Fused tricyclic derivatives and their pharmaceutical uses

Abstract

The present application discloses fused tricyclic derivatives and pharmaceutical uses thereof, specifically compounds of formula (III) and pharmaceutically acceptable salts thereof: [C1] TIFF2023542161000159.tif37156

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and benefit of: 1) Chinese Patent Application No. 2020110405194 filed with the State Intellectual Property Office of the People's Republic of China on September 28, 2020; 2) Chinese Patent Application No. 2020116150610 filed with the State Intellectual Property Office of the People's Republic of China on December 30, 2020; and 3) Chinese Patent Application No. 2021103575941 filed with the State Intellectual Property Office of the People's Republic of China on April 1, 2021. 3) the priority and benefit of Chinese Patent Application No. 2021106482667 filed with the State Intellectual Property Office of China on June 10, 2021; and 5) the priority and benefit of Chinese Patent Application No. 2021110940827 filed with the State Intellectual Property Office of China on September 17, 2021, the contents of which are incorporated herein by reference in their entireties.

[0002] <Technical field> The present application relates to fused tricyclic derivatives and their pharmaceutical uses, in particular to compounds of formula (III) and pharmaceutically acceptable salts thereof: [Background technology]

[0003] A single molecule with dual activity at muscarinic M3 and β2-adrenergic receptors (MABAs) offers related advantages over two-component combinations, such as synergistic drug targeting due to its consistent pharmacokinetic properties. It can also be formulated with other therapeutic agents (e.g., inhaled glucocorticoids) to facilitate triple-component combination therapy. Therefore, novel drugs that simultaneously possess activity as β2-receptor agonists and muscarinic receptor antagonists and are suitable for the treatment of respiratory diseases (e.g., asthma, COPD) are believed to be of great clinical value and significance. Summary of the Invention [Means for solving the problem]

[0004] The present application provides a compound represented by formula (III) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R1 is H, halogen, C 1~4 selected from alkyl groups and phenyl groups; Each R2 is independently H, halogen, or C 1~4 alkyl groups, or or two R2 and the connected thiophene ring form a benzothiophene; n is selected from 1 or 2, T1 is selected from a single bond, -NH-, or -N(CH3)-; L1 is selected from a single bond or -CH2-; Structural Unit [ka] teeth, [ka] Selected from Ring A may optionally contain one or two R b C replaced by 4~6 a cycloalkenyl group, a 4- to 6-membered heterocycloalkenyl group, a 5- to 6-membered heteroaryl group, [ka] or a phenyl group; Each R b are each independently selected from -F, -Cl, -Br, -I, -CH, or -CHCH; Ring B is selected from a cyclopentyl group, a cyclohexyl group, or a 6- to 10-membered heterocycloalkyl group, and the 6- to 10-membered heterocycloalkyl group may optionally be one R a is replaced by R a is selected from -F, -Cl, a methyl group, -OH, or -CN; The "hetero" in the "6- to 10-membered heterocycloalkyl group" includes one, two, or three heteroatoms or heteroatom groups independently selected from O, S, NH, and N, provided that the nitrogen atom is optionally quaternized with halomethane.

[0005] In some embodiments of the present application, R1 is selected from H, -Cl, -Br, a methyl group, a t-butyl group, or a phenyl group.

[0006] In some embodiments of the present application, R1 is H, halogen, or C 1~4 It is selected from alkyl groups.

[0007] In some embodiments of the present application, R1 is selected from H, -Cl, -Br, a methyl group, or a t-butyl group.

[0008] In some embodiments of the present application, each R2 is independently selected from H, -Cl, -Br, a methyl group, or a t-butyl group.

[0009] In some embodiments of the present application, each R2 is independently H, halogen, or C 1~4 It is selected from alkyl groups.

[0010] In some embodiments of the present application, R1 and R2 are both H.

[0011] In some embodiments of the present application, the structural unit [ka] teeth, [ka] Selected from.

[0012] In some embodiments of the present application, the structural unit [ka] teeth, [ka] Selected from.

[0013] In some embodiments of the present application, the structural unit [ka] teeth, [ka] Selected from.

[0014] In some embodiments of the present application, T1 is selected from a single bond or -N(CH3)-.

[0015] In some embodiments of the present application, ring B is selected from a cyclohexyl group or a 6- to 10-membered heterocycloalkyl group, and the 6- to 10-membered heterocycloalkyl group optionally has one R a is replaced by

[0016] In some embodiments of the present application, the ring B is a cyclopentyl group, a cyclohexyl group, or optionally one R a piperidinyl, piperazinyl, morpholinyl, dioxanyl, dithianyl, tetrahydrooxazinyl, tetrahydrothiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl, dioxepanyl, [ka] Selected from.

[0017] In some embodiments of the present application, the ring B is a cyclohexyl group or optionally one R a piperidinyl groups, piperazinyl groups substituted by [ka] Selected from.

[0018] In some embodiments of the present application, the ring B is a cyclohexyl group or optionally one R a is replaced by [ka] Selected from.

[0019] In some embodiments of the present application, the ring B is selected from a cyclohexyl group. [ka] Selected from.

[0020] In some embodiments of the present application, the ring B is [ka] Selected from.

[0021] In some embodiments of the present application, the ring B is [ka] Selected from.

[0022] In some embodiments of the present application, the structural unit [ka] teeth, [ka] Selected from.

[0023] In some embodiments of the present application, the structural unit [ka] teeth, [ka] Selected from.

[0024] In some embodiments of the present application, the structural unit [ka] teeth, [ka] Selected from.

[0025] In some embodiments of the present application, the structural unit [ka] teeth, [ka] Selected from.

[0026] In some embodiments of the present application, the structural unit [ka] teeth, [ka] Selected from.

[0027] In some embodiments of the present application, the structural unit [ka] teeth, [ka] Selected from.

[0028] In some embodiments of the present application, the structural unit [ka] teeth, [ka] Selected from.

[0029] In some embodiments of the present application, R b are each independently selected from -F, -Cl, -Br, -I, or -CH3.

[0030] In some embodiments of the present application, R b is selected from -CH3.

[0031] In some embodiments of the present application, R a is selected from -F, -CH3, -OH, or -CN.

[0032] In some embodiments of the present application, R a is selected from -CH3, or -OH.

[0033] In some embodiments of the present application, the ring A is C 4~6 a cycloalkenyl group, a 4- to 6-membered heterocycloalkenyl group, a 5- to 6-membered heteroaryl group, [ka] or a phenyl group, 4~6 The cycloalkenyl group, the 4- to 6-membered heterocycloalkenyl group, and the 5- to 6-membered heteroaryl group may optionally contain one or two R b is replaced by

[0034] In some embodiments of the present application, the ring A optionally contains one or two R b is replaced by [ka] , a pyrrolyl group, a thienyl group, a furyl group, a pyrazolyl group, an imidazolyl group, an oxazolyl group, a thiazolyl group, a triazolyl group, a pyridinyl group, a pyrimidinyl group, a pyrazinyl group, a pyridazinyl group, [ka] or a phenyl group.

[0035] In some embodiments of the present application, the ring A optionally contains one or two R b is replaced by [ka] , a pyrazolyl group, or a phenyl group.

[0036] In some embodiments of the present application, ring A is [ka] Selected from.

[0037] In some embodiments of the present application, ring A is [ka] Selected from.

[0038] In some embodiments of the present application, ring A is [ka] Selected from.

[0039] In some embodiments of the present application, ring A is [ka] Selected from.

[0040] In some embodiments of the present application, the heterocycloalkyl, heterocycloalkenyl, and heteroaryl groups contain 1, 2, or 3 heteroatoms selected from N, O, and S.

[0041] In some embodiments of the present application, the heterocycloalkyl group, heterocycloalkenyl group, and heteroaryl group contain one or two heteroatoms selected from N and O.

[0042] In some embodiments of the present application, the 6- to 10-membered heterocycloalkyl group comprises a monocyclic, spirocyclic, or bridged ring.

[0043] In some embodiments of the present application, the 6- to 10-membered heterocycloalkyl group comprises a monocyclic or spirocyclic ring.

[0044] In some embodiments of the present application, the compound is selected from the structures shown in (III-1), (III-2), (III-3), (IV-1), (IV-2), and (V-1), [ka] wherein R1, R2, T1, n, L1 and ring B are as defined herein.

[0045] The present application provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof: [ka] During the ceremony, R1 is H, halogen and C 1~4 alkyl groups, Each R2 is independently selected from H, halogen, and C 1~4 alkyl groups, n is selected from 1 and 2; T1 is selected from a single bond, —NH— and —N(CH3)—; Structural Unit [ka] teeth, [ka] Selected from Ring A is [ka] and a phenyl group; Ring B is a cyclohexyl group, a piperidinyl group, [ka] Selected from.

[0046] In some embodiments of the present application, the compound or pharmaceutically acceptable salt thereof is selected from the structure shown in formula (II-1): [ka] wherein R1, R2, T1, n, and ring B are as defined herein.

[0047] In some embodiments of the present application, R1 is selected from H, -Cl, -Br, and a t-butyl group.

[0048] In some embodiments of the present application, each R2 is independently selected from H, -Cl, -Br, and a t-butyl group.

[0049] Further embodiments of the present application are any combination of the above variables.

[0050] The present application further provides the following compound or a pharmaceutically acceptable salt thereof: [ka] [ka] [ka]

[0051] The present application further provides the following compound or a pharmaceutically acceptable salt thereof: [ka] [ka] [ka]

[0052] The present application further provides a pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof, which may further comprise a pharmaceutically acceptable additive.

[0053] The present application further provides the use of the compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease (COPD).

[0054] The present application further provides use of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition in the manufacture of a medicament for the treatment of chronic obstructive pulmonary disease (COPD).

[0055] The present application further provides a use of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition for treating chronic obstructive pulmonary disease (COPD).

[0056] The present application further provides the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition for treating chronic obstructive pulmonary disease (COPD).

[0057] The present application further provides a method for treating chronic obstructive pulmonary disease (COPD), comprising administering to an individual in need thereof a therapeutically effective amount of the compound or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition. [Effects of the Invention]

[0058] The compound of the present invention has dual activity as an antagonist of muscarinic M3 receptors and an agonist of β2 adrenergic receptors, and its activity on β1 receptors is selective. Compared with the reference compound AZD8871, it has a faster clearance rate after intravenous administration, and a longer half-life, higher exposure, and higher bioavailability after tracheal administration via nebulizer.

[0059] "Definitions and Explanations" Unless otherwise specified, the following terms and expressions used herein have the following meanings: Unless specifically defined, a particular term or expression is to be understood in its ordinary, undefined or ambiguous sense. When a trade name is mentioned herein, it refers to the corresponding product or its active ingredient.

[0060] As used herein, the term "pharmaceutically acceptable" refers to compounds, materials, compositions and / or dosage forms that are medically determined to be suitable for use in contact with human or animal tissue, are not toxic or irritating, and are not likely to cause an allergic reaction or other problem or complication, and for which the benefit-risk ratio is reasonable.

[0061] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present application prepared from a compound having certain substituents found in the present application and a relatively non-toxic acid or base. When a compound of the present application contains a relatively acidic functional group, a base addition salt is obtained by contacting such a compound with a sufficient amount of base in a pure solution or in a suitable inert solvent. When a compound of the present application contains a relatively basic functional group, an acid addition salt is obtained by contacting such a compound with a sufficient amount of acid in a pure solution or in a suitable inert solvent. Certain compounds of the present application contain basic or acidic functional groups and can therefore be converted into any base or acid addition salt.

[0062] The pharmaceutically acceptable salts of the present application can be synthesized from parent compounds that contain an acid or base group by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or free base form of these compounds with the stoichiometrically appropriate base or acid in water, an organic solvent, or a mixture of both.

[0063] Unless otherwise specified, the term "isomer" is intended to include geometric isomers, cis / trans isomers, stereoisomers, enantiomers, optical isomers, diastereomers and tautomers.

[0064] The compounds of the present application may exist in particular geometric or stereoisomeric forms. All such compounds and mixtures thereof are contemplated within the scope of the present application, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures, e.g., enantiomer- or diastereomer-enriched mixtures. Additional asymmetric carbon atoms may be present in substituents, such as alkyl groups. All of these isomers and mixtures thereof are within the scope of the present application.

[0065] Unless otherwise specified, the terms "enantiomers" or "optical isomers" refer to stereoisomers that are mirror images of one another.

[0066] Unless otherwise stated, the terms "cis / trans isomers" or "geometric isomers" result from the inability to freely rotate about a double bond or a single bond of a ring-forming carbon atom.

[0067] Unless otherwise specified, the term "diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another.

[0068] Unless otherwise specified, "(+)" represents dextrorotatory, "(-)" represents levorotatory, and "(±)" represents racemic.

[0069] Unless otherwise stated, solid wedge bonds ( [ka] ) and wedge-shaped dashed bond ( [ka] ) represents the absolute configuration of the chiral center, and the linear solid bond ( [ka] ) and linear dashed bond ( [ka] ) indicates the relative configuration of the chiral center, and the wavy line ( [ka] ) and solid wedge-shaped connection ( [ka] ) or wedge-shaped dashed bond ( [ka] ) or a wavy line ( [ka] ) and a straight solid line connection ( [ka] ) or linear dashed bond ( [ka] )

[0070] Unless otherwise specified, the terms "enriched in one isomer," "enriched in an isomer," "enriched in one enantiomer," or "enantiomer-enriched" refer to at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 96%, or at least 97%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, but less than 100%, of a particular isomer or enantiomer.

[0071] Unless otherwise specified, the terms "isomeric excess" or "enantiomeric excess" refer to the difference in relative percentage abundance of two isomers or two enantiomers. For example, if one isomer or enantiomer is present at 90% and the other isomer or enantiomer is present at 10%, the isomeric or enantiomeric excess (ee) is 80%.

[0072] Optically active (R)- and (S)-isomers, and D- and L-isomers, can be prepared by asymmetric synthesis, chiral reagents, or other conventional techniques. Enantiomers of certain compounds of the present invention can be prepared by asymmetric synthesis or derivatization with chiral auxiliaries. The diastereomeric mixture of products can be separated, and the desired pure enantiomers can be obtained by removal of the auxiliary groups. Alternatively, if the molecule contains basic (e.g., amino) or acidic (e.g., carboxy) functional groups, the diastereomeric salts can be formed with an appropriate optically active acid or base, followed by separation and subsequent recovery of the diastereomers to obtain the pure enantiomers. Separation of enantiomers and diastereomers is also commonly accomplished by chromatography, using chiral stationary phases, optionally combined with chemical derivatization (e.g., carbamate formation from amines).

[0073] The compounds of the present application may contain unnatural proportions of isotopes of one or more atoms that constitute such compounds. For example, the compounds may contain tritium ( 3 H), iodine-125( 125 I) or carbon-14 ( 14 The compound may be labeled with a radioactive isotope, such as C. Alternatively, deuterium may be substituted for hydrogen to produce a deuterated drug, where the bond formed between deuterium and carbon is stronger than the bond formed between hydrogen and carbon, and compared with non-deuterated drugs, deuterated drugs have the advantages of reduced toxicity and side effects, improved drug stability and therapeutic efficacy, and extended biological half-life. All isotopic variants of the compounds of the present application, whether radioactive or not, are within the scope of the present application.

[0074] Unless otherwise specified, the term "C 1~4 The term "alkyl group" refers to a linear or branched saturated hydrocarbon group consisting of 1 to 4 carbon atoms. 1~4 The alkyl group is C 1~2 , C 1~3 , C 2~3 It may contain an alkyl group, and may be monovalent (e.g., a methyl group), divalent (e.g., a methylene group), or polyvalent (e.g., a methine group). 1~4 Examples of alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl, s-butyl, and t-butyl) groups.

[0075] Unless otherwise specified, "C 4~6 "Cycloalkyl group" refers to a saturated cyclic hydrocarbon group of 4 to 6 carbon atoms, and is a monocyclic or bicyclic ring system, 4~6 The cycloalkyl group is C 4~5 , C 5~6 It may be monovalent, divalent or polyvalent, and may contain cycloalkyl groups. 4~6 Examples of cycloalkyl groups include, but are not limited to, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0076] Unless otherwise specified, the term "C 4~6 The term "cycloalkenyl group" refers to an incompletely saturated cyclic hydrocarbon group consisting of 4 to 6 carbon atoms, and is a monocyclic or bicyclic ring system. 4~6 The cycloalkenyl group is C 4~5 , C 5~6 It includes a cycloalkenyl group and may be monovalent, divalent or polyvalent. 4~6 Non-limiting examples of cycloalkenyl groups include, but are not limited to, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl groups, and the like.

[0077] Unless otherwise specified, the term "4- to 6-membered heterocycloalkyl group," by itself or in combination with other terms, refers to a saturated cyclic group consisting of 4 to 6 ring atoms, of which 1, 2, 3, or 4 are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, provided that the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO or S(O)). p and p is 1 or 2). It includes monocyclic and bicyclic ring systems, of which bicyclic ring systems include spiro rings, fused rings, and bridged rings. In the "4- to 6-membered heterocycloalkyl group," a heteroatom may occupy a position connected to another part of the heterocycloalkyl molecule. The 4- to 6-membered heterocycloalkyl group includes 5- to 6-membered, 4-membered, 5-membered, and 6-membered heterocycloalkyl groups. Examples of 4- to 6-membered heterocycloalkyl groups include azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, etc.), tetrahydrofuryl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (1-piperidinyl, 2- piperidinyl group (including 1-piperazinyl group, 2-piperazinyl group, etc.), morpholinyl group (including 3-morpholinyl group, 4-morpholinyl group, etc.), dioxanyl group, dithianyl group, isoxazolidinyl group, isothiazolidinyl group, 1,2-oxazinyl group, 1,2-thiazinyl group, hexahydropyridazinyl group, etc.

[0078] Unless otherwise specified, the term "4- to 6-membered heterocycloalkenyl group" refers to a partially unsaturated (but not fully unsaturated heteroaryl group) non-aromatic ring consisting of 4 to 6 ring atoms, in which 1, 2, 3, or 4 of the ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, provided that the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO or S(O)p, where p is 1 or 2). Monocyclic and bicyclic ring systems are included, of which bicyclic ring systems include spiro, fused, and bridged rings. In addition, in the "4- to 6-membered heterocycloalkenyl group," the heteroatoms are not heterocycloalkenyl groups. Keni The 4- to 6-membered heterocycloalkenyl group may occupy a position where the heterocycloalkenyl group is attached to another part of the molecule. Alkenyl Examples of 4- to 6-membered heterocycloalkenyl groups include, but are not limited to, dihydropyrrolyl, dihydrofuryl, dihydropyridinyl, tetrahydropyridinyl, dihydropyranyl, and the like.

[0079] Unless otherwise specified, the terms "5- to 6-membered heteroaromatic ring" and "5- to 6-membered heteroaryl group" are used interchangeably herein, and the term "5- to 6-membered heteroaryl group" refers to a monocyclic group having a conjugated π-electron system and consisting of five or six ring atoms, one, two, three, or four of which are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, provided that the nitrogen atom is optionally quaternized and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO or S(O)). pand p is 1 or 2. The 5- to 6-membered heteroaryl group can be attached to the rest of the molecule via a heteroatom or a carbon atom. The 5- to 6-membered heteroaryl group includes 5- and 6-membered heteroaryl groups. Examples of the 5- to 6-membered heteroaryl group include a pyrrolyl group (including an N-pyrrolyl group, a 2-pyrrolyl group, a 3-pyrrolyl group, etc.), a pyrazolyl group (including a 2-pyrazolyl group, a 3-pyrazolyl group, etc.), an imidazolyl group (including an N-imidazolyl group, a 2-imidazolyl group, a 4-imidazolyl group, a 5-imidazolyl group, etc.), an oxazolyl group (including a 2-oxazolyl group, a 4-oxazolyl group, a 5-oxazolyl group, etc.), a triazolyl group (including a 1H-1,2,3-triazolyl group, a 2H-1,2,3-triazolyl group, a 1H-1,2,4-triazolyl group, a 4H-1,2,4-triazolyl group, etc.), ... and the like), tetrazolyl group, isoxazolyl group (including 3-isoxazolyl group, 4-isoxazolyl group, 5-isoxazolyl group, and the like), thiazolyl group (including 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, and the like), furyl group (including 2-furyl group, 3-furyl group, and the like), thienyl group (including 2-thienyl group, 3-thienyl group, and the like), pyridinyl group (including 2-pyridinyl group, 3-pyridinyl group, 4-pyridinyl group, and the like), pyrazinyl group, pyrimidinyl group (including 2-pyrimidinyl group, 4-pyrimidinyl group, and the like).

