), washed with saturated brine (10 mL × 3), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The crude product obtained by concentration under reduced pressure 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.

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

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

[0282] Example 14 Synthesis route:

Chemical Structure

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

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

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

[0286] Example 15 Synthesis route:

Chemical formula

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

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

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

[0290] Compound 15: e.e.% = 82.26%, RT = 0.879 min. 11H NMR (400 MHz, CD3OD) δ 7.55 - 7.25 (m, 3H), 6.97 - 6.83 (m, 2H), 6.76 (d, J = 8.3 Hz, 1H), 5.24 - 5.04 (m, 1H), 4.32 - 4.26 (m, 2H), 4.24 - 4.14 (m, 1H), 4.05 - 3.96 (m, 1H), 3.85 - 3.77 (m, 1H), 3.32 - 3.19 (m, 5H), 3.08 - 2.97 (m, 1H), 2.95 (s, 3H), 2.94 - 2.88 (m, 1H), 2.82 - 2.69 (m, 1H), 2.09 - 1.80 (m, 2H). MS-ESI calculated value [M+H] + 439, measured value 439.

[0291] Example 16 Synthesis route: [Chemical formula]

[0292] Step 1 Intermediate Q (239 mg, 491 μmol), Compound 8-1 (87 mg, 491 μmol) and potassium phosphate (261 mg, 1.23 mmol) were added to tetrahydrofuran (3 mL) and water (1 mL). Under the protection of nitrogen gas, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (64 mg, 98 μmol) was added to the reaction solution. The reaction solution was heated to 70 °C under the protection of nitrogen gas and reacted for 12 hours. The reaction solution 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, concentrated under reduced pressure, and the obtained crude product was separated by silica gel column chromatography (dichloromethane / methanol, 10 / 1, V / V) to obtain Compound 16-1. MS-ESI calculated value [M-55] + 482, measured value 482.

[0293] Step 2 Compound 16-1 (167 mg, 310 μmol) was added to formic acid (0.5 mL) and water (0.1 mL), and the reaction solution was stirred at 25 °C for 3 hours. The reaction solution was quenched with sodium bicarbonate solution (10 mL), extracted with ethyl acetate (10 mL × 3), the organic phases were combined, washed with saturated brine (20 mL × 2), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high-performance liquid chromatography (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 27% - 57%, 9 min) to obtain compound 16. The e.e. value of compound 16 was measured by SFC (chromatography column: Chiralpak AD-3 50 mm × 4.6 mm I.D., 3 μm; mobile phase: phase A was supercritical CO2, phase B was a methanol solution of 0.05% diethylamine; gradient: phase B 40%).

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

[0295] Example 17 Synthesis route:

Chemical Structure

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

[0297] Step 2 Compound 17-1 (80 mg, 154 μmol) was added to formic acid (1.5 mL) and water (0.15 mL), and the reaction solution was stirred at 25 °C for 2 hours. The reaction solution was quenched with sodium bicarbonate solution (50 mL), extracted with dichloromethane (50 mL × 2), the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain a crude product. The crude product was separated by preparative high performance liquid chromatography (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 37% - 67%, 8 min) to obtain Compound 17. The e.e. value of Compound 17 was measured by SFC (chromatography column: Chiralpak AD-3 150 mm × 4.6 mm I.D., 3 μm; mobile phase: phase A was supercritical CO2, phase B was an ethanol solution containing 0.05% diethylamine; gradient: phase B 40%).

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

[0299] Example 18 Synthesis route:

Chemical Structure

[0300] Step 1 Intermediate D (50 mg, 106 μmol), Intermediate S (33 mg, 117 μmol) and potassium phosphate (56 mg, 266 μmol) were added to THF (6 mL) and water (3 mL). Under nitrogen gas protection, [1,1'-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (14 mg, 22 μmol) was added to the reaction solution. The reaction solution was heated to 70 °C and reacted for 5 hours under nitrogen gas protection. The crude product obtained by concentrating the reaction solution under reduced pressure was separated by silica gel column chromatography (petroleum ether / ethyl acetate, 1 / 1, V / V) to obtain Compound 18-1. 1 H NMR (400 MHz, CDCl3) δ 7.70 (d, J=8.3 Hz, 1H), 7.49-7.31 (m, 5H), 7.26 (d, J=7.5 Hz, 1H), 5.27-5.11 (m, 1H), 4.22-4.00 (m, 3.5H), 3.96 (s, 3H), 3.81-3.70 (m, 0.5H), 3.61-3.42 (m, 1.5H), 3.32-3.05 (m, 3.5H), 2.04-1.85 (m, 2H), 1.45 (s, 9H). MS-ESI calculated value [M+Na] + 562, measured value 562.