[0080] Unless otherwise specified, the term "6- to 10-membered heterocycloalkyl group," by itself or in combination with other terms, each represents a saturated cyclic group of 6 to 10 ring atoms, of which 1, 2, 3, or 4 are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, provided that the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., NO or S(O)). p(wherein p is 1 or 2). It includes monocyclic, bicyclic, and tricyclic ring systems, of which bicyclic and tricyclic ring systems include spiro rings, fused rings, and bridged rings. In the "6- to 10-membered heterocycloalkyl group," the heteroatom may occupy any position connected to the other part of the heterocycloalkyl molecule. The 6- to 10-membered heterocycloalkyl group includes 6- to 7-membered, 6- to 8-membered, 6- to 9-membered, 6-membered, 7-membered, 8-membered, 9-membered, and 10-membered heterocycloalkyl groups. Examples of 6- to 10-membered heterocycloalkyl groups include, but are not limited to, piperidinyl groups (including 1-piperidinyl groups, 2-piperidinyl groups, 3-piperidinyl groups, etc.), piperazinyl groups (including 1-piperazinyl groups, 2-piperazinyl groups, etc.), morpholinyl groups (including 3-morpholinyl groups, 4-morpholinyl groups, etc.), dioxanyl groups, dithianyl groups, isoxazolidinyl groups, isothiazolidinyl groups, 1,2-oxazinyl groups, 1,2-thiazinyl groups, hexahydropyridazinyl groups, homopiperazinyl groups, homopiperidinyl groups, dioxepanyl groups, and the like.

[0081] Unless otherwise stated, the terms "halo" or "halogen," by themselves or as part of another substituent, refer to a fluorine, chlorine, bromine, or iodine atom.

[0082] Carbon atoms marked with an "*" are chiral carbon atoms and exist in the form of a single enantiomer, either (R) or (S), or enriched in one enantiomer.

[0083] The term "optional" or "optionally" means that the subsequently described event or circumstance may, but does not necessarily, occur, and the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur.

[0084] The term "substituted" refers to the replacement of any one or more hydrogen atoms of a particular atom with a substituent (substituents include deuterium and hydrogen variants), provided that the valence of the particular atom is normal and the resulting compound is stable. When the substituent is oxygen (=O), two hydrogen atoms are replaced. Oxygen substitution does not occur in aryl groups. The term "optionally substituted" refers to the possibility of substitution or non-substitution. Unless otherwise specified, the type and number of substituents are not limited as long as they are chemically feasible.

[0085] When a particular variable (e.g., R) occurs more than once in a compound composition or structure, it is defined independently in each occurrence. Thus, for example, if a group is substituted with zero to two R, that group is optionally substituted with up to two R, where R is independently selected in each occurrence. Additionally, combinations of substituents and / or variants thereof are permitted only in those situations where such combinations result in stable compounds.

[0086] When the number of connecting groups is 0, such as -(CRR)0-, the connecting group is a single bond.

[0087] When the number of substituents is 0, it means that the substituent is not present, for example, -A-(R)0 means that the structure is actually -A.

[0088] When a substituent is null, it means that the substituent is not present; for example, when X is null in AX, it means that the structure is actually A.

[0089] When a variable is selected from a single bond, it represents that the two groups connected by it are directly connected. For example, if L represents a single bond in ALZ, it represents that the structure is actually AZ.

[0090] If the bond of a substituent can cross more than one atom of a ring, then such substituent can be bonded to any atom of the ring, e.g., a structural unit [ka] In the case of the substituent R, the substituent R can be substituted at any position on the cyclohexyl group or cyclohexadiene. If a listed substituent does not specify through which atom it is attached to the substituted group, such a substituent can be attached through any atom. For example, a pyridinyl group can be attached as a substituent to the substituted group through any one of the carbon atoms of the pyridine ring.

[0091] When the direction of connection is not specified for a listed connecting group, there is no restriction on the direction of connection, for example, [ka] When the connecting group L is -MW-, in this case, ring A and ring B are connected in the same direction as -MW- is read from left to right. [ka] or by connecting ring A and ring B in the opposite direction from left to right, [ka] Combinations of the above connecting groups, substituents and / or variants thereof are permissible only if such combinations result in stable compounds.

[0092] Unless otherwise specified, if a group has one or more connectable sites, any one or more of the sites on the group can be connected to other groups via a chemical bond. If the destination of the chemical bond is not specified and there are H atoms at the connectable sites, when the chemical bond is connected, the number of H atoms at that site is reduced by the number of connecting chemical bonds to form a group of the corresponding valence. The chemical bond connecting the site to other groups is represented by a straight solid bond ( [ka] ), linear dashed bond ( [ka] ), or wavy line ( [ka] For example, in -OCH3, the linear solid bond represents a connection to another functional group via the oxygen atom of the functional group, [ka] In the formula, a linear dashed bond represents a bond between the nitrogen atoms of the group and another functional group, [ka] In the formula, the wavy lines indicate that the phenyl group is connected to another functional group via the carbon atoms at positions 1 and 2 of the phenyl group. [ka] indicates that any connectable site of the piperidinyl group can be connected to another group via one chemical bond, and at least [ka] Even if an H atom is displayed next to -N-, [ka] for, [ka] wherein when one chemical bond is connected, one H is removed from that site to form the corresponding monovalent piperidinyl group.

[0093] Unless otherwise specified, the number of ring atoms is generally defined as the number of members in the ring. For example, a "5- to 7-membered ring" refers to a "ring" consisting of 5 to 7 atoms arranged in a ring.

[0094] The term "protecting group" includes, but is not limited to, "amino-protecting group," "hydroxy-protecting group," and "thiol-protecting group." The term "amino-protecting group" refers to a protecting group suitable for preventing side reactions at the nitrogen of an amino group. Representative amino-protecting groups include, but are not limited to, a formyl group, an acyl group (e.g., an alkanoyl group (e.g., an acetyl group, a trichloroacetyl group, a trifluoroacetyl group)), an alkoxycarbonyl group (e.g., a t-butoxycarbonyl group (Boc)), an arylmethyloxycarbonyl group (e.g., a benzyloxycarbonyl group (Cbz) or a 9-fluorenylmethyloxycarbonyl group (Fmoc)), an arylmethyl group (e.g., a benzyl group (Bn), a trityl group (Tr), or a 1,1-di-(4'-methoxyphenyl)methyl), a silyl group (e.g., a trimethylsilyl group (TMS), a t-butyldimethylsilyl group (TBS)), and the like. The term "hydroxy-protecting group" refers to a protecting group suitable for preventing side reactions of a hydroxy group. Representative hydroxy-protecting groups include, but are not limited to, alkyl groups (e.g., methyl, ethyl, t-butyl), acyl groups (e.g., alkanoyl groups (e.g., acetyl)), arylmethyl groups (e.g., benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), diphenylmethyl (DPM)), silyl groups (e.g., trimethylsilyl (TMS), t-butyldimethylsilyl (TBS)), and the like.

[0095] The compounds of the present application include the specific embodiments listed below, embodiments in combination with other chemical synthetic methods, and equivalent alternatives familiar to those skilled in the art, and preferred embodiments can be prepared by a variety of synthetic methods familiar to those skilled in the art, including but not limited to the examples of the present application.

[0096] The structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. When the present invention relates to the absolute configuration of a compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in the case of single crystal X-ray diffraction (SXRD), diffraction intensity data is collected from a cultivated single crystal using a Bruker D8 venture diffractometer, with a CuKα radiation source and a φ / ω scanning method. After collecting the relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure using a direct method (Shelxs97).

[0097] The solvents used in the present invention are commercially available. The following abbreviations are used in this application: aq. and HO represent water, eq represents equivalent, Boc represents t-butoxycarbonyl group, PE represents petroleum ether, ACN represents acetonitrile, EtOAc represents ethyl acetate, EtOH represents ethanol, MeOH represents methanol, TBS represents t-butyldimethylsilyl group, HPLC represents high performance liquid chromatography, LCMS represents liquid chromatography-mass spectrometry, rt represents room temperature, mp represents melting point, °C represents degrees Celsius, h represents hours, mL represents milliliters, mM represents millimoles / liter, mmol represents millimole, μmol represents micromoles, H NMR represents proton nuclear magnetic resonance, MS represents mass spectrometry, min represents minutes, and pH represents the negative logarithm of the molar concentration of hydrogen ions.

[0098] Compounds are named according to conventional naming conventions in the art or using the software ChemDraw®; commercially available compounds use the names given in the manufacturer's catalogue. DETAILED DESCRIPTION OF THE INVENTION

[0099] The present application will now be described in detail using examples, but these are not intended to limit the present application in any way. The present application, including specific embodiments, has been described in detail herein. It will be apparent to those skilled in the art that various modifications and improvements can be made to the specific embodiments of the present application without departing from the spirit and scope of the present application. All reagents used in the present application are commercially available products and can be used without purification.

[0100] Example 1 [ka] Synthetic Route: [ka]

[0101] Step 1: Synthesis of Compound 1-2 Compound 1-1 (15 g) was dissolved in acetic acid (75 mL) and water (75 mL), and sodium perborate (17.33 g) was added with stirring. The reaction mixture was cooled to 0°C, and a solution of potassium iodide (18.70 g) in water (150 mL) was slowly added dropwise. The reaction mixture was warmed to room temperature (25°C) and stirred for 30 minutes. After the reaction was completed, the reaction mixture was filtered, and the filter cake was washed with 500 mL of water. The solid was collected and concentrated to dryness under reduced pressure to obtain compound 1-2, which was used directly in the next step. 1 H NMR (400MHz, CDCl3) δ:7.32(d,J=8.4Hz,1H),6.30(d,J=8.4Hz,1H),3.65(s,2H),2.92~2.84(m,4H),2.18~2.05(m,2H). MS-ESI calculated value [M+H] + 260, actual measured value 260.0.

[0102] Step 2: Synthesis of Compounds 1-3 Compound 1-2 (26.5 g) was dissolved in tetrahydrofuran (250 mL), and acetic anhydride (15.66 g) and diisopropylethylamine (26.44 g) were added. The reaction mixture was heated to 45° C. and stirred for 16 hours. After the reaction was completed, the mixture was diluted with 500 mL of ethyl acetate, washed with 500 mL of water and 500 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain compound 1-3, which was used directly in the next step. MS-ESI calculated value [M+H] + 302, actual measured value 302.0.

[0103] Step 3: Synthesis of Compounds 1-4 To a suspension of compound 1-3 (5 g) in acetic anhydride (50 mL) was added concentrated nitric acid (2.41 g, purity 65%) at 0 °C. The reaction mixture was stirred at 0 to 25 °C for 2 h. After completion of the reaction, the reaction mixture was filtered and the filter cake was washed with 50 mL of petroleum ether. The solid was collected and concentrated to dryness under reduced pressure to give compound 1-4, which was used directly in the next step. 1 H NMR(400MHz, CDCl3)δ:8.69(s,1H),8.26(s,1H),3.06~2.97(m,4H),2.26~2.21(m,3H),2.14(t,J=7.6Hz,2H). MS-ESI calculated value [M+H] + 347, actual value 346.9.

[0104] Step 4: Synthesis of Compounds 1-5 Compound 1-4 (14.5 g) was dissolved in ethanol (400 mL), and hydrochloric acid solution (6 M, 139.64 mL) was added. The reaction mixture was heated to 85° C. and stirred for 72 hours. After the reaction was completed, most of the ethanol was removed under reduced pressure, and the precipitated solid was collected by filtration and concentrated to dryness under reduced pressure to give compound 1-5, which was used directly in the next step. 1 H NMR (400MHz, CDCl3) δ: 8.38 (s, 1H), 5.96 (s, 2H), 3.03~2.83 (m, 4H), 2.28~2.09 (m, 2H). MS-ESI calculated value [M+H] +305, actual value 304.9.

[0105] Step 5: Synthesis of Compounds 1-6 Compound 1-5 (8.5 g) was dissolved in dimethyl sulfoxide (100 mL), and cuprous oxide (799.95 mg) and acetylnitrile (3.86 g) were added. The reaction mixture was heated to 130 °C and stirred for 4 hours. After completion of the reaction, the mixture was cooled to room temperature, poured into 750 mL of water, and extracted with ethyl acetate (350 mL × 2). The organic phases were combined, washed with saturated brine (350 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0 to 30%) to obtain compound 1-6. 1 H NMR(400MHz, CDCl3)δ:8.38(s,1H),6.37(s,2H),3.15(t,J=7.6Hz,2H),2.84(t,J=7.6Hz,2H),2.35~2.26(m,2H).

[0106] Step 6: Synthesis of Compounds 1-7 A mixture of cuprous chloride (6.25 g) and acetonitrile (470 mL) was heated to 65 °C, and t-butyl nitrite (5.99 g) was added in one portion, followed by compound 1-6 (4.72 g) in several portions. The reaction mixture was stirred at 65 °C for 30 minutes. After completion of the reaction, the mixture was cooled to room temperature and concentrated to dryness under reduced pressure. Ethyl acetate (500 mL) and hydrochloric acid solution (6 M, 200 mL) were added to the residue, and the layers were separated. The organic phase was washed with saturated brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0-10%) to obtain compound 1-7. 1 H NMR (400MHz, CDCl3)δ:8.01(s,1H),3.28(t,J=7.6Hz,2H),3.16(t,J=7.6Hz,2H),2.31(t,J=7.6Hz,2H).

[0107] Step 7: Synthesis of Compounds 1-8 Compound 1-7 (3.74 g) was dissolved in tetrahydrofuran (150 mL), triethylamine (4.25 g) and 3-aminopropanol (3.79 g) were added, and the reaction mixture was heated to 65 °C and stirred for 16 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, poured into 300 mL of water, and extracted with ethyl acetate (300 mL). The organic phase was washed with saturated brine (300 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: dichloromethane = 100%) to obtain compound 1-8. 1 H NMR(400MHz,CDCl3)δ:8.66(s,1H),8.37(s,1H),3.90~3.75(m,4H),3.29(t,J=7.2Hz,2 H),3.04(t,J=7.6Hz,2H),2.23~2.13(m,2H),1.96~1.88(m,2H),1.47(t,J=4.4Hz,1H). MS-ESI calculated value [M+H] + 262, actual value 261.9.

[0108] Step 8: Synthesis of Compounds 1-9 Compound 1-8 (2.35 g) was dissolved in a mixture of methanol, tetrahydrofuran, and water (135 mL, volume ratio = 1:1:1), and reduced iron powder (3.01 g) and ammonium chloride (2.41 g) were added. The reaction mixture was heated to 70 °C and stirred for 2 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was collected, concentrated to dryness under reduced pressure, and purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0 to 50%) to obtain compound 1-9. 1 H NMR (400MHz, CDCl3)δ:6.79(s,1H),3.91~3.81(m,2H),3.41(s,2H),3.05~2.92(m,4H),2.16~2.08(m,2H),1.88~1.79(m,2H). MS-ESI calculated value [M+H] + 232, actual value 232.0.

[0109] Step 9: Synthesis of Compounds 1-10 Compound 1-9 (2 g) was dispersed in a hydrochloric acid solution (6 M, 14.41 mL) and the mixture was cooled to 0 °C. A solution of sodium nitrite (894.97 mg) in water (8 mL) was slowly added dropwise at 0 °C. The reaction mixture was stirred at 0 to 25 °C for 1 hour. After the reaction was completed, the reaction mixture was partitioned between ethyl acetate (200 mL) and water (200 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain compound 1-10, which was used directly in the next step. MS-ESI calculated value [M+H] + 243, actual value 243.0.

[0110] Step 10: Synthesis of Compounds 1-11 Compound 1-10 (2 g) was dissolved in formic acid (80 mL, 75% purity) and nickel-aluminum alloy (3.54 g) was added. The reaction mixture was heated to 90 °C and stirred for 16 h. The reaction mixture was filtered, the filtrate was collected, and concentrated to dryness under reduced pressure. 200 mL of ethanol was added, and an aqueous solution of sodium hydroxide (2 M, 41.28 mL) was added with stirring. The reaction mixture was stirred at 25 °C for 1 h. After completion of the reaction, the reaction mixture was cooled in an ice bath, and the pH was adjusted to 6-7 with the addition of 2N hydrochloric acid. Most of the methanol was removed under reduced pressure, and the mixture was extracted with ethyl acetate (250 mL × 2). The organic phase was washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give compound 1-11, which was used directly in the next step. MS-ESI calculated value [M+H] + 246, actual value 246.0.

[0111] Step 11: Synthesis of Compounds 1-12 Compound 1-11 (250 mg) was dissolved in dichloromethane (20 mL), and triethylamine (309.41 mg) and methanesulfonyl chloride (233.51 mg) were added. The reaction mixture was stirred at 25°C for 30 minutes. A two-pot reaction was performed. After completion of the reaction, the reaction mixture was separated into dichloromethane (200 mL) and water (200 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 1-12 was obtained by separation and purification using flash silica gel chromatography (eluent: methanol / dichloromethane = 0-2%). MS-ESI calculated value [M+H] + 324, actual measured value 324.0.

[0112] Step 12: Synthesis of Compounds 1-13' Compound 2-1-2 (11.09 g) dissolved in anhydrous toluene (100 mL) was added to compound 5-4 (10 mg) dissolved in anhydrous toluene (100 mL), followed by the addition of sodium hydride (872 mg, 60% purity). The reaction mixture was stirred at 155 °C for 2 hours. The reaction mixture was cooled to room temperature, quenched with 4% aqueous sodium bicarbonate (200 mL), extracted with ethyl acetate (200 mL × 2), and the combined organic phases were washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 20:1 to 6:1) to obtain compound 1-13'. MS-ESI calculated value [M+H-18] + 434, actual value 434.1.

[0113] Step 13: Synthesis of Compounds 1-13 Compound 1-13' (400 mg) was dissolved in ethyl acetate (4 mL), and then a hydrochloric acid-ethyl acetate solution (6.64 mL, 4 M) was added. The reaction mixture was stirred at 25°C for 2 hours. The pH of the reaction mixture was adjusted to approximately 8 with saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was washed with saturated aqueous sodium carbonate (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, Compound 1-13. MS-ESI calculated value [M+H] + 352, actual value 352.1.

[0114] Step 14: Synthesis of Compounds 1-14 Compound 1-13 (200 mg) was dissolved in acetonitrile (20 mL), and diisopropylethylamine (220.62 mg), potassium iodide (141.69 mg), and compound 1-12 (184.00 mg) were added. The reaction mixture was heated to 90°C and stirred for 16 hours. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure and purified by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-5%) to obtain compound 1-14. MS-ESI calculated value [M+H] + 579, actual value 579.2.

[0115] Step 15: Synthesis of acetate salts of compounds 1-15 Compound 1-15-1 (2 g) was added to benzylamine (4.92 g). The reaction mixture was stirred at 150 °C under microwave irradiation for 30 minutes. The reaction mixture was quenched with water (40 mL) and extracted with ethyl acetate (40 mL × 3). The organic phases were combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether: ethyl acetate = 10:1 to 0:1, dichloromethane: methanol = 20:1 to 10:1) to obtain compound 1-15-2. MS-ESI calculated value [M+H] + 401, actual measured value 401.1.

[0116] Compound 1-15-2 (50 mg) was dissolved in DCM (1 mL), and then 2,6-lutidine (26.8 mg) and t-butyldimethylsilyl trifluoromethanesulfonate (36.30 mg) were added at 0 °C. The reaction mixture was stirred at 20 °C for 2 hours. The mixture was quenched with water (2 mL) and extracted with dichloromethane (2 mL × 2). The combined organic phase was washed with saturated brine (2 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 1-15-3 as a crude product. MS-ESI calculated value [M+H] + 515, actual value 515.2.

[0117] Compound 1-15-3 (10 g) was dissolved in methanol (100 mL), and then acetic acid (1.67 mL) and Pd(OH) (2 g, 20%) were added. The reaction mixture was stirred at 20° C. under a hydrogen atmosphere (15 psi) for 16 hours. The mixture was filtered and concentrated under reduced pressure to give the acetate salt of compound 1-15 as a crude product. MS-ESI calculated value [M+H] + 335, actual value 334.9.

[0118] Step 16: Synthesis of Compounds 1-16 Compound 1-14 (325 mg) and compound 1-15 (187.83 mg) were dissolved in methanol (10 mL) and tetrahydrofuran (8 mL). 4A molecular sieves (300 mg), diisopropylethylamine (217.73 mg), and sodium triacetylborohydride (595.09 mg) were added, and the reaction mixture was stirred at 25°C for 3 hours. Sodium triacetylborohydride (595.09 mg) was then added, and the reaction mixture was stirred at 25°C for 16 hours. Sodium triacetylborohydride (595.09 mg) was then added, and the reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated to dryness, 10 mL of water was added, and the mixture was extracted with dichloromethane (20 mL x 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by flash silica gel chromatography (eluent: methanol / dichloromethane = 0 to 10%) to obtain compound 1-16. MS-ESI calculated value [M+H] + 897, actual value 897.5.

[0119] Step 17: Synthesis of the trifluoroacetate salt of compound 1 Compound 1-16 (213 mg) was dissolved in tetrahydrofuran (5 mL), triethylamine trihydrofluoride (191.35 mg) was added, and the reaction mixture was stirred at 25 °C for 16 hours. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure and separated by high-performance liquid chromatography (column type: Welch Xtimate C18, length x inner diameter: 100 mm x 40 mm, 3 μm. Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.075% trifluoroacetic acid). Gradient elution method: Acetonitrile was gradient eluted from 17% to 57%, and the elution time was 8 minutes). The trifluoroacetate salt of compound 1 was obtained. 1 H NMR(400MHz,DMSO-d6)δ:10.86~10.34(m,2H),9.87(s,1H),9.43~9.01(m,2H),8.15(d,J=9.6Hz,1H),8.07(s, 1H),7.47(d,J=4.0Hz,2H),7.31(s,1H),7.15(d,J=7.6Hz,1H),7.07(s,2H),7.03~6.76(m,3H),6.53(d,J=9.6H z,1H),6.28(s,1H),5.42(d,J=8.0Hz,1H),4.78(s,3H),4.38(s,2H),3.36(s,4H),3.19(s,2H),3.09(s,2H),2 .71(s,3H),2.54(s,1H),2.32(s,2H),2.22(s,2H),1.99(s,4H),1.64(d,J=7.6Hz,2H),1.46(d,J=10.8Hz,2H). MS-ESI calculated value [M+H] + 783, actual value 783.4.

[0120] Example 2 [ka] Synthetic Route: [ka]

[0121] Step 1: Synthesis of Compound 2-1 Compounds 2-1-1 (1.80 g) and 2-1-2 (2.79 g) were dissolved in anhydrous toluene (50 mL). Sodium hydride (168 mg, 60% purity) was added in several portions at room temperature. The reaction mixture was then heated to 130 °C and stirred for 14 hours. The reaction mixture was cooled to room temperature, and water (20 mL) was added to the mixture to quench the reaction. The mixture was then extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain compound 2-1. MS-ESI calculated value [M+H-18] + 418, measured value 418.

[0122] Step 2: Synthesis of compound 2-2 Compound 2-1 (1.10 g) was dissolved in dioxane (2 mL), and then a hydrochloric acid / dioxane solution (10 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 30 minutes. The pH of the reaction mixture was adjusted to approximately 7 with saturated aqueous sodium carbonate solution and extracted with ethyl acetate (40 mL). The organic phase was discarded, and the aqueous phase was subsequently adjusted to approximately 10 with saturated aqueous sodium carbonate solution and then extracted with dichloromethane:methanol = 10:1 (30 mL × 4). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain compound 2-2 as a crude product. MS-ESI calculated value [M+H] + 336, actual value 336.

[0123] Step 3: Synthesis of Compound 2-3 Compound 2-2 (135 mg) was dissolved in acetonitrile (10 mL), and diisopropylethylamine (156.04 mg), potassium iodide (167.02 mg), and compound 1-12 (130.14 mg) were added. The reaction mixture was heated to 90°C and stirred for 16 hours. After completion of the reaction, the reaction mixture was poured into 30 mL of water and extracted with dichloromethane (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 2-3 was obtained by separation and purification using preparative thin-layer chromatography (eluent: methanol:dichloromethane = 1:20). MS-ESI calculated value [M+H] + 563, actual value 563.3.

[0124] Step 4: Synthesis of Compounds 2-5 Compound 2-3 (115 mg) and compound 1-15 (68.36 mg) were dissolved in methanol (5 mL) and tetrahydrofuran (4 mL). 4A molecular sieves (150 mg) and sodium triacetylborohydride (216.57 mg) were added, and the reaction mixture was stirred at 25°C for 16 hours. Further sodium triacetylborohydride (216.57 mg) was added, and the reaction mixture was stirred at 25°C for 71 hours. The reaction mixture was concentrated to dryness, 10 mL of water was added, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, concentrated to dryness under reduced pressure, and purified by preparative thin-layer chromatography (eluent: methanol:dichloromethane = 1:20) to obtain compound 2-5. MS-ESI calculated value [M+H] + 881, actual value 881.4.

[0125] Step 5: Synthesis of the formate salt of compound 2 Compound 2-5 (96 mg) was dissolved in tetrahydrofuran (5 mL), triethylamine trihydrofluoride (87.81 mg) was added, and the reaction mixture was stirred at 25 °C for 16 hours. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure and separated by high-performance liquid chromatography (column type: Phenomenex Gemini-NX C18, length x inner diameter: 75 mm x 30 mm, 3 μm. Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.225% formic acid). Gradient elution method: acetonitrile was gradient eluted from 0% to 30%, elution time: 7 min) to obtain the formate salt of compound 2. 1 H NMR(400MHz,DMSO-d6)δ:10.77~9.94(m,1H),8.21(s,2H),8.13(d,J=10.0Hz,1H),7.78(s,1H),7.46(d,J=4.4Hz, 2H),7.06(d,J=3.6Hz,3H),7.00~6.95(m,2H),6.91(d,J=8.4Hz,1H),6.42(d,J=9.6Hz,1H),5.14(s,1H),4.91(t, J=6.8Hz,1H),4.67(t,J=6.4Hz,2H),3.91(s,6H),3.29(t,J=6.8Hz,2H),3.22(s,2H),3.17(s,1H),3.14(s,2H),2 .94(t,J=7.2Hz,2H),2.87~2.76(m,2H),2.54(s,1H),2.41(t,J=6.4Hz,2H),2.21~2.07(m,4H),1.90~1.81(m,2H). MS-ESI calculated value [M+H] + 767, actual value 767.4.

[0126] Example 3 [ka] Synthetic Route: [ka]

[0127] Step 1: Synthesis of Compound 3-1 Compound 3-1-1 (1 g) and compound 2-1-2 (1.26 g) were dissolved in toluene (20 mL), and 4-dimethylaminopyridine (607.01 mg) was added. The reaction mixture was heated to 120 °C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature and quenched by pouring into 50 mL of saturated aqueous ammonium chloride solution. The mixture was then extracted with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 3-1 was isolated and purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0 to 30%) to obtain compound 3-1.

[0128] Step 2: Synthesis of compound 3-2 Compound 3-1 (681 mg) was dissolved in ethyl acetate (5 mL). A hydrogen chloride / ethyl acetate solution (4 M, 12.06 mL) was added, and the reaction mixture was stirred at 25°C for 2 hours. After the reaction was completed, the mixture was diluted with 100 mL of ethyl acetate, and the pH was adjusted to 7-8 with sodium carbonate solution. The organic phase was separated, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was pulped with 5 mL of ethyl acetate, filtered, and the solid was collected and concentrated to dryness under reduced pressure to obtain compound 3-2. MS-ESI calculated value [M+H] + 324, actual measured value 324.0.

[0129] Step 3: Synthesis of compound 3-3 Compound 3-2 (100 mg) was dissolved in acetonitrile (10 mL), and diisopropylethylamine (119.88 mg), potassium iodide (128.31 mg), and compound 1-12 (99.98 mg) were added. The reaction mixture was heated to 90°C and stirred for 16 hours. After completion of the reaction, the reaction mixture was poured into 30 mL of water and extracted with dichloromethane (50 mL x 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 3-3 was obtained by separation and purification using preparative thin-layer chromatography (eluent: methanol:dichloromethane = 1:20). MS-ESI calculated value [M+H] + 551, actual value 551.3.

[0130] Step 4: Synthesis of Compounds 3-5 Compound 3-3 (121 mg) and compound 1-15 (73.49 mg) were dissolved in methanol (5 mL) and tetrahydrofuran (4 mL). 4A molecular sieves (150 mg) and sodium triacetylborohydride (232.84 mg) were added, and the reaction mixture was stirred at 25 °C for 16 hours. Further sodium triacetylborohydride (232.84 mg) was added, and the reaction mixture was stirred at 25 °C for 71 hours. The reaction mixture was concentrated to dryness, 10 mL of water was added, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 3-5 was isolated and purified by preparative thin-layer chromatography (eluent: methanol:dichloromethane = 1:20) to obtain compound 3-5. MS-ESI calculated value [M+H] + 869, actual value 869.4.

[0131] Step 5: Synthesis of the formate salt of compound 3 Compound 3-5 (130 mg) was dissolved in tetrahydrofuran (5 mL), triethylamine trihydrofluoride (120.56 mg) was added, and the reaction mixture was stirred at 25 °C for 16 hours. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure and separated by high-performance liquid chromatography (column type: Welch Xtimate C18, length x inner diameter: 100 mm x 40 mm, 3 μm. Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.075% trifluoroacetic acid). Gradient elution method: acetonitrile was gradient eluted from 10% to 50%, elution time: 8 min) to obtain the formate salt of compound 3. 1 H NMR(400MHz,DMSO-d6)δ:10.51(s,2H),10.08~9.66(m,1H),9.18(d,J=19.2Hz,2H),8.23~8.05 (m,2H),7.46(s,3H),7.25~7.06(m,3H),6.98(d,J=7.2Hz,3H),6.53(d,J=9.2Hz,1H),6.25(s, 1H),5.41(d,J=9.2Hz,1H),5.20~4.90(m,1H),4.80(s,2H),4.38(s,2H),3.53~3.32(m,5H),3. 22~3.09(m,6H),2.73(s,1H),2.33~2.20(m,3H),2.10(s,1H),2.06~1.85(m,3H),1.75(s,1H). MS-ESI calculated value [M+H] + 756, actual value 756.1.

[0132] Example 4 [ka] Synthetic Route: [ka]

[0133] Step 1: Synthesis of compound 4-1-2 Compound 4-1-1 (250 mg) was dissolved in methanol (4 mL), and sodium borohydride (118 mg) was added at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. Water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (10 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 4-1-2 as a crude product. 1 H NMR(400MHz,CD3OD)δ:3.60~3.54(m,4H),3.32~3.30(m,1H),1.90~1.77(m,4H),1.58~1.48(m,2H),1.43(s,9H),1.36~1.26(m,2H).

[0134] Step 2: Synthesis of compound 4-1-4 Compounds 4-1-2 (161 mg) and 2-1-2 (170 mg) were dissolved in anhydrous toluene (4 mL). Potassium t-butoxide (45 mg) and anhydrous magnesium sulfate (161 mg) were added in portions at room temperature. The reaction mixture was then heated to 120 °C and stirred for 2 hours. The reaction mixture was then cooled to room temperature, and sodium hydride (13 mg, 60% purity) was added. The reaction mixture was then heated to 120 °C and stirred for 2 hours. The reaction mixture was then cooled to room temperature, and the reaction mixture was quenched by adding saturated aqueous ammonium chloride (10 mL) to the mixture in an ice bath. The mixture was then extracted with ethyl acetate (10 mL × 2). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain compound 4-1-4. MS-ESI calculated value [M+H-18-56] + 390, actual value 390.

[0135] Step 3: Synthesis of compound 4-2 Compound 4-1-4 (200 mg) was dissolved in dioxane (2 mL), and then aqueous formic acid (4 mL, 75% concentration) was added. The reaction mixture was stirred at 60° C. for 14 hours. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium carbonate solution (10 mL) was added to the residue, followed by extraction with ethyl acetate (20 mL×4). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain crude compound 4-2 (150 mg, colorless oil, 85% purity). MS-ESI calculated value [M+H] + 364, actual value 364.

[0136] Step 4: Synthesis of compound 4-3 Compound 1-12 (62 mg) was dissolved in acetonitrile (10 mL), and diisopropylethylamine (74.34 mg), potassium iodide (47.74 mg), and compound 4-2 (69.69 mg) were added. The reaction mixture was heated to 90°C and stirred for 16 hours. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure and purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0 to 50%, methanol / dichloromethane = 0 to 5%) to obtain compound 4-3. MS-ESI calculated value [M+H] + 591, actual value 591.2.

[0137] Step 5: Synthesis of Compound 4-5 Compound 4-3 (40 mg) and compound 1-15 (22.65 mg) were dissolved in methanol (2.5 mL) and tetrahydrofuran (2 mL). 4A molecular sieves (50 mg) and sodium triacetylborohydride (71.75 mg) were added, and the reaction mixture was stirred at 25°C for 16 hours. Further sodium triacetylborohydride (71.75 mg) was added, and the reaction mixture was stirred at 25°C for 24 hours. The reaction mixture was concentrated to dryness, 10 mL of water was added, and the mixture was extracted with dichloromethane (20 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 4-5 was isolated and purified by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-2%) to give compound 4-5. MS-ESI calculated value [M+H] + 909, actual value 909.5.

[0138] Step 6: Synthesis of the formate salt of compound 4 Compound 4-5 (35 mg) was dissolved in tetrahydrofuran (5 mL), triethylamine trihydrofluoride (31.03 mg) was added, and the reaction mixture was stirred at 25 °C for 16 hours. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure and separated by high-performance liquid chromatography (column type: Phenomenex Gemini-NX C18, length x inner diameter: 75 mm x 30 mm, 3 μm. Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.225% formic acid). Gradient elution method: acetonitrile was gradient eluted from 0% to 30%, elution time: 7 min) to obtain the formate salt of compound 4. 1 H NMR(400MHz,DMSO-d6)δ:10.32(s,1H),8.20(s,1H),8.13(d,J=9.6Hz,1H),7.76(s,1H),7.46(d,J=4 .4Hz,2H),7.27(s,1H),7.11~7.04(m,3H),7.00~6.94(m,2H),6.90(d,J=8.0Hz,1H),6.41(d,J=9.6H z,1H),5.12(s,1H),4.78(s,1H),4.68(s,2H),3.88(s,2H),3.30(d,J=6.8Hz,2H),2.97(d,J=3.2Hz, 4H), 2.95~2.74(m,6H),2.54(s,2H),2.22~2.13(m,2H),1.89(s,2H),1.62(s,4H),1.54~1.34(m,4H). MS-ESI calculated value [M+H] + 795, actual value 795.5.

[0139] (Examples 5 and 6) [ka] Synthetic Route: [ka]

[0140] Step 1: Synthesis of compound 5-4-2 Lithium aluminum hydride (9.70 g) was dissolved in tetrahydrofuran (500 mL), and compound 5-4-1 (11.0 g) was added in portions at 0 °C. The reaction mixture was heated to 75 °C and stirred for 14 hours. Water (10 mL) was carefully and slowly added dropwise to the reaction mixture at 0 °C to quench the reaction. Then, 4N aqueous sodium hydroxide solution (10 mL) was added, and finally, water (20 mL) was added. The mixture was filtered, and the filtrate was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was pulverized with petroleum ether (80 mL) at room temperature for 20 minutes, filtered, and concentrated under reduced pressure to obtain compound 5-4-2. 1 H NMR (400MHz, CDCl3)δ:3.63~3.56(m,1H),2.40(s,3H),2.34~2.32(m,1H),1.97~1.92(m,4H),1.35~1.25(m,2H),1.15~1.08(m,2H).

[0141] Step 2: Synthesis of compound 5-4 Compound 5-4-2 (4.1 g) was dissolved in dichloromethane (30 mL) and isopropanol (30 mL). Di-t-butyl dicarbonate (9.70 g) was added at room temperature, and the reaction mixture was stirred at room temperature for 15 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product, compound 5-4. 1 H NMR(400MHz,CDCl3)δ:4.05~3.74(m,1H),3.58~3.52(m,1H),2.70(s,3H),2.05~1 .98(m,2H),1.82~1.78(m,2H),1.72~1.66(m,2H),1.52(s,9H),1.44~1.36(m,2H).

[0142] Step 3: Synthesis of compound 5-3 Compound 5-1 (0.677 g) was dissolved in tetrahydrofuran (60 mL), and n-butyllithium (1.22 mL, concentration 2.5 M) was added at -70°C. The mixture was then evacuated and filled with nitrogen three times and stirred at -70°C for 20 minutes. 5-2 (0.569 g) dissolved in 6 mL of tetrahydrofuran was added to the reaction solution, and the mixture was reacted at -70°C for 1 hour. 20 mL of ammonium chloride was added to the reaction solution at -70°C. aqueous solution The mixture was quenched with 20 mL of water, extracted three times with 60 mL of ethyl acetate, and the organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After concentration, the mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain compound 5-3. MS-ESI calculated value [M+H-18] + 306.9, actual value 306.9.

[0143] Step 4: Synthesis of compound 5-5 Compound 5-3 (200 mg) was dissolved in toluene (2.5 mL), sodium hydride (40.19 mg, purity 60%) and 5-4 (212 mg) were added, and the mixture was evacuated and filled with nitrogen three times, and then reacted at 120° C. for 12 hours. The reaction solution was added with 5 mL of saturated ammonium chloride. aqueous solution The mixture was quenched with 5 mL of water, and the organic phase was extracted with three 30 mL portions of ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. After concentration, the extract was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain compound 5-5. MS-ESI calculated value [M+H-18] + 490, actual value 490.

[0144] Step 5: Synthesis of Compound 5-6 Compound 5-5 (245 mg) was dissolved in 1,4-dioxane (2 mL), and the mixture was evacuated and refilled with nitrogen three times. HCl / dioxane (6.45 mL, 4 M concentration) was added under a nitrogen atmosphere, and the mixture was allowed to react at 25°C for 1 hour to obtain crude product 5-6. No purification was required for this reaction. The reaction of the raw materials was confirmed to be complete by thin layer chromatography or mass spectrometry, and more than 85% of the product in the reaction solution was directly used in the next step. MS-ESI calculated value [M+H] + 408, actual value 408.

[0145] Step 6: Synthesis of Compounds 5-7 Compound 5-6 (70 mg) was dissolved in acetonitrile (7 mL), and the mixture was evacuated and refilled with nitrogen three times. Compound 1-12 (55 mg), DIPEA (66 mg), and KI (42 mg) were added under a nitrogen atmosphere, and the mixture was stirred at 90°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0 to 10:1) to obtain compound 5-7. MS-ESI calculated value [M+H] + 634, actual value 634.

[0146] Step 7: Preparation of Compounds 5-7A and 5-7B Compound 5-7 (253 mg) was separated and purified by chiral liquid chromatography to give Compound 5-7A and Compound 5-7B.

[0147] SFC separation method (column: AS-3 150 mm x 4.6 mm, 3 μm, mobile phase: A: carbon dioxide, B: ethanol (containing 0.05% ammonium hydroxide) 40%-40%, flow rate: 2.5 mL / min, column temperature: 40 °C).

[0148] The retention time of compound 5-7A on a high-performance chiral liquid phase column was 5.656 minutes.

[0149] The retention time of compound 5-7B on a high-performance chiral liquid phase column was 6.234 minutes.

[0150] Step 8: Synthesis of Compounds 5-8 Compound 5-7A (50 mg) and compound 1-15 (34.5 mg) were dissolved in anhydrous methanol (3 mL) and anhydrous tetrahydrofuran (1.5 mL). DIEA (22.6 mg) and NaBH(OAc)3 (92 mg) were added, and the reaction mixture was reacted at 20°C for 12 hours. NaBH(OAc)3 (92 mg) was added and the reaction mixture was continued for 8 hours. NaBH(OAc)3 (92 mg) was added and the reaction mixture was continued for 14 hours. An aqueous solution of Na2CO3 (5 mL, 4% concentration) was added to the reaction mixture, and then the mixture was extracted with ethyl acetate (60 mL) in three portions. The resulting solution was dried, concentrated, and recovered to obtain product 5-8. The recovered product did not require any purification and was directly used in the next step of the reaction. MS-ESI calculated value [M+H] + 953, actual measured value 953.

[0151] Step 9: Synthesis of the formate salt of compound 5 Compound 5-8 (67 mg) was dissolved in anhydrous tetrahydrofuran (2 mL), and triethylamine trihydrofluoride (80 mg) was added. The reaction mixture was then reacted at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and 1 mL of DMSO and 1 mL of acetonitrile were added. The mixture was then separated by high-performance liquid chromatography (formic acid method: preparative column type: Phenomenex Gemini-NX C18, length x inner diameter: 75 x 30 mm, 3 μm. Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. Mobile phase system: acetonitrile / water (containing 0.225% formic acid). Gradient elution method: acetonitrile was gradient eluted from 15% to 35%, and the elution time was 7 minutes), to obtain the formate salt of compound 5. MS-ESI calculated value [M+H] + 839, actual value 839. 1H NMR(400MHz,DMSO-d6)δ:10.32(s,1H),8.18(s,2H),8.16~8.11(m,1H),7.77(s,1H),7.48~7.43(m,1H),7.1 5~7.03(m,3H),7.00~6.95(m,1H),6.94~6.89(m,1H),6.85~6.82(m,1H),6.73~6.69(m,1H),6.46~6.40(m,1 H),5.12(s,1H),4.77~4.60(m,4H),3.89(s,2H),2.99~2.90(m,2H),2.90~2.76(m,3H),2.47~2.43(m,3H),2 .33(s,1H),2.24~2.09(m,5H),2.08~1.94(m,3H),1.90(s,2H),1.68(s,2H),1.46~1.31(m,5H),1.30(s,9H).

[0152] The formate salt of compound 6 was prepared by a two-step reaction using compound 5-7B as the starting material, following the synthetic route for the formate salt of compound 5.