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

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

[0303] Example 19 Synthesis route:

Chemical Structure

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

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

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

[0307] Example 20 Synthesis route:

Chemical Structure

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

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

[0310] Compound 20: e.e.% = 99.46%, RT = 0.598 min. 11H NMR (400 MHz, CD3OD) δ 8.60 (d, J = 1.5 Hz, 1H), 8.15 (s, 1H), 7.63 - 7.42 (m, 4H), 6.62 (d, J = 3.0 Hz, 1H), 5.16 - 5.08 (m, 1H), 4.13 - 3.99 (m, 2H), 3.93 (s, 3H), 3.83 - 3.74 (m, 1H), 3.38 - 3.32 (m, 1H), 3.30 - 3.23 (m, 2H), 3.01 - 2.91 (m, 1H), 2.91 - 2.79 (m, 2H), 1.98 - 1.79 (m, 2H). MS-ESI calculated value [M + H] + 422, measured value 422.

[0311] Example 21 Synthesis route:

Chemical formula

[0312] Step 1 Intermediate D (50 mg, 105 μmol), Intermediate V (49 mg, 200 μmol) and potassium carbonate (58 mg, 421 μmol) were added to dioxane (10 mL) and water (5 mL). Under nitrogen gas protection, [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (17 mg, 21 μmol) was added to the reaction solution. The reaction solution was heated to 85 °C under nitrogen gas protection and reacted for 12 hours. The crude product obtained by concentrating the reaction solution 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.

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

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

[0315] Example 22 Synthesis route:

Chemical Structure

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

[0317] Step 2 Compound 22-1 (70 mg, 101 μmol) was added to formic acid (1.5 mL) and water (0.3 mL), and the reaction solution was reacted at 25 °C for 2 hours. The reaction solution was added to saturated sodium bicarbonate solution (50 mL), the pH was adjusted to 8 with saturated sodium bicarbonate solution, and extracted with 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 a crude product. The crude product was separated by preparative high performance liquid chromatography (column: Phenomenex Gemini-NX C18 75 mm × 30 mm × 3 μm; mobile phase: phase A 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 e.e. value of the formate salt of compound 22 was measured by SFC (chromatographic column: Chiralcel AD-3 50 mm × 4.6 mm I.D., 3 μm; mobile phase: phase A was supercritical CO2, phase B was an ethanol solution containing 0.05% diethylamine; gradient: phase B 5% - 40%).

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

[0319] Example 23 Synthesis route:

Chem.

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

[0321] Step 2 Compound 23-1 (60 mg, 87 μmol) was added to formic acid (1.5 mL) and water (0.15 mL), and the reaction solution was reacted at 25 °C for 2 hours. The reaction solution was added to saturated sodium bicarbonate solution (50 mL), adjusted to pH > 8 with saturated sodium bicarbonate solution, extracted with 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 a crude product. The crude product was separated by preparative high-performance liquid chromatography (column: Phenomenex Gemini-NX C18 75 mm × 30 mm × 3 μm; mobile phase: phase A is an aqueous solution containing 0.025% formic acid, phase B is acetonitrile; gradient: phase B 0% - 20%, 7 min) to obtain the formate salt of compound 23. The e.e. value of the formate salt of compound 23 was measured by SFC (chromatographic column: Chiralcel IA 100 mm × 4.6 mm I.D., 3 μm; mobile phase: phase A is n-hexane containing 0.1% diethylamine, phase B is an ethanol solution containing 0.1% diethylamine; gradient: phase B 80%).

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

[0323] Example 24 Synthetic route:

Chemical Structure

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

[0325] Step 2 Compound 24-1 (110 mg, 182 μmol) was added to formic acid (1.5 mL) and water (0.15 mL), and the reaction solution was reacted at 25 °C for 2 hours. The reaction solution was added to saturated sodium bicarbonate solution (50 mL), the pH was adjusted to 8 with saturated sodium bicarbonate solution, and extracted with 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 a crude product. The crude product was separated by preparative high performance liquid chromatography (column: Phenomenex Gemini-NX 80 mm × 40 mm × 3 μm; mobile phase: phase A was an aqueous solution containing 0.05% ammonia monohydrate, phase B was acetonitrile; gradient: phase B 36% - 66%, 8 min) to obtain compound 24. The e.e. value of compound 24 was measured by SFC (chromatography column: Chiralcel IG-3 100 mm × 4.6 mm I.D., 3 μm; mobile phase: phase A was supercritical CO2, phase B was an ethanol solution containing 0.05% diethylamine; gradient: phase B 40%).

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

[0327] Biological activity evaluation: Experimental Example 1: DPP1 enzyme activity inhibition effect test

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

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

[0330] The test compound was diluted 5-fold to the 8th concentration with a multi-channel pipette, i.e., diluted from 1 mM to 12.8 nM. Next, using 1× experimental buffer, each gradient of the test compound was diluted into a working solution of 4% DMSO, and 5 μL / well was added to the corresponding wells to set up a double-well experiment. Centrifuged at 1000 rpm for 1 minute.