[0153] Formate salt of compound 6: 1 H NMR(400MHz,DMSO-d6)δ:10.26(s,1H),8.15(s,1H),8.14~8.10(m,1H),7.72(s,1H),7.46~7.42(m,1H),7.12 ~7.03(m,4H),6.99~6.94(m,1H),6.91~6.87(m,1H),6.85~6.80(m,1H),6.72~6.69(m,1H),6.43~6.38(m,1H), 5.08(s,1H),4.74~4.64(m,3H),3.83(s,2H),2.97~2.90(m,2H),2.79~2.74(m,1H),2.66(s,2H),2.42~2.42(m ,1H),2.32(s,2H),2.23~2.08(m,7H),2.03~1.92(m,3H),1.89(s,2H),1.65(s,2H),1.33(s,5H),1.29(s,9H). MS-ESI calculated value [M+H] + 839, actual value 839.

[0154] Example 7 [ka] Synthetic Route: [ka]

[0155] Step 1: Synthesis of compound 7-2 Compound 2-1-2 (2.5 g) was dissolved in dichloromethane (7 mL), and the mixture was evacuated and filled with nitrogen three times. NCS (2.36 g) was added at 25° C. The mixture was then stirred at 25° C. for 12 hours. The reaction mixture was distilled under reduced pressure and then separated by preparative high-performance liquid chromatography to obtain compound 7-2. MS-ESI calculated value [M+H-18] + 305, actual value 305.

[0156] Step 2: Synthesis of compound 7-4 Compound 7-2 (500 mg) was dissolved in toluene (5 mL), sodium hydride (61.88 mg, purity 60%) and 7-3 (311.34 mg) were added, and the mixture was evacuated and filled with nitrogen three times, and then reacted at 120° C. for 12 hours. The reaction solution was added with 10 mL of saturated ammonium chloride. aqueous solution The mixture was quenched with 10 mL of water, extracted with three 600 mL portions of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. After concentration, the mixture was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain compound 7-4. MS-ESI calculated value [M+H-18] + 474, actual value 474.

[0157] Step 3: Synthesis of compound 7-5 Compound 7-4 (0.596 g) was dissolved in 1,4-dioxane (2 mL), and the mixture was evacuated and refilled with nitrogen three times. HCl / dioxane (18.15 mL, 4 M concentration) was added under a nitrogen atmosphere, and the mixture was allowed to react at 25°C for 1 hour to obtain crude product 7-5. No purification was required for this reaction. The reaction completion of the reactants was confirmed by thin layer chromatography or mass spectrometry, and more than 85% of the product in the reaction solution was directly used in the next step. MS-ESI calculated value [M+H] + 392.3, actual value 391.8.

[0158] Step 4: Synthesis of compound 7-6 Compound 7-5 (200 mg) was dissolved in acetonitrile (20 mL), and the mixture was evacuated and refilled with nitrogen three times. Compound 1-12 (164.85 mg), DIPEA (197.66 mg), and KI (800 mg) were added under a nitrogen atmosphere, and the mixture was stirred at 90°C for 16 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0 to 10:1) to obtain compound 7-6. MS-ESI calculated value [M+H] + 619, actual value 619.

[0159] Step 5: Synthesis of compound 7-7 Compound 7-6 (210 mg) and compound 1-15 (148.58 mg) were dissolved in anhydrous methanol (4 mL) and anhydrous tetrahydrofuran (2 mL). DIEA (97.34 mg) and NaBH(OAc)3 (399.08 mg) were added, and the reaction mixture was allowed to react at 20°C for 12 hours. NaBH(OAc)3 (399.08 mg) was then added and the reaction mixture was allowed to react for another 8 hours. NaBH(OAc)3 (399.08 mg) was then added and the reaction mixture was allowed to react for another 14 hours. An aqueous solution of Na2CO3 (5 mL, 4% concentration) was then added to the reaction mixture, and the mixture was extracted with ethyl acetate (60 mL) in three portions. The resulting solution was dried, concentrated, and recovered to obtain product 7-7. The recovered product did not require any purification and was directly used in the next step of the reaction. MS-ESI calculated value [M+H] + 938, actual value 938.

[0160] Step 6: Synthesis of the trifluoroacetate salt of compound 7 Compound 7-7 (350 mg) was dissolved in anhydrous tetrahydrofuran (6 mL), and triethylamine trihydrofluoride (350 mg) was added. The reaction mixture was then reacted at 25°C for 16 hours. The reaction mixture was concentrated under reduced pressure, and 1 mL of DMSO and 1 mL of acetonitrile were added. The mixture was then purified by high-performance liquid chromatography (formic acid method: preparative column type: Welch Xtimate C18, length x inner diameter: 100 x 40 mm, 3 μm. Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare the sample solution. Mobile phase: acetonitrile / water (containing 0.075% trifluoroacetic acid). Gradient elution method: acetonitrile was gradient eluted from 28% to 58%, and the elution time was 8 minutes), to obtain the trifluoroacetate salt of compound 7. MS-ESI calculated value [M+H] + 823, actual measured value 823. 1 H NMR(400MHz,DMSO-d6)δ:10.61(s,1H),10.48(s,1H),10.33~10.01(m,1H),9.39~9.16(m,2H),8.16( s,1H),8.08(s,1H),7.82(s,1H),7.25~7.07(m,1H),7.02~7.00(m,2H),6.99~6.91(m,2H),6.59~6.4 8(m,1H),5.50~5.37(m,1H),5.20~4.97(m,1H),4.81(s,2H),4.39(s,2H),3.58~3.50(m,1H),3.49~3 .44(m,1H),3.39~3.34(m,2H),3.29~3.11(m,6H),2.38~2.18(m,6H),2.14~1.93(m,4H),1.80(s,2H).

[0161] (Examples 8 and 9) [ka] Synthetic Route: [ka]

[0162] Step 1: Synthesis of compound 8-1 Compound 2-1-2 (2 g) was dissolved in anhydrous dichloromethane (45 mL), and then N-bromosuccinimide (2.10 g) was added. The reaction mixture was stirred at 25°C for 36 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography to obtain compound 8-1. MS-ESI calculated value [M+H-18] + 314,316, actual value 314.6.

[0163] Step 2: Synthesis of compound 8-2 Compound 8-1 (1.18 g) and compound N-Boc-4-hydroxypiperidine (1.32 mg) were dissolved in anhydrous toluene (13 mL). Sodium hydride (141.6 mg, purity 60%) was added in several portions at room temperature. The reaction mixture was then heated to 120 °C and stirred for 18 hours. The reaction mixture was cooled to 0 °C, and saturated aqueous ammonium chloride (20 mL) was added to the reaction mixture to quench the reaction. The mixture was then extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain compound 8-2. 1 H NMR(400MHz,CDCl3)δ ppm:7.31~7.29(dd,J=5.02Hz,1H),7.18~7.16(m,1H),6.99~6.97(dd,J=5.02Hz,1H),6.94(s,2H),5.14~5.10 (m,1H),3.47(m,1H),3.46~3.43(m,2H),3.39~3.32(m,2H),1.89~1.85(m,2H),1.74~1.67(m,2H),1.46(s,9H). MS-ESI calculated value [M+H-18] + 484,486, actual value 485.9.

[0164] Step 3: Preparation of Compounds 8-2A and 8-2B Compound 8-2 (550 mg) was separated and purified by chiral liquid chromatography to obtain compounds 8-2A and 8-2B.

[0165] SFC separation method (column: DAICEL CHIRALCEL OJ (250 mm × 30 mm, 10 μm), mobile phase: A: carbon dioxide, B: ethanol (containing 0.1% ammonium hydroxide): 45%–45%, flow rate: 70 mL / min, column temperature: 40 °C).

[0166] Retention time of compound 8-2A: 3.212 min, calculated value by MS-ESI [M+H] + 484,486, actual value 485.8.

[0167] Retention time of compound 8-2B: 3.919 min, calculated value by MS-ESI [M+H] + 484,486, actual value 485.8.

[0168] Step 4: Synthesis of compound 8-3 Compound 8-2A (180 mg) was dissolved in dioxane (2 mL), and then a hydrochloric acid / dioxane solution (8 mL, 4 M) was added. The reaction mixture was stirred at 25 °C for 2 hours. The pH of the reaction mixture was adjusted to approximately 8 with saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, compound 8-3. MS-ESI calculated value [M+H] + 402,404, actual value 403.9.

[0169] Step 5: Synthesis of compound 8-4 Compound 8-3 (140 mg) was dissolved in acetonitrile (5 mL), and compound 1-12 (112 mg), N,N-diisopropylethylamine (134.9 mg), and potassium iodide (231 mg) were added at room temperature. The reaction mixture was stirred at 90°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0 to 20:1) to obtain compound 8-4. MS-ESI calculated value [M+H] + 629,631, actual value 629.

[0170] Step 6: Synthesis of compound 8-5 Compound 8-4 (100 mg) and compound 1-15 (53.1 mg, acetate salt) were dissolved in anhydrous methanol (4 mL) and anhydrous tetrahydrofuran (2 mL), and N,N-diisopropylethylamine (82.1 mg) and sodium borohydride acetate (134.6 mg) were added. The reaction mixture was stirred at 25 °C for 24 hours. Sodium borohydride acetate (134.6 mg) was then added to the reaction mixture, and the mixture was stirred for 24 hours. Sodium borohydride acetate (134.6 mg) was then added to the reaction mixture, and the mixture was stirred for 24 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate (15 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with water (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 8-5 as a crude product. MS-ESI calculated value [M+H] + 947,949, actual value 949.4.

[0171] Step 7: Synthesis of the trifluoroacetate salt of compound 8 Compound 8-5 (130 mg) was dissolved in anhydrous tetrahydrofuran (4 mL), and triethylamine trihydrofluoride (130 mg) was added to the reaction mixture. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (HPLC) using a Welch Xtimate C18 column (length x inner diameter: 100 x 40 mm, 3 μm). The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. The mobile phase was acetonitrile / water (containing 0.75% trifluoroacetic acid). Gradient elution was performed using a gradient elution method from 23% to 53% acetonitrile over an 8-minute period. Compound 8 (trifluoroacetate) was obtained. 1 H NMR(400MHz,DMSO-d6)δ ppm:10.52~10.50(m,2H),9.99~9.86(m,1H),9.23~9.13(m,2H),8.15~8.08(m,2H),7.59 ~7.48(m,2H),7.15~7.13(m,1H),7.10~7.08(m,1H),6.99~6.97(m,2H),6.54~6.52(m,1H ),6.25(s,1H),5.43~5.41(m,1H),5.13~4.97(m,1H),4.80(s,2H),4.37(s,2H),3.14~3. 07(m,8H),2.80(s,2H),2.33(s,3H),2.24~2.22(m,3H),2.10~1.95(m,4H),1.79(s,2H). MS-ESI calculated value [M+H] + 833,835, actual value 835.

[0172] The trifluoroacetate salt of compound 9 was prepared by a four-step reaction using compound 8-2B as the starting material, following the synthetic route for the trifluoroacetate salt of compound 8.

[0173] Trifluoroacetate salt of compound 9: 1H NMR(400MHz,DMSO-d6)δ ppm:10.50(s,2H),9.87~9.73(m,1H),9.14(s,2H),8.14~8.08(m,2H),7.59~7.48(m, 2H),7.15~7.09(m,3H),6.99~6.91(m,3H),6.21(s,1H),5.42~5.40(m,1H),5.13~4.9 7(m,1H),4.80(s,2H),4.38(s,2H),3.38~3.34(m,1H),3.15~3.07(m,8H),2.80(s,1H) ),2.67~2.56(m,1H),2.33~2.21(m,5H),2.11(m,1H),2.10~1.95(m,3H),1.77(s,1H). MS-ESI calculated value [M+H] + 833,835, actual value 835.

[0174] Example 10 [ka] Synthetic Route: [ka]

[0175] Step 1: Synthesis of compound 10-1 Compound 7-2 (474 ​​mg) and compound 5-4 (370 mg) were dissolved in anhydrous toluene (5 mL). Sodium hydride (58.6 mg, purity 60%) was added in several portions at room temperature. The reaction mixture was then heated to 120 °C and stirred for 18 hours. The reaction mixture was cooled to 0 °C, and saturated aqueous ammonium chloride solution (20 mL) was added to quench the reaction. The mixture was then extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain compound 10-1. 1H NMR(400MHz,CDCl3)δ ppm:6.93~6.92(m,2H),6.80~6.78(m,2H),4.88~4.80(m,1H),4.79~4.69(m, 1H), 2.71 (s, 3H), 2.09 (s, 2H), 1.77 (s, 2H), 1.59~1.54 (m, 4H), 1.47 (s, 9H). MS-ESI calculated value [M+H-18] + 502, actual value 501.9.

[0176] Step 2: Synthesis of compound 10-2 Compound 10-1 (286 mg) was dissolved in anhydrous dioxane (1 mL), and then a hydrochloric acid / dioxane solution (10 mL, 4 M) was added. The reaction mixture was stirred at 25° C. for 2 hours. The pH of the reaction mixture was adjusted to approximately 8 with saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, compound 10-2. MS-ESI calculated value [M+H] + 420, actual value 419.8.

[0177] Step 3: Synthesis of compound 10-3 Compound 10-2 (212 mg) was dissolved in acetonitrile (8 mL), and compound 1-12 (163 mg), N,N-diisopropylethylamine (195 mg), and potassium iodide (334.8 mg) were added at room temperature. The reaction mixture was stirred at 90°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0 to 20:1) to obtain compound 10-3. MS-ESI calculated value [M+H] + 647, actual value 646.9.

[0178] Step 4: Synthesis of compound 10-4 Compound 10-3 (210 mg) and compound 1-15 (108 mg, acetate salt) were dissolved in anhydrous methanol (4 mL) and anhydrous tetrahydrofuran (2 mL), and N,N-diisopropylethylamine (125 mg) and sodium borohydride acetate (206 mg) were added. The reaction mixture was stirred at 25 °C for 24 hours. Sodium borohydride acetate (206 mg) was then added to the reaction mixture, and the mixture was stirred for 12 hours. Sodium borohydride acetate (206 mg) was then added to the reaction mixture, and the mixture was stirred for 12 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 10-4 as a crude product. MS-ESI calculated value [M+H] + 965, actual value 965.2.

[0179] Step 5: Synthesis of the trifluoroacetate salt of compound 10 Compound 10-4 (210 mg) was dissolved in anhydrous tetrahydrofuran (5 mL), and triethylamine trihydrofluoride (203.9 mg) was added to the reaction mixture. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (HPLC) using a Welch Xtimate C18 column (length x inner diameter: 100 mm x 40 mm, 3 μm). The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. The mobile phase was acetonitrile / water (containing 0.075% trifluoroacetic acid). Gradient elution was performed using a gradient elution method (30% to 60% acetonitrile) over an 8-minute period. The trifluoroacetate salt of compound 10 was obtained. 1H NMR(400MHz,DMSO-d6)δ ppm:10.57~10.50(m,2H),9.90(s,1H),9.29~9.17(m,2H),8.16~8.13(m,1H),8.08(m,1H),7.73 (m,1H),7.18~7.14(m,1H),7.01~6.97(m,3H),6.95~6.94(m,2H),6.54~6.51(m,1H),6.27(s,1H) ,5.44~5.41(m,1H),4.80~4.73(m,3H),4.38(s,1H),3.38~3.34(m,4H),3.20~3.07(m,5H),2.71~ 2.70(m,3H),2.54(s,1H),2.35~2.20(m,4H),2.00(s,4H),1.68~1.60(m,2H),1.53~1.44(m,2H). MS-ESI calculated value [M+H] + 851, actual value 851.2.

[0180] Example 11 [ka] Synthetic Route: [ka]

[0181] Step 1: Synthesis of compound 11-2 Compound 11-1 (14 g) was dissolved in acetone (150 mL), and potassium hydroxide (7.22 g) and potassium iodide (12.18 g) were added at 0°C. The reaction mixture was stirred at 0°C for 2 hours. After completion of the reaction, the reaction mixture was quenched by adding 200 mL of saturated aqueous ammonium chloride solution and concentrated under reduced pressure to remove most of the acetone. The residue was stirred at room temperature for 30 minutes. The solid was collected by filtration, washed with 500 mL of water, and concentrated to dryness under reduced pressure. Compound 11-2 was obtained by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0-50%). 1H NMR (400MHz, CDCl3)δ:8.16(s,1H),8.14(d,J=8.0Hz,1H),8.04(d,J=8.0Hz,1H),7.26~7.21(m,1H),4.27(s,3H). MS-ESI calculated value [M+H] + 178, actual value 178.0.

[0182] Step 2: Synthesis of compound 11-3 Compound 11-2 (9.33 g) was dissolved in a mixture of methanol, tetrahydrofuran, and water (300 mL, volume ratio = 1:1:1), and reduced iron powder (17.65 g) and ammonium chloride (14.09 g) were added. The reaction mixture was heated to 70 °C and stirred for 2 hours. After the reaction was completed, the reaction mixture was filtered, and the filtrate was collected, concentrated to dryness under reduced pressure, and purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0 to 60%) to obtain compound 11-3. MS-ESI calculated value [M+H] + 148, actual value 147.9.

[0183] Step 3: Synthesis of compound 11-4 Compound 11-3 (1 g) was dissolved in acetic acid (5 mL) and water (5 mL), and sodium perborate (1.05 g) was added with stirring. The reaction mixture was cooled to 0 °C, and a solution of potassium iodide (1.13 g) in water (10 mL) was slowly added dropwise. The reaction mixture was warmed to room temperature (25 °C) and stirred for 30 minutes. After completion of the reaction, the reaction mixture was filtered, and the filter cake was washed with 100 mL of water. The solid was collected, concentrated to dryness under reduced pressure, and purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0-40%) to obtain compound 11-4. MS-ESI calculated value [M+H] + 274, actual value 273.8.

[0184] Step 4: Synthesis of compound 11-5 Compound 11-4 (7.8 g) was dissolved in tetrahydrofuran (100 mL), and acetic anhydride (4.37 g) and diisopropylethylamine (4.52 g) were added. The reaction mixture was heated to 45 °C and stirred for 16 hours. After the reaction was completed, the reaction mixture was concentrated to dryness under reduced pressure, pulped with 50 mL of petroleum ether, stirred for 30 minutes, filtered, and the solid was collected and concentrated to dryness under reduced pressure to give compound 11-5, which was used directly in the next step. 1 H NMR (400MHz, DMSO-d6)δ:9.92(s,1H),7.84(s,1H),7.50(d,J=7.6Hz,1H),6.93(d,J=7.6Hz,1H),4.09(s,3H),2.12(s,3H). MS-ESI calculated value [M+H] + 316, actual value 315.9.

[0185] Step 5: Synthesis of compound 11-6 To a suspension of compound 11-5 (4.25 g) in acetic acid (75 mL) was added concentrated nitric acid (1.96 g, purity 65%) at 0 °C. The reaction mixture was stirred at 45 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated to 10 mL, filtered, and the solid was collected and concentrated to dryness under reduced pressure. Compound 11-6 was obtained by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-3%). MS-ESI calculated value [M+H] + 361, actual value 361.0.

[0186] Step 6: Synthesis of compound 11-7 Compound 11-6 (3.24 g) was dissolved in ethanol (120 mL), and hydrochloric acid solution (6 M, 29.99 mL) was added. The reaction mixture was heated to 85°C and stirred for 16 hours. After the reaction was completed, most of the ethanol was removed under reduced pressure. The precipitated solid was collected by filtration, concentrated to dryness under reduced pressure, and purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0-30%) to give compound 11-7. MS-ESI calculated value [M+H] + 319, actual value 319.0.

[0187] Step 7: Synthesis of compound 11-8 Compound 11-7 (1.23 g) was dissolved in N,N-dimethylformamide (25 mL) and, under nitrogen protection, tris(dibenzylideneacetone)dipalladium (177.06 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (184.35 mg), and zinc cyanide (544.93 mg) were added. The reaction mixture was heated to 80 °C under a nitrogen atmosphere and stirred for 16 h. After completion of the reaction, the mixture was cooled to room temperature, poured into 500 mL of water, and extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with saturated brine (500 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0-30%) to give compound 11-8. 1 H NMR (400MHz, DMSO-d6) δ: 8.36 (br s, 2H), 8.32 (s, 1H), 8.12 (s, 1H), 4.44 (s, 3H).

[0188] Step 8: Synthesis of Compound 11-9 A mixture of cuprous chloride (1.80 g) and acetonitrile (250 mL) was heated to 65 °C, and t-butyl nitrite (1.72 g) was added in one portion, followed by compound 11-8 (1.45 g) in several portions. The reaction mixture was stirred at 65 °C for 30 min. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. Ethyl acetate (500 mL) and hydrochloric acid solution (6 M, 100 mL) were added to the residue, and the layers were separated. The organic phase was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give compound 11-9, which was used directly in the next step.

[0189] Step 9: Synthesis of Compounds 11-10 Compound 11-9 (1.6 g) was dissolved in tetrahydrofuran (150 mL), triethylamine (1.71 g) and 3-aminopropanol (1.52 g) were added, and the reaction mixture was heated to 65 °C and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, poured into 150 mL of water, and extracted with ethyl acetate (150 mL). The organic phase was washed with saturated brine (150 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0 to 50%) to give compound 11-10. MS-ESI calculated value [M+H] + 276, actual value 276.0.