[0331] After the culture was completed, 5 μL / well of the enzyme mixture was taken and added to a white microplate. At this point, the amount of DPP1 enzyme in each well was 5 ng, and 5 μL / well of 1× experimental buffer was added to the blank control well.

[0332] Dilute Gly-Arg-AMC (hydrochloride) to 25 μM with 1× experimental buffer, take 10 μL / well and add it to a white microplate. At this point, the substrate concentration is 12.5 μM. Centrifuge the microplate at 1000 rpm for 1 minute in a centrifuge. At this point, the concentration of the compound ranges from 10 μM to 0.128 nM. After centrifugation, cover the microplate with a membrane and incubate at 25 °C for 60 minutes.

[0333] After incubation, fluorescence detection was performed at an excitation wavelength of 360 nm and an emission wavelength of 460 nm using a multi-label analyzer.

[0334] Data analysis: When converting the raw data to enzyme activity using the equation (Sample - Min) / (Max - Min)×100%, the IC 50 value was obtained by curve fitting using four parameters (obtained from the log(inhibitor) vs. response - Variable slope mode of GraphPad Prism).

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

[0336] Min: Does not contain recombinant human cathepsin C / DPP1 and recombinant human cathepsin L (rhCathepsin L).

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

[0338]

Table 1

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

[0340] Experimental Example 2: DPP1 Activity Inhibition Test with U937 Cells Experimental Materials: 1) Experimental Reagents and Consumables

[0341]

Table 2

[0342] 2) Experimental Equipment

[0343]

Table 3

[0344] Experimental Method: 1) Cell Seeding (1) Cell Culture Medium: 89% RPMI1640, 10% Fetal Bovine Serum, and 1% Penicillin-Streptomycin. (2) The medium was preheated in a 37°C water bath. (3) The cell suspension in the cell culture flask was taken out, placed in a 15 mL centrifuge tube, put into a centrifuge, and centrifuged at 1000 rpm / min for 5 minutes. (4) After centrifugation, the supernatant was discarded, 2 mL of medium was added to resuspend the cells, an appropriate amount of the cell suspension was taken out and mixed uniformly with trypan blue, and about 0.01 mL of the cell suspension was taken out for counting. (5) The cell suspension was diluted with the medium to the cell density required for plating (6.67×10^5 cells / ml). (6) 30 μL of the cell suspension was added to each well of the cell plate, and it was placed in an incubator at 37°C containing 5% CO2 for culturing for use. (7) The required amount of cells and medium were taken, and the culture was continued in a new T75 culture flask.

[0345] 2) Drug Administration (1) The test compound was prepared into a 10 mM solution with DMSO. (2) The compound was diluted 5-fold at 8 concentration gradients, i.e., from 2 mM to 0.0256 μM. A double-well experiment was set up. 78 μL of medium was added to the intermediate plate. Next, 2 μL of the gradient-diluted compound per well was transferred to the intermediate plate according to the corresponding positions. After uniform mixing, 10 μL per well was transferred to the cell plate. The final concentration of the compound transferred to the cell plate was from 10 μM to 0.128 nM. The cell plate was placed in a CO2 incubator and cultured for 1 hour. (3) After culturing for 1 hour, a 100 μM Gly-Phe-AFC probe solution, i.e., a 60 mM Gly-Phe-AFC probe stock solution diluted to a 500 μM working solution with medium, and 10 μL per well was transferred to the cell plate. The cell plate was placed in a CO2 incubator and cultured for 1 hour.

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

[0347] Data analysis: When the raw data was converted to the inhibition rate using the equation (Sample - Min) / (Max - Min)×100%, the IC 50 value was obtained by curve fitting using four parameters (obtained from the "log(inhibitor) vs. response -- Variable slope" mode of GraphPad Prism). Table 2 provides the inhibitory activity of the compounds of the present invention against DPP1 in U937 cells.

[0348]

Table 4

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

[0350] Experimental Example 3: Pharmacokinetic Evaluation of the Compounds of the Present Invention in Mice Experimental Objective: To test the pharmacokinetics of the compounds in CD-1 mice.

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

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

[0353]

Table 5

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

[0355] Experimental Example 4: Pharmacokinetic Evaluation of the Compounds of the Present Invention in Rats Experimental Objective: To test the in vivo pharmacokinetics of the compounds in SD rats.