[0190] Step 10: Synthesis of Compound 11-11 Compound 11-10 (1.15 g) was dissolved in ethanol (100 mL), and palladium / carbon (5 mg, 10% purity) was added. The reaction mixture was stirred under a hydrogen atmosphere (15 psi) at 25° C. for 16 hours. After the reaction was completed, the reaction mixture was filtered, and the filter cake was washed with 50 mL of ethanol. The filtrate was collected and concentrated to dryness under reduced pressure to obtain compound 11-11. MS-ESI calculated value [M+H] + 246, actual value 246.2.

[0191] Step 11: Synthesis of Compounds 11-12 Compound 11-11 (1 g) was dispersed in a 6 M hydrochloric acid solution (6.79 mL), and the mixture was cooled to 0 °C. A solution of sodium nitrite (421.97 mg) in water (6 mL) was slowly added dropwise at 0 °C. The reaction mixture was stirred at 0 to 25 °C for 1 hour. After the reaction was completed, the reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain compound 11-12, which was used directly in the next step. MS-ESI calculated value [M+H] + 257, actual value 257.2.

[0192] Step 12: Synthesis of Compounds 11-13 Compound 11-12 (745.00 mg) was dissolved in formic acid (100 mL, 75% purity) and nickel-aluminum alloy (1.25 g) was added. The reaction mixture was heated to 90 °C and stirred for 16 h. The reaction mixture was filtered, and the filtrate was collected and concentrated to dryness under reduced pressure to give compound 11-13, which was used directly in the next step. MS-ESI calculated value [M+H] + 288, actual value 288.1.

[0193] Step 13: Synthesis of Compounds 11-14 Compound 11-13 (835 mg) was dissolved in 60 mL of ethanol, and an aqueous solution of sodium hydroxide (1 M, 14.53 mL) was added with stirring. The reaction mixture was stirred at 15 °C for 1 hour. After completion of the reaction, the mixture was cooled in an ice bath, and the pH was adjusted to 6-7 with 2N hydrochloric acid. Most of the methanol was removed under reduced pressure, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give compound 11-14, which was used directly in the next step. MS-ESI calculated value [M+H] + 260, actual value 259.9.

[0194] Step 14: Synthesis of Compounds 11-15 Compound 11-14 (450 mg) was dissolved in dichloromethane (25 mL), and triethylamine (878.17 mg) and methanesulfonyl chloride (409.00 mg) were added. The reaction mixture was stirred at 25°C for 30 minutes. A two-pot reaction was performed. After completion of the reaction, the reaction mixture was separated into dichloromethane (250 mL) and water (250 mL). The organic phase was washed with saturated brine (250 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 11-15 was obtained by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-10%). MS-ESI calculated value [M+H] + 338, actual value 338.1.

[0195] Step 15: Synthesis of Compounds 11-16 Compound 1-13 (100 mg) was dissolved in acetonitrile (10 mL), and diisopropylethylamine (110.31 mg), potassium iodide (141.69 mg), and compound 11-15 (95.98 mg) were added. The reaction mixture was heated to 90°C and stirred for 16 hours. After completion of the reaction, the reaction mixture was poured into 50 mL of water, extracted with dichloromethane (50 mL x 2), and the layers were separated. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 11-16 was obtained by separation and purification using flash silica gel chromatography (eluent: methanol / dichloromethane = 0-10%). MS-ESI calculated value [M+H] + 593, actual value 593.2.

[0196] Step 16: Synthesis of Compounds 11-17 Compound 11-16 (107 mg) and compound 1-15 (60.38 mg) were dissolved in methanol (5 mL) and tetrahydrofuran (4 mL). Sodium triacetylborohydride (191.30 mg) was added, and the reaction mixture was stirred at 25°C for 40 hours. Sodium triacetylborohydride (191.30 mg) was then added, and the reaction mixture was stirred at 25°C for 16 hours. Sodium triacetylborohydride (595.09 mg) was then added, and the reaction mixture was stirred at 25°C for 3 hours. The reaction mixture was concentrated to dryness, 50 mL of water was added, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 11-17 was obtained by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-10%) to give compound 11-17. MS-ESI calculated value [M+H] + 911, actual measurement 911.5.

[0197] Step 17: Synthesis of Compound 11 Compound 11-17 (110 mg) was dissolved in tetrahydrofuran (5 mL), triethylamine trihydrofluoride (97.30 mg) was added, and the reaction mixture was stirred at 25° C. for 16 hours. After the reaction was completed, the mixture was allowed to stand, the supernatant was discarded, the solid was washed with 10 mL of tetrahydrofuran, 5 mL of acetonitrile was added, and the mixture was stirred at 25° C. for 30 minutes. After filtration, the filter cake was concentrated to dryness under reduced pressure to obtain compound 11. 1 H NMR(400MHz,DMSO-d6)δ:8.30(s,1H),8.21(s,1H),8.11(d,J=10.0Hz,1H),7.65(s,1H),7.50~7.43(m,3H),7.23( s,1H),7.08~7.03(m,4H),7.00~6.95(m,3H),6.89(d,J=8.0Hz,1H),6.39(d,J=10.0Hz,1H),5.14(d,J=3.2Hz,1H) ,5.05(t,J=6.8Hz,2H),4.77(t,J=6.4Hz,1H),4.66(s,1H),4.49(s,3H),4.34(s,1H),4.20~4.15(m,2H),2.98~2. 90(m,1H),2.82~2.77(m,2H),2.20(s,2H),2.17(s,3H),1.93~1.85(m,2H),1.68~1.60(m,2H),1.40~1.25(m,4H). MS-ESI calculated value [M+H] + 797.0, actual value 797.7.

[0198] Example 12 [ka] Synthetic Route: [ka]

[0199] Step 1: Synthesis of compound 12-2 Compound 12-1 (10 g) was dissolved in t-butanol (60 mL). Triethylamine (11.23 g) was added, and the reaction mixture was heated to reflux. Diphenylphosphoryl azide (15.28 g) was slowly added dropwise, and the reaction mixture was stirred at 90 °C for 16 hours. After the reaction was completed, the reaction mixture was concentrated to dryness, dissolved in 500 mL of ethyl acetate, and washed with 500 mL of 2 M sodium hydroxide solution. The organic phase was separated, concentrated to dryness under reduced pressure, and then pulped at room temperature with 600 mL of a petroleum ether / ethyl acetate (v:v = 5:1) mixed solvent. The mixture was filtered, and the filtrate was collected and concentrated to dryness under reduced pressure to obtain compound 12-2. MS-ESI calculated value [M+H-100] + 152, actual value 151.8, MS-ESI calculated value [M+H-56] + 196, actual value 195.9.

[0200] Step 2: Synthesis of compound 12-3 Compound 12-2 (5.40 g) was dissolved in ethanol (150 mL), followed by the addition of sodium iodide (6.45 g) and [bis(trifluoroacetoxy)iodo]benzene (13.86 g). The reaction mixture was stirred at 50 °C for 14 hours in an air atmosphere. The reaction was quenched with saturated aqueous sodium thiosulfate (120 mL) and extracted with ethyl acetate (150 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 10:1) to obtain compound 12-3. MS-ESI calculated value [M+H-100] + 278, measured value 278.

[0201] Step 3: Synthesis of compound 12-4 Acetic acid (200 mL) was placed in a reaction flask, and concentrated nitric acid (3.86 g, 65% content) was slowly added at -78 °C. Next, compound 12-3 (10.0 g) was dissolved in acetic acid (100 mL) and slowly added dropwise to the reaction flask at -78 °C. After the addition was complete, the reaction solution was warmed to 0 °C and stirred for 1 hour. The reaction solution was slowly poured into stirring ice water (3 L) and stirred for 30 minutes. Next, it was filtered, and the filter cake was washed three times with water (500 mL). The solid was dissolved in ethyl acetate (600 mL), washed twice with water (500 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Ethyl acetate (50 mL) was added to the residue, and the solution was dissolved at 50 °C. The mixture was then cooled to room temperature to precipitate a solid. Next, petroleum ether (200 mL) was added to the reaction flask, pulped, stirred for 30 minutes, filtered, and the solid was collected to obtain compound 12-4. 1 H NMR (400MHz, CDCl3) δ: 8.05 (s, 1H), 7.07 (s, 1H), 4.48~4.45 (m, 2H), 4.37~4.34 (m, 2H), 1.49 (s, 9H).

[0202] Step 4: Synthesis of compound 12-5 Compound 12-4 (6.00 g) was dissolved in dimethyl sulfoxide (90 mL), followed by the addition of cuprous oxide (508 mg) and 1-cyanoethanal (2.45 g). The reaction mixture was stirred at 130 °C for 14 hours under a nitrogen atmosphere. Water (150 mL) and ethyl acetate (150 mL) were added to the reaction mixture, which was then filtered. The filtrate was extracted with ethyl acetate (100 mL x 3). The organic phase was washed with saturated brine (300 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 12-5 as a crude product. 1 H NMR (400MHz, CDCl3) δ: 8.14 (s, 1H), 4.50~4.47 (m, 2H), 4.43~4.41 (m, 2H).

[0203] Step 5: Synthesis of compound 12-6 A mixture of copper chloride (2.43 g) and acetonitrile (40 mL) was heated to 60 °C, and t-butyl nitrite (2.33 g) was added in one portion, followed by compound 12-5 (2.00 g) in several portions. The reaction mixture was stirred at 60 °C for 30 min. After the reaction was completed, the reaction mixture was cooled to room temperature, water (50 mL) was added, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain the crude compound. The crude product was then pulped with ethyl acetate (20 mL) and petroleum ether (10 mL) at room temperature, stirred for 5 min, filtered, and the filter cake was collected to obtain compound 12-6. 1 H NMR (400MHz, CDCl3) δ: 7.85 (s, 1H), 4.55~4.50 (m, 4H).

[0204] Step 6: Synthesis of compound 12-7 Compound 12-6 (1.2 g) was dissolved in tetrahydrofuran (15 mL), triethylamine (1.51 g) and 3-aminopropanol (1.12 g) were added, and the reaction mixture was heated to 60 °C and stirred for 14 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (40 mL × 2). The organic phase was washed with saturated brine (30 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 12-7 as a crude product. MS-ESI calculated value [M+H] + 280, actual measured value 280.

[0205] Step 7: Synthesis of Compound 12-8 Compound 12-7 (1.25 g) was dissolved in ethanol (40 mL), and palladium / carbon (1 g, 10% purity) was added. The reaction mixture was stirred at room temperature under a hydrogen atmosphere (15 psi) for 14 hours. After completion of the reaction, the reaction mixture was filtered, the filter cake was washed with ethanol, and the filtrate was collected and concentrated under reduced pressure to give compound 12-8 as a crude product. 1H NMR (400MHz, CD3OD) δ:6.56(s,1H),4.31(s,4H),3.70~3.65(m,2H),3.32~3.27(m,2H),1.78~1.71(m,2H).

[0206] Step 8: Synthesis of Compound 12-9 Compound 12-8 (1.1 g) was dissolved in aqueous hydrochloric acid (6 M, 20 mL), and a solution of sodium nitrite (456.74 mg) in water (10 mL) was slowly added dropwise at 0 °C. The reaction mixture was stirred at 15 °C for 2 h. After the reaction was completed, the mixture was partitioned between dichloromethane (20 mL) and water (20 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give compound 12-9, which was used directly in the next step. MS-ESI calculated value [M+H] + 261, actual value 261.

[0207] Step 9: Synthesis of Compound 12-10 Compound 12-9 (760 mg) was dissolved in formic acid (40 mL, 75% purity), and nickel-aluminum alloy (1.25 g) was added. The reaction mixture was heated to 90°C and stirred for 14 hours. An additional nickel-aluminum alloy (1.25 g) was added. The reaction mixture was heated to 90°C and stirred for 20 hours. The reaction mixture was filtered, the filtrate was collected, and concentrated to dryness under reduced pressure. Ethanol (10 mL) and aqueous sodium hydroxide solution (4 M, 10 mL) were added to the concentrate. The reaction mixture was stirred at 15°C for 1 hour. After completion of the reaction, the reaction mixture was extracted with dichloromethane (40 mL × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0 to 20:1) to obtain compound 12-10. MS-ESI calculated value [M+H] + 264, actual value 264.

[0208] Step 10: Synthesis of Compounds 12-11 Compound 12-10 (50 mg) was dissolved in dichloromethane (6 mL), and triethylamine (96.10 mg) and methanesulfonyl chloride (43.51 mg) were added. The reaction mixture was stirred at 15°C for 1 hour. After completion of the reaction, the reaction mixture was separated into dichloromethane (10 mL) and water (10 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0 to 20:1) to obtain compound 12-11. MS-ESI calculated value [M+H] + 342, actual value 342.

[0209] Step 11: Synthesis of Compound 12-12 Compound 12-11 (52 mg) was dissolved in acetonitrile (15 mL), and diisopropylethylamine (59.07 mg), potassium iodide (126.44 mg), and compound 1-13 (53.55 mg) were added. The reaction mixture was heated to 90°C and stirred for 14 hours. After the reaction was completed, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0 to 20:1) to obtain compound 12-12. MS-ESI calculated value [M+H] + 597, actual value 597.

[0210] Step 12: Synthesis of Compounds 12-13 Compound 1-15 (50 mg, acetate salt) and compound 12-12 (74.87 mg) were dissolved in methanol (4 mL) and tetrahydrofuran (2 mL). Diisopropylethylamine (32.76 mg) and sodium triacetylborohydride (134.30 mg) were added, and the reaction mixture was stirred at 20°C for 12 hours. Sodium triacetylborohydride (134.30 mg) was then added, and the reaction mixture was stirred at 20°C for another 5 hours. A 5% aqueous solution of sodium bicarbonate (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 2). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 12-13 as a crude product. MS-ESI calculated value [M+H]+ 915, found value 915.

[0211] Step 13: Synthesis of the formate salt of compound 12 Compound 12-13 (90 mg) was dissolved in tetrahydrofuran (5 mL), triethylamine trihydrofluoride (79.27 mg) was added, and the reaction mixture was stirred at 15 °C for 14 hours. After the reaction was complete, the mixture was allowed to stand, the supernatant was discarded, and the solid was washed with 5 mL of tetrahydrofuran. The residue was then separated by high-performance liquid chromatography (column type: Phenomenex Gemini-NX C18, length x inner diameter: 75 mm x 30 mm, 3 μm). Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.225% formic acid). Gradient elution method: acetonitrile was gradient eluted from 0% to 30%, with an elution time of 7 min) to obtain the formate salt of compound 12. 1H NMR(400MHz,DMSO-d6)δ:8.28(s,2H),8.15~8.10(m,1H),7.48~7.44(m,3H),7 .08~7.03(m,3H),6.99~6.95(m,2H),6.93~6.90(m,1H),6.45~6.40(m,1H),5.0 8~5.03(m,1H),4.71~4.63(m,3H),4.42~4.34(m,4H),3.78(s,2H),2.81~2.62 (m,3H),2.13(s,3H),1.99~1.89(m,4H),1.69~1.61(m,3H),1.39~1.29(m,5H). MS-ESI calculated value [M+H] + 801, actual measured value 801.

[0212] (Examples 13 and 14) [ka] Synthetic Route: [ka]

[0213] Step 1: Synthesis of compound 13-1 Compound 5-2 (2 g) and compound 5-4 (2.24 g) were dissolved in anhydrous xylene (30 mL), and then 4- J Methylaminopyridine (1.99 g) was added. The reaction mixture was stirred at 140° C. for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 3:1) to obtain compound 13-1. MS-ESI calculated value [M+H+23] + 390, actual value 389.8.

[0214] Step 2: Synthesis of compound 13-2 Compound 2-bromo-5-methylthiophene (250.6 mg) was dissolved in anhydrous tetrahydrofuran (2.7 mL), and n-butyllithium solution (2.5 M, 0.57 mL) was slowly added dropwise at −78° C., followed by stirring at this temperature for 1 hour. Compound 13-1 (0.4 g) was dissolved in anhydrous tetrahydrofuran (2.7 mL), and added dropwise to the reaction solution at −78° C., followed by stirring for 1 hour.

[0215] The reaction mixture was quenched by adding saturated aqueous ammonium chloride (30 mL) at 0°C and extracted with ethyl acetate (30 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain compound 13-2. 1 H NMR(400MHz,CDCl3)δ ppm:6.69~6.59(m,1H),6.58~6.57(m,1H),6.39(s,1H),6.38~6.33(m,1H),6.03~6.02(m,1H),4.23~4.16(m,1H),4.06 (s,1H),3.41(s,1H),2.13(s,3H),1.86(s,3H),1.51~1.49(m,2H),1.17~1.16(m,2H),1.04~0.91(m,4H),0.88(s,9H). MS-ESI calculated value [M+H+23] + 488, actual value 488.2.

[0216] Step 3: Preparation of Compounds 13-2a and 13-2b Compound 13-2 (520 mg) was separated and purified by chiral liquid chromatography to obtain compounds 13-2a and 13-2b.

[0217] SFC separation method: Column (DAICEL CHIRALCEL IC (250 mm × 30 mm, 10 μm)), mobile phase: A: carbon dioxide, B: 40% to 40% ethanol (containing 0.1% ammonium hydroxide), flow rate: 70 mL / min, column temperature: 40°C.

[0218] Retention time of compound 13-2a: 5.757 min, calculated value by MS-ESI [M+H-18] + 448, actual value 448.4.

[0219] Retention time of compound 13-2b: 6.484 min, calculated value by MS-ESI [M+H-18] + 448, actual value 448.3.

[0220] Step 4: Synthesis of compound 13-3 Compound 13-2a (130 mg) was dissolved in anhydrous tetrahydrofuran (5 mL), and then aqueous hydrochloric acid (69.8 μL, 4 M) was added. The reaction mixture was stirred at 25° C. for 18 hours. The pH of the reaction mixture was adjusted to approximately 8 with saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, compound 13-3. MS-ESI calculated value [M+H] + 366, actual value 365.9.

[0221] Step 5: Synthesis of compound 13-4 Compound 13-3 (85 mg) was dissolved in acetonitrile (4 mL), and compound 1-12 (75.2 mg), N,N-diisopropylethylamine (120 mg), and potassium iodide (154 mg) were added at room temperature. The reaction mixture was stirred at 90°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0 to 20:1) to obtain compound 13-4. MS-ESI calculated value [M+H] + 593, actual value 593.1.

[0222] Step 6: Synthesis of compound 13-5 Compound 13-4 (86 mg) and compound 1-15 (48.5 mg, acetate salt) were dissolved in anhydrous methanol (4 mL) and anhydrous tetrahydrofuran (2 mL), and N,N-diisopropylethylamine (75 mg) and sodium borohydride acetate (92.2 mg) were added. The reaction mixture was stirred at 25 °C for 24 hours. Sodium borohydride acetate (92.2 mg) was then added to the reaction mixture, and the mixture was stirred for 24 hours. Sodium borohydride acetate (92.2 mg) was then added to the reaction mixture, and the mixture was stirred for 24 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, compound 13-5. MS-ESI calculated value [M+H] + 912, actual value 911.6.

[0223] Step 7: Synthesis of the trifluoroacetate salt of compound 13 Compound 13-5 (120 mg) was dissolved in anhydrous tetrahydrofuran (4 mL), and triethylamine trihydrofluoride (120 mg) was added to the reaction mixture. The mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (HPLC) using a Welch Xtimate C18 column (length x inner diameter: 100 mm x 40 mm, 3 μm). The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. The mobile phase was acetonitrile / water (containing 0.075% trifluoroacetic acid). Gradient elution was performed using a gradient elution method (20% to 50% acetonitrile) over an 8-minute period. The trifluoroacetate salt of compound 13 was obtained. 1H NMR(400MHz,DMSO-d6)δ ppm:10.53~10.49(m,2H),9.74(s,1H),9.22~9.16(m,2H),8.15~8.08(m,2H),7.47~7.46(m,1H),7.16~7.14 (m,2H),7.07~7.06(m,1H),7.00~6.96(m,2H),6.83~6.82(m,1H),6.65~6.64(m,1H),6.55~6.53(m,1H),6.2 6(s,1H),5.43~5.41(m,1H),4.81~4.71(m,3H),4.39(s,2H),3.38~3.34(m,4H),3.18~3.08(m,4H),2.72~2. 70(m,3H),2.55(s,1H),2.38(s,3H),2.32~2.21(m,1H),2.00(s,4H),1.68~1.60(m,2H),1.48~1.45(m,2H). MS-ESI calculated value [M+H] + 797, actual value 797.2.

[0224] The synthesis of the trifluoroacetate salt of compound 14 is carried out by a four-step reaction using compound 13-2b as a starting material, with reference to the synthesis route for the trifluoroacetate salt of compound 13; specifically, see steps 8 to 11.

[0225] Step 8: Synthesis of Compound 14-1 Compound 13-2b (140 mg, 300.7 μmol) was dissolved in anhydrous tetrahydrofuran (2 mL), and then aqueous hydrochloric acid (1 mL, 4.0 mmol, 4 M) was added. The reaction mixture was stirred at 25° C. for 18 hours. The pH of the reaction mixture was adjusted to approximately 8 with saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 14-1 as a crude product. MS-ESI calculated value [M+H] + 366, actual value 365.9.

[0226] Step 9: Synthesis of compound 14-2 Compound 14-1 (52.5 mg, 143.6 μmol) was dissolved in acetonitrile (6 mL), and compound 1-12 (46.4 mg, 143.6 μmol), N,N-diisopropylethylamine (74.2 mg, 574.5 μmol), and potassium iodide (95.3 mg, 574.5 μmol) were added at room temperature. The reaction mixture was stirred at 90°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0 to 20:1) to obtain compound 14-2. MS-ESI calculated value [M+H] + 593, actual value 593.

[0227] Step 10: Synthesis of compound 14-3 Compound 14-2 (90 mg, 151.8 μmol) and compound 1-15 (50 mg, 149 μmol, acetate salt) were dissolved in anhydrous methanol (3 mL) and anhydrous tetrahydrofuran (1.5 mL), and N,N-diisopropylethylamine (78.4 mg, 607 μmol) and sodium borohydride acetate (96.5 mg, 455.5 μmol) were added. The reaction mixture was stirred at 25°C for 24 hours. Sodium borohydride acetate (96.5 mg, 455.5 μmol) was then added to the reaction mixture, and the mixture was stirred for 24 hours. Sodium borohydride acetate (96.5 mg, 455.5 μmol) was then added to the reaction mixture, and the mixture was stirred for 24 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with brine (20 mL×2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 14-3 as a crude product. MS-ESI calculated value [M+H] + 912, actual value 911.4.

[0228] Step 11: Synthesis of the trifluoroacetate salt of compound 14 Compound 14-3 (75 mg, 61.7 μmol) was dissolved in anhydrous tetrahydrofuran (4 mL), and triethylamine trihydrofluoride (56 mg, 348 μmol) was added to the reaction mixture. The mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (HPLC) using a Welch Xtimate C18 column (length x inner diameter: 100 mm x 40 mm, 3 μm). The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. The mobile phase was acetonitrile / water (containing 0.075% trifluoroacetic acid). Gradient elution was performed using a gradient elution method from 22% to 52% acetonitrile over an 8-minute period. The trifluoroacetate salt of compound 14 was obtained.

[0229] Trifluoroacetate salt of compound 14: 1 H NMR(400MHz,DMSO-d6)δ ppm:10.5(s,2H),9.53(s,1H),9.11(s,2H),8.14~8.08(m,2H),7.47~7.46(m,1H),7.16~7. 14(m,2H),7.07~7.06(m,1H),6.99~6.96(m,2H),6.65~6.64(m,1H),6.56~6.53(m,1H),6.2 4(s,1H),5.42~5.40(m,1H),4.79~4.74(m,3H),4.38(s,2H),3.19~3.08(m,4H),2.72~2.66 (m,4H),2.39(s,4H),2.33~2.22(m,6H),1.99(s,5H),1.68~1.60(m,2H),1.48~1.45(m,2H). MS-ESI calculated value [M+H] + 797, actual value 797.1.

[0230] (Examples 15 and 16) [ka] Synthetic Route: [ka]

[0231] Step 1: Synthesis of compound 15-1 Compound 8-1 (726 mg) and compound 5-4 (500 mg) were dissolved in anhydrous toluene (6 mL), and then sodium hydride (87.2 mg, purity 60%) was added. The reaction mixture was stirred at 120 °C for 4 hours. The reaction mixture was cooled to 0 °C, and saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture to quench the reaction. The mixture was then extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain compound 15-1. MS-ESI calculated value [M+H-18] + 514, actual value 513.9.

[0232] Step 2: Preparation of Compounds 15-1a and 15-1b Compound 15-1 (243 mg) was separated and purified by chiral liquid chromatography to obtain compounds 15-1a and 15-1b.

[0233] SFC separation method: column (DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm)), mobile phase: A: carbon dioxide, B: 55% to 55% ethanol (containing 0.1% ammonium hydroxide), flow rate: 70 mL / min, column temperature: 40°C.

[0234] Retention time of compound 15-1a: 0.688 min, calculated value by MS-ESI [M+H-18] + 514, actual value 513.9.

[0235] Retention time of compound 15-1b: 1.345 min, calculated value by MS-ESI [M+H-18] + 514, actual value 513.8.

[0236] Step 3: Preparation of compound 15-2 Compound 15-1a (120 mg) was dissolved in anhydrous dioxane (2 mL), and then a solution of hydrochloric acid in dioxane (4 mL, 4 M) was added. The reaction mixture was stirred at 25° C. for 4 hours. The pH of the reaction mixture was adjusted to approximately 8 with saturated aqueous sodium carbonate, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was washed with saturated aqueous sodium carbonate (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, compound 15-2. MS-ESI calculated value [M+H] + 430, actual value 429.8.

[0237] Step 4: Preparation of compound 15-3 Compound 15-2 (79 mg) was dissolved in acetonitrile (4 mL), and compound 1-12 (59.3 mg), N,N-diisopropylethylamine (94.8 mg), and potassium iodide (121 mg) were added at room temperature. The reaction mixture was stirred at 90°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0 to 20:1) to obtain compound 15-3. MS-ESI calculated value [M+H] + 657 sum 659, actual value 659.

[0238] Step 5: Preparation of compound 15-4 Compound 15-3 (46 mg) and compound 1-15 (23.4 mg, acetate salt) were dissolved in anhydrous methanol (3 mL) and anhydrous tetrahydrofuran (1.5 mL), and N,N-diisopropylethylamine (27.1 mg) and sodium borohydride acetate (44.4 mg) were added. The reaction mixture was stirred at 25 °C for 24 hours. Sodium borohydride acetate (44.4 mg) was then added to the reaction mixture, and the mixture was stirred for 24 hours. Sodium borohydride acetate (44.4 mg) was then added to the reaction mixture, and the mixture was stirred for 24 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 15-4 as a crude product. MS-ESI calculated value [M+H-42] + 933, actual value 933.4.

[0239] Step 6: Preparation of the trifluoroacetate salt of compound 15 Compound 15-4 (102 mg) was dissolved in anhydrous tetrahydrofuran (4 mL), and triethylamine trihydrofluoride (100 mg) was added to the reaction mixture. The mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure, and the residue was purified by high-performance liquid chromatography (HPLC) using a Welch Xtimate C18 column (length x inner diameter: 100 mm x 40 mm, 3 μm). The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. The mobile phase was acetonitrile / water (containing 0.075% trifluoroacetic acid). Gradient elution was performed using a gradient elution method from 25% to 55% acetonitrile over an 8-minute period. The trifluoroacetate salt of compound 15 was obtained. 1H NMR(400MHz,DMSO-d6)δ ppm:10.50(s,2H),9.68(s,1H),9.16(s,2H),8.15~8.08(m,2H),7.52~7.50(m,2H),7.17~7.14 (m,1H),7.10~7.08(m,1H),7.00(s,2H),6.94~6.90(m,1H),6.55~6.53(m,1H),6.25(s,1H),5. 43~5.41(m,1H),4.79~4.77(m,3H),4.38(s,2H),3.37(s,4H),3.19~3.10(m,4H),2.72~2.67(m ,3H),2.33(s,3H),2.25~2.21(m,3H),2.01~1.99(m,4H),1.65~1.63(m,2H),1.49~1.46(m,2H). MS-ESI calculated value [M+H] + 861, actual value 861.2.

[0240] The synthesis of the trifluoroacetate salt of compound 16 was carried out by a four-step reaction using compound 15-1b as the starting material, following the synthesis route for the trifluoroacetate salt of compound 15.

[0241] Trifluoroacetate salt of compound 16: 1 H NMR(400MHz,DMSO-d6)δ ppm:10.54~10.50(m,2H),9.74(s,1H),9.21~9.15(m,2H),8.15~8.07(m,2H),7.51~7.50(m,2H),7. 16~7.14(m,1H),7.08~7.07(m,1H),7.00~6.97(m,3H),6.93~6.92(m,1H),6.55~6.52(m,1H),6.26( s,1H),5.43~5.40(m,1H),4.78~4.77(m,3H),4.38(s,2H),3.38~3.36(m,4H),3.18~3.07(m,4H),2. 71~2.67(m,3H),2.54(s,1H),2.32~2.20(m,4H),2.00(s,4H),1.68~1.57(m,2H),1.52~1.46(m,2H). MS-ESI calculated value [M+H] + 861, actual value 861.

[0242] (Examples 17 and 18) [ka] Synthetic Route: [ka]

[0243] Step 1: Synthesis of compound 17-1 Compound 5-2 (1.3 g) and compound 2-1-1 (1.00 g) were dissolved in anhydrous toluene (40 mL), and 4-dimethylaminopyridine (859 mg) was added at room temperature. The reaction mixture was then heated to 120°C and reacted for 14 hours with stirring. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0 to 25%) to obtain compound 17-1. MS-ESI calculated value [M+H-56] + 296, actual value 295.9.

[0244] Step 2: Synthesis of compound 17-2 Compound 2-bromo-5-phenylthiophene (204 mg) was dissolved in tetrahydrofuran (8 mL) and n-butyllithium solution (2.5 M tetrahydrofuran solution, 0.34 mL) was slowly added dropwise under nitrogen protection at -60 °C. The reaction mixture was stirred at -60 °C for 30 minutes. Compound 17-1 (200 mg) was dissolved in tetrahydrofuran (3 mL) and slowly added dropwise to the reaction mixture at -60 °C. After the addition was completed, the mixture was stirred at -50 °C for 1 hour. The reaction mixture was warmed to 0 °C and quenched with saturated aqueous ammonium chloride solution (10 mL). The mixture was extracted with ethyl acetate (15 mL × 2). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0-25%) to give compound 17-2. MS-ESI calculated value [M+H-18] +494, actual value 494.4.

[0245] Step 3: Chiral resolution to obtain compounds 17-2a and 17-2b Compound 17-2 was separated and purified by chiral liquid chromatography to give compounds 17-2a and 17-2b.

[0246] SFC separation method: Column: DAICEL CHIRALPAK AD 250 mm x 30 mm, 10 μm, mobile phase: A: carbon dioxide, B: ethanol (containing 0.1% ammonium hydroxide), flow rate: 70 mL / min, column temperature: 40°C.

[0247] Retention time of compound 17-2a: 0.889 min, calculated value by MS-ESI [M+H-18] + 494, actual value 494.4.

[0248] Retention time of compound 17-2b: 1.302 min, calculated value by MS-ESI [M+H-18] + 494, actual value 494.4.

[0249] Step 4: Synthesis of compound 17-3 Compound 17-2a (250.0 mg) was dissolved in tetrahydrofuran (10 mL), and then aqueous hydrochloric acid (10 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 14 hours. The pH of the reaction mixture was adjusted to approximately 9 with saturated aqueous sodium carbonate, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 17-3, which was used directly in the next step. MS-ESI calculated value [M+H] + 412, actual value 411.9.

[0250] Step 5: Synthesis of compound 17-4 Compound 17-3 (100 mg) was dissolved in acetonitrile (10 mL), and compound 1-12 (78.5 mg), potassium iodide (161 mg), and N,N-diisopropylethylamine (94.2 mg) were added at room temperature. The reaction mixture was stirred at 90°C for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-5%) to give compound 17-4. MS-ESI calculated value [M+H] + 639, actual value 639.1.

[0251] Step 6: Synthesis of compound 17-5 Compound 17-4 (77.7 mg) and compound 1-15 (40.0 mg, acetate salt) were dissolved in anhydrous methanol (4 mL) and anhydrous tetrahydrofuran (2 mL), and sodium borohydride acetate (107 mg) and N,N-diisopropylethylamine (26.2 mg) were added. The reaction mixture was stirred at 25 °C for 12 hours. Sodium borohydride acetate (107 mg) was then added to the reaction mixture, and the mixture was stirred for 5 hours. The reaction was quenched by adding 4% aqueous sodium bicarbonate (5 mL) and extracted with ethyl acetate (10 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 17-5, which was used directly in the next step. MS-ESI calculated value [M+H] + 957, actual value 957.2.

[0252] Step 7: Synthesis of the formate salt of compound 17 Compound 17-5 (35 mg) was dissolved in tetrahydrofuran (3 mL), and triethylamine trihydrofluoride (29.5 mg) was added to the reaction mixture. The mixture was stirred at room temperature for 14 h. After the reaction was completed, the supernatant was discarded, and the precipitated solid was concentrated under reduced pressure. The residue was separated by high-performance liquid chromatography (HPLC) (column type: Phenomenex Gemini-NX C18, length x inner diameter: 75 mm x 30 mm, 3 μm). Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare the sample solution. Mobile phase: acetonitrile / water (containing 0.225% formic acid). Gradient elution method: acetonitrile was gradient eluted from 0% to 30% with an elution time of 7 min) to obtain the formate salt of compound 17. 1 H NMR(400MHz,DMSO-d6)δ:8.36(s,1H),8.15~8.10(m,1H),7.70(s,1H),7.61~7.57(m,2H),7.50~7.48(m,1H),7.40 ~7.33(m,3H),7.31~7.27(m,1H),7.13~7.12(m,1H),7.06~7.03(m,2H),7.02~6.98(m,1H),6.90~6.86(m,1H),6.4 2~6.37(m,1H),5.08~5.04(m,1H),4.95~4.91(m,1H),4.67~4.61(m,2H),3.80(s,2H),3.06(s,2H),2.99(s,2H),2 .93~2.87(m,2H),2.82~2.66(m,4H),2.35~2.31(m,1H),2.29~2.25(m,2H),2.17~2.07(m,5H),1.82~1.78(m,2H). MS-ESI calculated value [M+H] + 843, actual value 843.2.

[0253] The synthesis of the formate salt of compound 18 was carried out in four reaction steps using compound 17-2b as the starting material, following the synthesis route for the formate salt of compound 17.

[0254] Formate salt of compound 18: 1H NMR(400MHz,DMSO-d6)δ:8.17(s,1H),8.15~8.10(m,1H),7.75(s,1H),7.61~7.57(m,2H),7.50~7.48(m, 1H),7.40~7.33(m,3H),7.31~7.26(m,1H),7.13~7.12(m,1H),7.07~7.04(m,2H),7.02~6.98(m,1H),6.9 1~6.88(m,1H),6.44~6.39(m,1H),5.13~5.08(m,1H),4.98~4.89(m,1H),4.68~4.61(m,2H),3.87(s,2H) ,3.16(s,2H),3.09(s,2H),2.95~2.72(m,6H),2.39~2.30(m,3H),2.20~2.07(m,5H),1.85~1.80(m,2H). MS-ESI calculated value [M+H] + 843, actual value 843.2.

[0255] Example 19 [ka] Synthetic Route: [ka]

[0256] Step 1: Synthesis of compound 19-2 Compound 19-1 (500 mg) was dissolved in methanol (10 mL) and sodium borohydride (158 mg) was added at 0° C. The reaction mixture was stirred at 0° C. for 30 minutes. Water (15 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL×2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 19-2, which was used directly in the next step. 1 H NMR (400MHz, CDCl3) δ:4.37~4.29(m,1H),3.36~3.29(m,4H),2.32~2.257(m,2H),1.70~1.68(m,2H),1.55~1.50(m,4H),1.45(s,9H).

[0257] Step 2: Synthesis of compound 19-3 Compound 7-2 (300.0 mg) and compound 19-2 (224 mg) were dissolved in anhydrous toluene (10 mL). Sodium hydride (18.5 mg, 60% purity) was added in portions at room temperature. The reaction mixture was then heated to 120 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature and quenched by slowly adding the mixture to a stirred saturated aqueous ammonium chloride solution (10 mL) in an ice bath. The mixture was then extracted with ethyl acetate (20 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0-25%) to give compound 19-3. MS-ESI calculated value [M+H-18-56] + 458, actual value 457.8.

[0258] Step 3: Synthesis of compound 19-4 Compound 19-3 (360.0 mg) was dissolved in dioxane (2 mL), and then hydrochloric acid / dioxane solution (10 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to approximately 9 with saturated aqueous sodium carbonate, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 19-4, which was used directly in the next step. MS-ESI calculated value [M+H] + 432, actual value 431.9.

[0259] Step 4: Synthesis of compound 19-5 Compound 19-4 (120.0 mg) was dissolved in acetonitrile (15 mL), and compound 1-12 (98.7 mg), potassium iodide (230 mg), and N,N-diisopropylethylamine (107.6 mg) were added at room temperature. The reaction mixture was stirred at 90°C for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-5%) to give compound 19-5. MS-ESI calculated value [M+H] + 659, actual value 659.

[0260] Step 5: Synthesis of compound 19-6 Compound 19-5 (83.6 mg) and compound 1-15 (50.0 mg, acetate salt) were dissolved in anhydrous methanol (4 mL) and anhydrous tetrahydrofuran (2 mL), and N,N-diisopropylethylamine (32.7 mg) and sodium borohydride acetate (134 mg) were added. The reaction mixture was stirred at 25 °C for 12 hours. Sodium borohydride acetate (134 mg) was then added to the reaction mixture, and the mixture was stirred for 5 hours. The reaction was quenched by adding 4% aqueous sodium bicarbonate (10 mL) and extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 19-6, which was used directly in the next step. MS-ESI calculated value [M+H] + 977, actual value 977.

[0261] Step 6: Synthesis of the formate salt of compound 19 Compound 19-6 (100 mg) was dissolved in tetrahydrofuran (5 mL), and triethylamine trihydrofluoride (82.4 mg) was added to the reaction mixture. The mixture was stirred at room temperature for 14 h. After the reaction was completed, the supernatant was discarded, and the precipitated solid was concentrated under reduced pressure. The residue was separated by high-performance liquid chromatography (HPLC) (column type: Phenomenex Gemini-NX C18, length x inner diameter: 75 mm x 30 mm, 3 μm). Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.225% formic acid). Gradient elution method: Acetonitrile was gradient eluted from 0% to 30% with an elution time of 7 min) to obtain the formate salt of compound 19. 1 H NMR(400MHz,DMSO-d6)δ:8.19(s,2H),8.15~8.11(m,1H),7.77(s,1H),7.09~7.05(m,1H) ),7.02~6.99(m,2H),6.97~6.89(m,3H),6.45~6.40(m,1H),5.15~5.11(m,1H),5.06~5.0 0(m,1H),4.71~4.66(m,2H),3.90(s,2H),3.32~3.27(m,2H),2.97~2.90(m,2H),2.87~2. 79(m,2H),2.30~2.14(m,10H),2.06~1.98(m,2H),1.76~1.68(m,2H),1.49~1.41(m,4H). MS-ESI calculated value [M+H] + 863, actual value 863.1.

[0262] (Examples 20 and 21) [ka] Synthetic Route: [ka]

[0263] Step 1: Synthesis of compound 20-1 Benzothiophene (198 mg) was dissolved in tetrahydrofuran (20 mL) and, under nitrogen protection, lithium diisopropylamide solution (2.0 M tetrahydrofuran solution, 0.8 mL) was slowly added dropwise at -60 °C. The reaction mixture was stirred at -60 °C for 30 minutes. Compound 17-1 (400 mg) was dissolved in tetrahydrofuran (5 mL) and slowly added dropwise to the reaction mixture at -60 °C. After the addition was completed, the mixture was stirred at -50 °C for 1 hour. The reaction mixture was warmed to 0 °C and quenched with saturated aqueous ammonium chloride (10 mL). The mixture was extracted with ethyl acetate (15 mL × 2). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0-25%) to obtain compound 20-1. MS-ESI calculated value [M+H-56] + 430, actual value 429.8.

[0264] Step 2: Preparation of compounds 20-1A and 20-1B Compound 20-1 was separated and purified by chiral liquid chromatography to give compounds 20-1A and 20-1B.

[0265] SFC separation method: column (DAICEL CHIRALPAK OJ 250 mm x 30 mm, 10 μm), mobile phase: A: carbon dioxide, B: ethanol (containing 0.1% ammonium hydroxide), flow rate: 80 mL / min, column temperature: 40°C.

[0266] Retention time of compound 20-1A: 5.680 min, calculated value by MS-ESI [M+H-56] + 430, actual value 429.8.

[0267] Retention time of compound 20-1B: 6.705 min, calculated value by MS-ESI [M+H-56] + 430, actual value 429.8.

[0268] Step 3: Synthesis of compound 20-2 Compound 20-1A (200.0 mg) was dissolved in tetrahydrofuran (10 mL), and then aqueous hydrochloric acid (10 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 14 hours. The pH of the reaction mixture was adjusted to approximately 9 with saturated aqueous sodium carbonate, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 20-2, which was used directly in the next step. MS-ESI calculated value [M+H] + 386, actual value 385.9.

[0269] Step 4: Synthesis of compound 20-3 Compound 20-2 (83.9 mg) was dissolved in acetonitrile (20 mL), and compound 1-12 (100 mg), potassium iodide (215 mg), and N,N-diisopropylethylamine (100 mg) were added at room temperature. The reaction mixture was stirred at 90°C for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-5%) to give compound 20-3. MS-ESI calculated value [M+H] + 613, actual value 613.