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

[0357] Experimental operations: The pharmacokinetic properties of the compound in rodents after intravenous injection and oral administration were tested according to the standard protocol. In the experiment, the candidate compound was prepared into a clear solution and administered to two rats by single intravenous injection and oral administration respectively. The solvents for intravenous injection and oral administration were 5:95 DMSO and 10% aqueous hydroxypropyl-β-cyclodextrin solution. Whole blood samples within 24 hours were collected into commercially available EDTA2K anticoagulant tubes, centrifuged at 6000 g for 3 minutes, and the supernatant was separated to obtain plasma samples. An acetonitrile solution containing an internal standard was added at 20 times the volume to precipitate proteins, centrifuged, the supernatant was taken, the same volume of water was added, centrifuged again, and the supernatant was sampled. The blood drug concentration was quantitatively analyzed by LC-MS / MS analysis, and pharmacokinetic parameters such as apparent volume of distribution, clearance, half-life, and area under the drug concentration-time curve were calculated.

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

[0359]

Table 6

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

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

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

[0363] Experimental operations: Using the standard protocol, the content of the compound in the bone marrow and plasma of mice after oral administration was tested. In the experiment, the candidate compound was prepared into a clear solution with 5:95 DMSO and 10% aqueous hydroxypropyl-β-cyclodextrin solution as the solvent, and orally administered to mice at a dose of 5 mg / kg once. Whole blood samples and bone marrow samples were collected at 0.25, 0.5, 1, 2, 4, 6, and 24 hours respectively. The whole blood samples were collected into commercially available EDTA2K anticoagulant tubes, centrifuged at 6000 g for 3 minutes, the supernatant was separated to obtain plasma samples, an acetonitrile solution containing the internal standard was added to precipitate proteins, centrifuged, the supernatant was taken, the same volume of water was added, and after mixing uniformly, the blood drug concentration was quantitatively analyzed by LC-MS / MS analysis, and the area under the drug concentration-time curve was calculated. The femurs and tibias on both sides of the mice were taken, the muscles were removed, one end was cut off, placed downward in a centrifuge tube, centrifuged at 8000 rpm for 1 minute, the precipitate was the bone marrow, the bone marrow was mixed with 50% methanol-water, homogenized and pulverized, the homogenate was taken, an acetonitrile solution containing the internal standard was added to precipitate proteins, centrifuged, the supernatant was taken, the same volume of water was added, and after mixing uniformly, the drug concentration in the bone marrow was quantitatively analyzed by LC-MS / MS analysis, and the area under the drug concentration-time curve was calculated.

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

[0365]

Table 7

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

[0367] Experimental Example 6: Evaluation of the Distribution of the Compound of the Present Invention in Rat Tissues (Bone Marrow) Experimental Objective: To test the distribution of the test compound in the bone marrow and plasma of SD rats.

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

[0369] Experimental Procedures: Using the standard protocol, the content of the test compound in the bone marrow and plasma of rats after oral administration was tested. In the experiment, the candidate compound was prepared into a clear solution with 5:95 DMSO and 10% aqueous hydroxypropyl-β-cyclodextrin solution as the solvent, and was orally administered to rats at a dose of 5 mg / kg once. Whole blood samples and bone marrow samples were collected at 0.25, 0.5, 1, 2, 4, 6, and 24 hours respectively. The whole blood samples were collected into commercially available EDTA2K anticoagulant tubes, centrifuged at 6000 g for 3 minutes, the supernatant was separated to obtain plasma samples, an acetonitrile solution containing the internal standard was added to precipitate proteins, centrifuged, the supernatant was taken, the same volume of water was added, and after mixing uniformly, the blood drug concentration was quantitatively analyzed by LC-MS / MS analysis, and the area under the drug concentration-time curve was calculated. The left femur of the rat was taken, the muscle was removed, one end was cut off, placed downward in a centrifuge tube, centrifuged at 8000 rpm for 1 minute, the precipitate was the bone marrow, the bone marrow was mixed with 50% methanol water, pulverized into a homogenate, the homogenate was taken, an acetonitrile solution containing the internal standard was added to precipitate proteins, centrifuged, the supernatant was taken, the same volume of water was added, and after mixing uniformly, the drug concentration in the bone marrow was quantitatively analyzed by LC-MS / MS analysis, and the area under the drug concentration-time curve was calculated.

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

[0371]

Table 8

[0372] Conclusion: The compound of the present invention has a higher distribution in the bone marrow of SD rats.

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

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

[0375] Experimental operation: The experimental animals were grouped and administered according to Table 7. Two hours after the final administration, the bone marrow of the animals was collected. First, red blood cells were lysed with a red blood cell lysate to retain lymphocytes, and then lymphocytes were lysed with a lymphocyte lysate. The supernatant was taken for protein quantification and measurement of neutrophil elastase enzyme activity, and the activity of neutrophil elastase in the sample was further calculated. The administration protocol is as shown in Table 7.

[0376]

Table 9

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

[0378] Conclusion: The compound of the present invention can significantly inhibit the activity of neutrophil elastase in rats.

Claims

【Claim 1】 A compound selected from the following formula or a pharmaceutically acceptable salt thereof. 【Chemical Formula 1】

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