[0270] Step 5: Synthesis of compound 20-4 Compound 20-3 (102.5 mg) and compound 1-15 (60.0 mg, acetate salt) were dissolved in anhydrous methanol (4 mL) and anhydrous tetrahydrofuran (2 mL), and sodium borohydride acetate (161 mg) and N,N-diisopropylethylamine (39.3 mg) were added. The reaction mixture was stirred at 25 °C for 12 hours. Sodium borohydride acetate (161 mg) was then added to the reaction mixture, and the mixture was stirred for 5 hours. The reaction was quenched by adding 4% aqueous sodium bicarbonate (5 mL) and extracted with ethyl acetate (8 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 20-4, which was used directly in the next step. MS-ESI calculated value [M+H] + 931, actual value 931.3.

[0271] Step 7: Synthesis of the formate salt of compound 20 Compound 20-4 (125 mg) was dissolved in tetrahydrofuran (5 mL), and triethylamine trihydrofluoride (108 mg) was added to the reaction mixture. The mixture was stirred at room temperature for 14 h. After the reaction was completed, the supernatant was discarded, and the precipitated solid was concentrated under reduced pressure. The residue was separated by high-performance liquid chromatography (HPLC) (column type: Phenomenex Gemini-NX C18, length x inner diameter: 75 mm x 30 mm, 3 μm). Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.225% formic acid). Gradient elution method: acetonitrile was gradient eluted from 0% to 30% with an elution time of 7 min) to obtain the formate salt of compound 20. 1 H NMR(400MHz,DMSO-d6)δ:8.20(s,2H),8.16~8.12(m,1H),7.92~7.88(m,1H),7.84~7.78(m,2H),7.53~ 7.50(m,1H),7.37(s,1H),7.35~7.29(m,2H),7.18~7.15(m,1H),7.10~7.06(m,1H),7.04~6.99(m,1H), 6.94~6.90(m,1H),6.47~6.40(m,1H),5.17~5.15(m,1H),4.99~4.93(m,1H),4.70~4.64(m,2H),3.93( s, 2H), 3.32~3.11 (m, 6H), 2.98 ~ 2.83 (m, 4H), 2.44 ~ 2.38 (m, 3H), 2.22 ~ 2.02 (m, 5H), 1.87 ~ 1.80 (m, 2H). MS-ESI calculated value [M+H] + 817, actual value 817.2.

[0272] The synthesis of the formate salt of compound 21 was carried out by a four-step reaction using compound 20-1B as the starting material, following the synthesis route for the formate salt of compound 20.

[0273] Formate salt of compound 21: 1 H NMR(400MHz,DMSO-d6)δ:8.20(s,2H),8.16~8.11(m,1H),7.91~7.87(m,1H),7.82~7.78(m,2H),7. 52~7.49(m,1H),7.38~7.29(m,3H),7.17~7.14(m,1H),7.10~7.05(m,1H),7.04~6.99(m,1H),6.94~ 6.89(m,1H),6.46~6.40(m,1H),5.17~5.15(m,1H),4.99~4.92(m,1H),4.68~4.63(m,2H),3.93(s,2) H), 3.32~3.11(m,6H),2.98~2.83(m,4H),2.44~2.38(m,3H),2.22~2.05(m,5H),1.87~1.80(m,2H). MS-ESI calculated value [M+H] + 817, actual value 817.2.

[0274] (Examples 22 and 23) [ka] Synthetic Route: [ka]

[0275] Step 1: Synthesis of compound 22-1 Compound 2-bromo-5-phenylthiophene (273 mg) was dissolved in tetrahydrofuran (15 mL) and n-butyllithium solution (2.5 M tetrahydrofuran solution, 0.49 mL) was slowly added dropwise under nitrogen protection at -60 °C. The reaction mixture was stirred at -60 °C for 30 minutes. Compound 13-1 (300 mg) was dissolved in tetrahydrofuran (4 mL) and slowly added dropwise to the reaction mixture at -60 °C. After the addition was completed, the mixture was stirred at -50 °C for 1 hour. The reaction mixture was warmed to 0 °C, quenched with saturated aqueous ammonium chloride (20 mL), extracted with ethyl acetate (30 mL × 2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0-25%) to give compound 22-1. MS-ESI calculated value [M+H-18] + 510, actual measured value 510.3.

[0276] Step 2: Preparation of Compounds 22-1a and 22-1b Compound 22-1 was separated and purified by chiral liquid chromatography to give compounds 22-1a and 22-1b.

[0277] SFC separation method: column (DAICEL CHIRALPAK AD 250 mm x 30 mm, 10 μm), mobile phase: A: carbon dioxide, B: ethanol (containing 0.1% ammonium hydroxide), flow rate: 50 mL / min, column temperature: 40°C.

[0278] Retention time of compound 22-1a: 2.290 min, calculated value by MS-ESI [M+H-18] + 510, actual value 509.9.

[0279] Retention time of compound 22-1b: 2.724 min, calculated value by MS-ESI [M+H-18] + 510, actual value 509.9.

[0280] Step 3: Synthesis of compound 22-2 Compound 22-1a (260.0 mg) was dissolved in dioxane (2 mL), and then a solution of hydrochloric acid in dioxane (10 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to approximately 9 with saturated aqueous sodium carbonate, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 22-2, which was used directly in the next step. MS-ESI calculated value [M+H] + 428, actual value 428.

[0281] Step 4: Synthesis of compound 22-3 Compound 22-2 (99.2 mg) was dissolved in acetonitrile (15 mL), and compound 1-12 (75 mg), potassium iodide (192 mg), and N,N-diisopropylethylamine (89.9 mg) were added at room temperature. The reaction mixture was stirred at 90°C for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-5%) to give compound 22-3. MS-ESI calculated value [M+H] + 655, actual value 655.1.

[0282] Step 5: Synthesis of compound 22-4 Compound 22-3 (89.6 mg) and compound 1-15 (45.0 mg, acetate salt) were dissolved in anhydrous methanol (4 mL) and anhydrous tetrahydrofuran (2 mL), and sodium borohydride acetate (36 mg) was added. The reaction mixture was stirred at 25 °C for 12 hours. Sodium borohydride acetate (121 mg) was then added to the reaction mixture, and the mixture was stirred for 5 hours. The reaction was quenched by adding 4% aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 22-4, which was used directly in the next step. MS-ESI calculated value [M+H] + 973, actual value 973.2.

[0283] Step 6: Synthesis of the formate salt of compound 22 Compound 22-4 (85 mg) was dissolved in tetrahydrofuran (5 mL), and triethylamine trihydrofluoride (70.4 mg) was added to the reaction mixture. The mixture was stirred at room temperature for 14 h. After the reaction was completed, the supernatant was discarded, and the precipitated solid was concentrated under reduced pressure. The residue was separated by high-performance liquid chromatography (HPLC) (column type: Phenomenex Gemini-NX C18, length x inner diameter: 75 mm x 30 mm, 3 μm). Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.225% formic acid). Gradient elution method: Acetonitrile was gradient eluted from 0% to 30% with an elution time of 7 min) to obtain the formate salt of compound 22. 1 H NMR(400MHz,DMSO-d6)δ:8.19(s,2H),8.15~8.11(m,1H),7.77(s,1H),7.62~7.58(m,2H),7.51~7 .46(m,1H),7.41~7.29(m,4H),7.14~7.11(m,1H),7.08~7.04(m,2H),7.01~6.97(m,1H),6.93~6.8 9(m,1H),6.44~6.40(m,1H),5.15~5.11(m,1H),4.70~4.66(m,2H),3.89(s,3H),3.32~3.25(m,3H ),2.98~2.75(m,5H),2.21~2.11(m,6H),2.01~1.91(m,4H),1.70~1.65(m,2H),1.41~1.30(m,4H). MS-ESI calculated value [M+H] + 859, actual value 859.2.

[0284] The synthesis of the formate salt of compound 23 was carried out by a four-step reaction using compound 22-1b as the starting material, following the synthesis route for the formate salt of compound 22.

[0285] Formate salt of compound 23: 1H NMR(400MHz,DMSO-d6)δ:8.19(s,2H),8.15~8.11(m,1H),7.78(s,1H),7.62~7.58(m,2H),7.51~7 .46(m,1H),7.41~7.29(m,4H),7.14~7.11(m,1H),7.09~7.04(m,2H),7.01~6.97(m,1H),6.93~6.8 9(m,1H),6.45~6.40(m,1H),5.16~5.11(m,1H),4.71~4.66(m,2H),3.91(s,3H),3.32~3.25(m,3H ),2.98~2.77(m,5H),2.21~2.11(m,6H),2.02~1.91(m,4H),1.70~1.65(m,2H),1.39~1.29(m,4H). MS-ESI calculated value [M+H] + 859, actual value 859.2.

[0286] (Examples 24 and 25) [ka] Synthetic Route: [ka]

[0287] Step 1: Synthesis of compound 24-2 Compound 2-1-2 (200.0 mg) and compound 24-1 (202 mg) were dissolved in anhydrous toluene (5 mL). Sodium hydride (15.7 mg, 60% purity) was added in several portions at room temperature. The reaction mixture was then heated to 120 °C and stirred for 2 hours. The reaction mixture was cooled to room temperature and quenched by slowly adding the mixture to a stirred saturated aqueous ammonium chloride solution (30 mL) in an ice bath. The mixture was then extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0-25%) to obtain compound 24-2. MS-ESI calculated value [M+H-18-56] + 406, actual value 405.8.

[0288] Step 2: Preparation of compounds 24-2A and 24-2B Compound 24-2 was separated and purified by chiral liquid chromatography to give Compound 24-2A and Compound 24-2B.

[0289] SFC separation method: column (DAICEL CHIRALPAK AD 250 mm x 30 mm, 10 μm), mobile phase: A: carbon dioxide, B: ethanol (containing 0.1% ammonium hydroxide), flow rate: 70 mL / min, column temperature: 40°C.

[0290] Retention time of compound 24-2A: 3.843 min, calculated value by MS-ESI [M+H-18-56] + 406, actual value 405.8.

[0291] Retention time of compound 24-2B: 4.425 min, calculated value by MS-ESI [M+H-18-56] + 406, actual value 405.8.

[0292] Step 3: Synthesis of compound 24-3 Compound 24-2A (240.0 mg) was dissolved in dioxane (3 mL), and then hydrochloric acid / dioxane solution (6 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 2 hours. The pH of the reaction mixture was adjusted to approximately 9 with saturated aqueous sodium carbonate, and the mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give compound 24-3, which was used directly in the next step. MS-ESI calculated value [M+H] + 380, actual measured value 380.

[0293] Step 4: Synthesis of compound 24-4 Compound 24-3 (60.0 mg) was dissolved in acetonitrile (15 mL), and compound 1-12 (59.85 mg), potassium iodide (154 mg), and N,N-diisopropylethylamine (71.94 mg) were added at room temperature. The reaction mixture was stirred at 90°C for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-5%) to give compound 24-4. MS-ESI calculated value [M+H] + 607, actual value 607.

[0294] Step 5: Synthesis of compound 24-5 Compound 24-4 (89.5 mg) and compound 1-15 (60.0 mg, acetate salt) were dissolved in anhydrous methanol (6 mL) and anhydrous tetrahydrofuran (3 mL), and N,N-diisopropylethylamine (39.3 mg) and sodium borohydride acetate (161 mg) were added. The reaction mixture was stirred at 25 °C for 12 hours. Sodium borohydride acetate (161 mg) was then added to the reaction mixture, and the mixture was stirred for 5 hours. The reaction was quenched by adding 4% aqueous sodium bicarbonate solution (20 mL) and extracted with ethyl acetate (20 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 24-5, which was used directly in the next step. MS-ESI calculated value [M+H] + 925, actual measured value 925.

[0295] Step 6: Synthesis of the formate salt of compound 24 Compound 24-5 (120 mg) was dissolved in tetrahydrofuran (6 mL), and triethylamine trihydrofluoride (104.5 mg) was added to the reaction mixture. The mixture was stirred at room temperature for 14 h. After the reaction was completed, the supernatant was discarded, and the precipitated solid was concentrated under reduced pressure. The residue was separated by high-performance liquid chromatography (HPLC) (column type: Phenomenex Gemini-NX C18, length x inner diameter: 75 mm x 30 mm, 3 μm). Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.225% formic acid). Gradient elution method: Acetonitrile was gradient eluted from 0% to 30% with an elution time of 7 min) to obtain the formate salt of compound 24. 1 H NMR(400MHz,DMSO-d6)δ:8.23(s,2H),8.16(d,J=12Hz,1H),7.87(s,1H),7.53~7.43(m,2 H),7.12~6.90(m,6H),6.46(d,J=12Hz,1H),5.34~5.29(m,1H),5.26~5.20(m,1H),4.75~4 .68(m,2H),4.03(s,2H),3.97~3.88(m,1H),3.77~3.70(m,1H),3.35~3.28(m,2H),3.08~ 2.85(m, 4H), 2.43~2.29(m, 5H), 2.24~1.91(m, 6H), 1.80~1.71(m, 1H), 1.53~1.30(m, 4H). MS-ESI calculated value [M+H] + 811, actual measured value 811.

[0296] The synthesis of the formate salt of compound 25 was carried out in four reaction steps using compound 24-2B as the starting material, following the synthesis route for the formate salt of compound 24.

[0297] Formate salt of compound 25: 1H NMR(400MHz,DMSO-d6)δ:8.18(s,2H),8.14(d,J=8Hz,1H),7.81(s,1H),7.51~7.44(m,2H) ),7.11~6.90(m,6H),6.44(d,J=8Hz,1H),5.33~5.28(m,1H),5.19~5.13(m,1H),4.74~4. 66(m,2H),3.94(s,2H),3.93~3.88(m,1H),3.76~3.70(m,1H),3.35~3.26(m,2H),3.00~2 .83(m,4H),2.38~2.26(m,5H),2.21~1.94(m,6H),1.77~1.71(m,1H),1.50~1.28(m,4H). MS-ESI calculated value [M+H] + 811, actual measured value 811.

[0298] (Examples 26 and 27) [ka] Synthetic Route: [ka]

[0299] Step 1: Synthesis of compound 26-1 Compound 5-2 (3 g) and compound 3-1-1 (2.98 g) were dissolved in anhydrous toluene (30 mL), and then 4- J Methylaminopyridine (2.62 g) was added. The reaction mixture was stirred at 120° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate=1:0 to 5:1) to obtain compound 26-1. 1H NMR(400MHz,CDCl3)δ ppm:8.11~8.10(m,1H),7.89~7.83(m,1H),7.23~7.20(m,1H),5.23~5.17(m,1H),3.8 3~3.77(m,2H),3.33~3.26(m,2H),2.02~1.98(m,2H),1.84~1.77(m,2H),1.48(s,9H).

[0300] Step 2: Synthesis of compound 26-2 Compound 2-bromo-5-phenylthiophene (986 mg) was dissolved in anhydrous tetrahydrofuran (30 mL) and n-butyllithium solution (2.5 M, 1.65 mL) was slowly added dropwise at -78 °C, followed by stirring at this temperature for 30 min. Compound 26-1 (1 g) was dissolved in anhydrous tetrahydrofuran (30 mL) and added dropwise to the reaction solution at -50 °C. The mixture was stirred for 1 h. The reaction was quenched by adding saturated aqueous ammonium chloride solution (20 mL) to the reaction solution at -50 °C, diluted with water (10 mL), and extracted with ethyl acetate (30 mL × 3). The combined organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 4:1) to obtain compound 26-2. 1 H NMR(400MHz,CDCl3)δ ppm:7.59~7.57(m,2H),7.39~7.32(m,2H),7.31~7.29(m,2H),7.25~7.24(m,1H),7.23~7.19(m,1H),7.17~7.13(m,1H),7 .02~6.99(m,1H),5.19~5.13(m,1H),4.78(s,1H),3.49~3.35(m,4H),1.91~1.85(m,2H),1.76~1.69(m,2H),1.46(s,9H). MS-ESI calculated value [M+H-18] + 482, actual value 481.9.

[0301] Step 3: Preparation of Compounds 26-2a and 26-2b Compound 26-2 (520 mg) was separated and purified by chiral liquid chromatography to give Compound 26-2a and Compound 26-2b.

[0302] SFC separation method: Column (DAICEL CHIRALCEL IC (250 mm × 30 mm, 10 μm)), mobile phase: A: carbon dioxide, B: 40% to 40% ethanol (containing 0.1% ammonium hydroxide), flow rate: 70 mL / min, column temperature: 40°C.

[0303] Retention time of compound 26-2a: 1.240 min, calculated value by MS-ESI [M+H] + 482, actual value 481.9.

[0304] Retention time of compound 26-2b: 1.501 min, calculated value by MS-ESI [M+H] + 482, actual value 481.9.

[0305] Step 4: Preparation of compound 26-3 Compound 26-2a (210 mg) was dissolved in anhydrous dioxane (2 mL), and then a hydrochloric acid / dioxane solution (5.7 mL, 4 M) was added. The reaction mixture was stirred at 25° C. for 3 hours. The pH of the reaction mixture was adjusted to about 8 with saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate (30 mL×3). The organic phases were combined, washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, compound 26-3. MS-ESI calculated value [M+H] + 400, actual measured value 400.

[0306] Step 5: Preparation of compound 26-4 Compound 26-3 (160 mg) was dissolved in acetonitrile (4 mL), and compound 1-12 (129.4 mg), N,N-diisopropylethylamine (155.2 mg), and potassium iodide (264 mg) were added at room temperature. The reaction mixture was stirred at 90°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0 to 20:1) to obtain compound 26-4. MS-ESI calculated value [M+H] + 627, actual value 627.1.

[0307] Step 6: Preparation of compound 26-5 Compound 26-4 (210 mg) and compound 1-15 (112 mg, acetate salt) were dissolved in anhydrous methanol (4 mL) and anhydrous tetrahydrofuran (2 mL), and N,N-diisopropylethylamine (82.1 mg) and sodium borohydride acetate (129 mg) were added. The reaction mixture was stirred at 25 °C for 24 hours. Sodium borohydride acetate (129 mg) was then added to the reaction mixture, and the mixture was stirred for 24 hours. Sodium borohydride acetate (129 mg) was then added to the reaction mixture, and the mixture was stirred for 24 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with water (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 26-5 as a crude product. MS-ESI calculated value [M+H] + 946, actual value 946.3.

[0308] Step 7: Preparation of the trifluoroacetate salt of compound 26 Compound 26-5 (249 mg) was dissolved in anhydrous tetrahydrofuran (2 mL), and triethylamine trihydrofluoride (300 mg) was added to the reaction mixture. The mixture was stirred at room temperature for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was separated by high-performance liquid chromatography (HPLC) using a Welch Xtimate C18 column (length x inner diameter: 100 mm x 40 mm, 3 μm). The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. The mobile phase was acetonitrile / water (containing 0.075% trifluoroacetic acid). Gradient elution was performed using a gradient elution method from 24% to 54% acetonitrile over an 8-minute period. Compound 26 (trifluoroacetate salt) was obtained. 1H NMR(400MHz,DMSO-d6)δ ppm:10.54~10.49(m,2H),10.30~10.17(m,1H),9.38(s,1H),9.17(m,1H),8.18~8.16(m,1H),8.10(s,1H), 7.62~7.60(m,2H),7.49(s,1H),7.41~7.36(m,5H),7.16~7.13(m,3H),7.00~6.98(m,2H),6.54~6.51(m,1H) ,6.25(s,1H),5.47~5.44(m,1H),5.15~4.98(m,1H),4.78(s,2H),4.37(s,2H),3.53(s,3H),3.18(s,2H),3 .11~3.08(m,5H),2.54(s,2H),2.33(s,2H),2.23~2.20(m,2H),2.11(s,1H),1.97(s,1H)1.87~1.81(m,1H). MS-ESI calculated value [M+H] + 831, actual value 831.

[0309] The synthesis of the trifluoroacetate salt of compound 27 was carried out in four reaction steps using compound 26-2b as the starting material, following the synthesis route for the trifluoroacetate salt of compound 26.

[0310] Trifluoroacetate salt of compound 27: 1 H NMR(400MHz,DMSO-d6)δ ppm:10.51(s,2H),9.75~9.62(m,1H),9.14(s,2H),8.14~8.09(m,2H),7.63~7.61(m,2H),7.50~7.48 (m,2H),7.43~7.37(m,3H),7.33~7.30(m,1H),7.18~7.08(m,3H),6.99~6.97(m,2H),6.56~6.53(m,1H) ),6.25(s,1H),5.42~5.40(m,1H),5.16~4.99(m,1H),4.78(s,2H),4.38(s,2H),3.36(s,3H),3.19~3. 08(m,7H),2.82(s,1H),2.33~2.20(m,3H),2.25~2.21(m,2H),2.15(s,1H),1.98(m,2H),1.78(s,1H). MS-ESI calculated value [M+H] + 831, actual value 831.

[0311] (Examples 28 and 29) [ka] Synthetic Route: [ka]

[0312] Step 1: Synthesis of compound 28-1 Compound 1-2 (3 g) was dissolved in anhydrous dichloromethane (20 mL), and then N-chlorosuccinimide (2.84 g) was added. The reaction mixture was then heated to 60°C and reacted for 18 hours with stirring. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. The residue was purified by high-performance liquid chromatography to obtain Compound 28-1 and Compound 7-2. MS-ESI calculated value [M+H-18] + 271, actual value 270.2.

[0313] Step 2: Synthesis of compound 28-2 Compound 28-1 (630 mg) and compound 5-4 (500 mg) were dissolved in anhydrous xylene (6 mL), and then sodium hydride (87.2 mg, purity 60%) was added. The reaction mixture was stirred at 120 °C for 4 hours. The reaction mixture was cooled to 0 °C, and saturated aqueous ammonium chloride solution (20 mL) was added to the reaction mixture to quench the reaction. The mixture was then extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:ethyl acetate = 1:0 to 5:1) to obtain compound 28-2. MS-ESI calculated value [M+H-18] + 468, actual value 467.9.

[0314] Step 3: Preparation of Compounds 28-2a and 28-2b Compound 28-2 (453 mg) was separated and purified by chiral liquid chromatography to give Compound 28-2a and Compound 28-2b.

[0315] SFC separation method: column (DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm)), mobile phase: A: carbon dioxide, B: 50% to 50% ethanol (containing 0.1% ammonium hydroxide), flow rate: 70 mL / min, column temperature: 40°C.

[0316] Retention time of compound 28-2a: 1.803 min, calculated value by MS-ESI [M+H-18] + 468, actual value 468.

[0317] Retention time of compound 28-2b: 1.345 min, calculated value by MS-ESI [M+H-18] + 468, actual value 467.9.

[0318] Step 4: Synthesis of compound 28-3 Compound 28-2a (130 mg) was dissolved in anhydrous dioxane (3 mL), and then a solution of hydrochloric acid in dioxane (4 mL, 4 M) was added. The reaction mixture was stirred at 25 °C for 4 hours. The pH of the reaction mixture was adjusted to about 8 with saturated aqueous sodium carbonate solution, and the mixture was extracted with ethyl acetate (20 mL × 3). The organic phases were combined, washed with saturated aqueous sodium chloride (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product, compound 28-3. MS-ESI calculated value [M+H] + 386, actual value 385.8.

[0319] Step 5: Synthesis of compound 28-4 Compound 28-3 (90 mg) was dissolved in acetonitrile (5 mL), and compound 1-12 (75.4 mg), N,N-diisopropylethylamine (120.4 mg), and potassium iodide (154.8 mg) were added at room temperature. The reaction mixture was stirred at 90°C for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane:methanol = 1:0 to 20:1) to obtain compound 28-4. MS-ESI calculated value [M+H] + 613, actual value 613.

[0320] Step 6: Synthesis of compound 28-5 Compound 28-4 (110 mg) and compound 1-15 (60 mg, acetate salt) were dissolved in anhydrous methanol (3 mL) and anhydrous tetrahydrofuran (1.5 mL), and N,N-diisopropylethylamine (2.7 mg) and sodium borohydride acetate (114.1 mg) were added. The reaction mixture was stirred at 25 °C for 24 hours. Sodium borohydride acetate (114.1 mg) was then added to the reaction mixture, and the mixture was stirred for 24 hours. Sodium borohydride acetate (114.1 mg) was then added to the reaction mixture, and the mixture was stirred for 24 hours. The reaction was quenched by adding saturated aqueous sodium bicarbonate (30 mL) and extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give the crude product, compound 28-5. MS-ESI calculated value [M+H] + 931, actual value 931.4.

[0321] Step 7: Synthesis of the trifluoroacetate salt of compound 28 Compound 28-5 (120 mg) was dissolved in anhydrous tetrahydrofuran (2 mL), and triethylamine trihydrofluoride (120.4 mg) was added to the reaction mixture. The mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure, and the residue was separated by high-performance liquid chromatography (HPLC) using a Welch Xtimate C18 column (length x inner diameter: 100 mm x 40 mm, 3 μm). The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. The mobile phase was acetonitrile / water (containing 0.075% trifluoroacetic acid). Gradient elution was performed using a gradient elution method from 22% to 52% acetonitrile over an 8-minute period. The trifluoroacetate salt of compound 28 was obtained. 1 H NMR(400MHz,DMSO-d6)δ ppm:10.51(s,2H),9.60(s,1H),9.14(s,2H),8.14~8.07(m,2H),7.51~7.50(m,2H),7.17~ 7.08(m,2H),7.00~6.97(m,3H),6.93~6.92(m,1H),6.55~6.52(m,1H),6.25(s,1H),5.42~ 5.40(m,1H),4.78~4.77(m,3H),4.38(s,2H),3.38~3.36(m,3H),3.18~3.09(m,5H),2.72~ 2.67(m,3H),2.33~2.21(m,5H),2.07~1.94(m,4H),1.68~1.57(m,2H),1.49~1.46(m,2H). MS-ESI calculated value [M+H] + 817, actual value 817.3.

[0322] The synthesis of the trifluoroacetate salt of compound 29 was carried out in four reaction steps using compound 28-2b as the starting material, following the synthesis route for the trifluoroacetate salt of compound 28.

[0323] Trifluoroacetate salt of compound 29: 1H NMR(400MHz,DMSO-d6)δ ppm:10.53~10.50(m,2H),9.56(s,1H),9.15(s,2H),8.15~8.08(m,2H),7.52~7.50(m, 2H),7.17~7.09(m,1H),7.08~7.07(m,1H),7.00~6.98(m,3H),6.97~6.92(m,1H),6.55~ 6.52(m,1H),6.26(s,1H),5.43~5.40(m,1H),4.81~4.77(m,3H),4.38(s,2H),3.19~3. 08(m,6H),2.72~2.71(m,3H),2.33~2.22(m,5H),2.01~1.97(m,5H),1.68~1.44(m,5H). MS-ESI calculated value [M+H] + 817, actual value 817.4.

[0324] Example 30 [ka] Synthetic Route: [ka]

[0325] Step 1: Synthesis of compound 30-1 Compound 3-2 (100 mg) was dissolved in acetonitrile (10 mL), and diisopropylethylamine (119.88 mg), potassium iodide (128.31 mg), and compound 1-12 (99.98 mg) were added. The reaction mixture was heated to 90 °C and stirred for 16 hours. After completion of the reaction, the reaction mixture was poured into 30 mL of water, extracted with dichloromethane (50 mL × 2), and the layers were separated. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 30-1 was obtained by separation and purification using a preparative silica gel thin-layer chromatography plate (eluent: methanol:dichloromethane = 1:20). MS-ESI calculated value [M+H] + 551, actual value 551.2.

[0326] Step 2: Synthesis of compound 30-2 Compound 30-1 (79 mg) was dissolved in a mixture of acetonitrile (10 mL), iodomethane (101.81 mg) was added, and the reaction mixture was heated to 40° C. and stirred for 16 hours. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure to obtain compound 30-2 as a crude product. MS-ESI calculated value [M-127+H] + 565, actual value 565.2.

[0327] Step 3: Synthesis of compound 30-3 Compound 30-2 (99 mg) and compound 1-15 (47.81 mg) were dissolved in methanol (5 mL) and tetrahydrofuran (4 mL). Sodium triacetylborohydride (151.47 mg) was added, and the reaction mixture was stirred at 25° C. for 16 hours. Sodium triacetylborohydride (151.47 mg) was added again, and the reaction mixture was stirred at 25° C. for 72 hours. The reaction mixture was concentrated to dryness to give compound 30-3 as a crude product. MS-ESI calculated value [M-127+H] + 883, actual value 883.4.

[0328] Step 4: Synthesis of compound 30-4 Compound 30-3 (144 mg) was dissolved in tetrahydrofuran (5 mL), triethylamine trihydrofluoride (229.59 mg) was added, and the reaction mixture was stirred at 25 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure and purified by high-performance liquid chromatography (trifluoroacetic acid method: preparative column type: Welch Xtimate C18, length x inner diameter: 100 mm x 40 mm, 3 μm. Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.075% trifluoroacetic acid). Gradient elution method: acetonitrile was gradient eluted from 15% to 45%, elution time: 9 min) to obtain compound 30-4. MS-ESI calculated value [M-114+H] + 769, actual value 769.1.

[0329] Step 5: Synthesis of the hydrobromide salt of compound 30 Compound 30-4 (14.5 mg) was dissolved in water (1 mL), and an aqueous solution of hydrobromic acid (16.61 mg, purity 40%) was added. The reaction mixture was stirred for 30 minutes at 25° C. After completion of the reaction, the reaction mixture was directly lyophilized to obtain the hydrobromide salt of compound 30. 1 H NMR(400MHz,DMSO-d6)δ:10.51(s,2H),9.39~9.01(m,2H),8.20~8.00(m,2H),7.81~7.46(m,2H),7.39(s,1 H),7.20~7.10(m,3H),7.05~6.95(m,3H),6.59~6.48(m,1H),6.25(s,1H),5.50~5.30(m,1H),5.15~5.00(m, 1H),4.90~4.75(m,2H),4.45~4.30(m,2H),3.47~3.43(m,2H),3.41~3.37(m,2H),3.32~3.26(m,2H),3.22~3 .15(m,2H),3.12~3.07(m,2H),3.06~3.00(m,3H),2.43~2.31(m,4H),2.28~2.16(m,4H),2.02~1.88(m,2H). MS-ESI calculated value [M-79+H] + 769, actual value 769.2.

[0330] Example 31 [ka] Synthetic Route: [ka]

[0331] Step 1: Synthesis of compound 31-2 Compound 31-1 (1.07 g) was dissolved in dichloromethane (10 mL), and sodium carbonate (2.59 g) and di-t-butyl dicarbonate (2.13 g) were added. The reaction mixture was stirred at 20°C for 12 hours. After completion of the reaction, the reaction mixture was poured into 50 mL of water and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The aqueous phase was extracted with a dichloromethane / isopropanol mixed solvent (25 mL x 4, v:v = 3:1). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. 20 mL of toluene was added, and the mixture was again concentrated to dryness under reduced pressure. The residues were combined to give compound 31-2. 1 H NMR (400MHz, CDCl3)δ:3.90~3.80(m,2H),3.48(s,2H),3.25~3.15(m,2H),1.95~1.70(m,2H),1.65~1.55(m,2H),1.54~1.48(m,2H),1.47(s,9H).

[0332] Step 2: Synthesis of compound 31-3 Compound 31-2 (250 mg) and compound 2-1-2 (274.9 mg) were dissolved in toluene (5 mL), Hydrogenation Sodium (21.62 mg, purity 60%) was added. The reaction mixture was heated to 120°C and stirred for 2 hours. After completion of the reaction, the reaction mixture was cooled to room temperature and poured into 100 mL of cold saturated aqueous ammonium chloride solution to quench the reaction, followed by extraction with ethyl acetate (50 mL × 2). The combined organic phases were washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 31-3 was isolated and purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0-40%) to obtain compound 31-3. MS-ESI calculated value [M-100+H] + 354, actual value 353.8.

[0333] Step 3: Synthesis of compound 31-4 Compound 31-3 (260 mg) was dissolved in dioxane (2 mL). Hydrogen chloride / dioxane solution (4 M, 7.17 mL) was added, and the reaction mixture was stirred at 25 °C for 2 hours. After the reaction was completed, saturated sodium carbonate solution was added to adjust the pH to 11-12, and the mixture was extracted with ethyl acetate (100 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to obtain compound 31-4. MS-ESI calculated value [M+H] + 354, actual value 353.8.

[0334] Step 4: Synthesis of compound 31-5 Compound 31-4 (85.48 mg) was dissolved in acetonitrile (10 mL), and diisopropylethylamine (93.76 mg), potassium iodide (120.43 mg), and compound 1-12 (77.96 mg) were added. The reaction mixture was heated to 90 °C and stirred for 16 hours. After completion of the reaction, the reaction mixture was poured into 50 mL of water, extracted with dichloromethane (50 mL × 2), and the layers were separated. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 31-5 was obtained by separation and purification using a preparative silica gel thin-layer chromatography plate (eluent: methanol:dichloromethane = 1:10). MS-ESI calculated value [M+H] + 581, actual value 580.9.

[0335] Step 5: Synthesis of compound 31-6 Compound 31-5 (81 mg) and compound 1-15 (46.65 mg) were dissolved in methanol (5 mL) and tetrahydrofuran (4 mL). Sodium triacetylborohydride (147.81 mg) was added, and the reaction mixture was stirred at 25 °C for 16 hours. The reaction mixture was poured into 50 mL of water and extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 31-6 was obtained by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-10%). MS-ESI calculated value [M+H]+ 899, actual value 899.2.

[0336] Step 6: Synthesis of the formate salt of compound 31 Compound 31-6 (60 mg) was dissolved in tetrahydrofuran (3 mL), triethylamine trihydrofluoride (53.78 mg) was added, and the reaction mixture was stirred at 25 °C for 16 h. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure and purified by high-performance liquid chromatography (formic acid method: preparative column type: Phenomenex Gemini-NX C18, length x inner diameter: 75 mm x 30 mm, 3 μm. Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.225% formic acid). Gradient elution method: acetonitrile was gradient eluted from 0% to 30%, elution time: 7 min). Compound 31 formate salt was obtained. 1 H NMR(400MHz,DMSO-d6)δ:10.36(s,1H),8.20(s,2H),8.14(d,J=10.0Hz,1H),7.82(s,1H),7.46(d,J=4.8Hz, 2H),7.13(d,J=3.2Hz,2H),7.08(d,J=8.0Hz,1H),6.97(t,J=4.4Hz,2H),6.92(d,J=8.0Hz,1H),6.44(d,J=10 .0Hz,1H),5.17(t,J=6.0Hz,1H),4.71(t,J=6.4Hz,2H),3.99~3.91(m,6H),3.30(t,J=6.8Hz,2H),2.95(t,J =7.2Hz,2H),2.90~2.84(m,2H),2.41~2.28(m,4H),2.21~2.12(m,2H),2.08~1.98(m,2H),1.51~1.33(m,4H). MS-ESI calculated value [M+H] + 785, actual value 785.4.

[0337] Example 32 [ka] Synthetic Route: [ka]

[0338] Step 1: Synthesis of compound 32-1 The compound 2-bromo-5-methylthiophene (2.0 g) was dissolved in tetrahydrofuran (30 mL), and isopropylmagnesium chloride-lithium chloride (1.3 M tetrahydrofuran solution, 9.6 mL) was slowly added dropwise under nitrogen protection at 0°C. The reaction mixture was reacted for 3 hours with stirring at 20°C. The reaction mixture was cooled to -78°C, and diethyl oxalate (1.82 g) was dissolved in tetrahydrofuran (4 mL) and slowly added dropwise to the reaction mixture at -78°C. After the addition was completed, the mixture was stirred at -78°C for 1 hour. The reaction mixture was warmed to 0°C, quenched with saturated aqueous ammonium chloride (100 mL), extracted with ethyl acetate (50 mL × 2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0-10%). After concentration, excess diethyl oxalate was removed by distillation using an oil pump in a 70°C water bath to obtain compound 32-1. 1 H NMR (400MHz, CDCl3) δ:7.97~7.95(m,1H),6.90~6.86(m,1H),4.42(q,J=8.0Hz,2H),2.59(s,3H),1.43(t,J=8.0Hz,3H).

[0339] Step 2: Synthesis of compound 32-2 Compound 32-1 (0.2 g) and compound 5-4 (462 mg) were dissolved in xylene (5 mL), and 4-dimethylaminopyridine (184 mg) was added at room temperature. The reaction mixture was then heated to 140°C and reacted for 14 hours with stirring. After completion of the reaction, the mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0 to 25%) to obtain compound 32-2. MS-ESI calculated value [M+Na] + 404, actual value 403.9.

[0340] Step 3: Synthesis of compound 32-3 Compound 2-bromo-5-methylthiophene (169 mg) was dissolved in tetrahydrofuran (10 mL) and n-butyllithium solution (2.5 M tetrahydrofuran solution, 0.41 mL) was slowly added dropwise under nitrogen protection at -60 °C. The reaction mixture was stirred at -60 °C for 30 minutes. Compound 32-2 (280 mg) was dissolved in tetrahydrofuran (4 mL) and slowly added dropwise to the reaction mixture at -60 °C. After the addition was completed, the mixture was stirred at -50 °C for 2 hours. The reaction mixture was warmed to 0 °C, quenched with saturated aqueous ammonium chloride (20 mL), extracted with ethyl acetate (30 mL × 2), washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0-25%) to give compound 32-3. MS-ESI calculated value [M+H-18] + 462, actual value 462.

[0341] Step 4: Synthesis of compound 32-4 Compound 32-3 (70.0 mg) was dissolved in tetrahydrofuran (5 mL), and then aqueous hydrochloric acid (5 mL, 4 M) was added. The reaction mixture was stirred at room temperature for 14 hours. The pH of the reaction mixture was adjusted to about 9 with saturated aqueous sodium carbonate, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure to give compound 32-4, which was used directly in the next step. MS-ESI calculated value [M+H] + 380, actual measured value 380.

[0342] Step 5: Synthesis of compound 32-5 Compound 32-4 (45.8 mg) was dissolved in acetonitrile (20 mL), and compound 1-12 (39 mg), potassium iodide (100 mg), and N,N-diisopropylethylamine (46.7 mg) were added at room temperature. The reaction mixture was stirred at 90°C for 14 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-5%) to give compound 32-5. MS-ESI calculated value [M+H] + 607, actual value 607.

[0343] Step 6: Synthesis of compound 32-6 Compound 32-5 (36.9 mg) and compound 1-15 (24.0 mg, acetate salt) were dissolved in anhydrous methanol (4 mL) and anhydrous tetrahydrofuran (2 mL), and sodium borohydride acetate (64.5 mg) and diisopropylethylamine (15.7 mg) were added. The reaction mixture was stirred at 25 °C for 12 hours. Sodium borohydride acetate (64.5 mg) was then added to the reaction mixture, and the mixture was stirred for 5 hours. The reaction was quenched by adding 4% aqueous sodium bicarbonate (5 mL) and extracted with ethyl acetate (10 mL × 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 32-6, which was used directly in the next step. MS-ESI calculated value [M+H] + 925, actual measured value 925.

[0344] Step 7: Synthesis of the formate salt of compound 32 Compound 32-6 (52 mg) was dissolved in tetrahydrofuran (4 mL), triethylamine trihydrofluoride (45.3 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 14 h. After the reaction was completed, the supernatant was discarded, and the precipitated solid was concentrated under reduced pressure. The residue was separated by high-performance liquid chromatography (HPLC) (column type: Phenomenex Gemini-NX C18, length x inner diameter: 75 mm x 30 mm, 3 μm). Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.225% formic acid). Gradient elution method: acetonitrile was gradient eluted from 0% to 30% with an elution time of 7 min) to obtain the formate salt of compound 32. 1 H NMR(400MHz,DMSO-d6)δ:8.19(s,1H),8.15~8.10(m,1H),7.73(s,1H),7.08~7.04(m,1H),6.97( s,1H),6.92~6.88(m,1H),6.82~6.79(m,2H),6.64~6.60(m,2H),6.43~6.37(m,1H),5.10~5.05( m,1H),4.72~4.61(m,3H),3.83(s,2H),2.95~2.89(m,2H),2.82~2.63(m,4H),2.42~2.35(m,9H) ,2.18~2.12(m,5H),2.01~1.95(m,2H),1.93~1.86(m,2H),1.68~1.62(m,2H),1.87~1.29(m,4H). MS-ESI calculated value [M+H] + 811, actual measured value 811.

[0345] Example 33 [ka] Synthetic Route: [ka]

[0346] Step 1: Synthesis of compound 33-2 Compound 33-1 (2.50 g) was dissolved in anhydrous t-butanol (5 mL), and triethylamine (3.05 g) was added at room temperature. The reaction mixture was then heated to 90°C. Diphenylphosphoryl azide (4.14 g) was then added in several portions to the stirred reaction mixture. The reaction mixture was stirred at 90°C for 14 hours. After the reaction was completed, the mixture was filtered while still hot and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0-10%) to obtain compound 33-2. 1 H NMR (400MHz, CDCl3) δ:7.48(s,1H),6.83~6.77(m,1H),6.59~6.55(m,1H),6.44~6.42(m,1H),5.94(s,2H),1.52(s,9H).

[0347] Step 2: Synthesis of compound 33-3 Compound 33-2 (250 mg) was dissolved in ethanol (10 mL), followed by the addition of sodium iodide (315 mg) and [bis(trifluoroacetoxy)iodo]benzene (679 mg). The reaction mixture was stirred at 50 °C for 14 hours in an air atmosphere. The reaction was quenched with saturated aqueous sodium thiosulfate (15 mL) and extracted with ethyl acetate (20 mL × 2). The combined organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-10%) to give compound 33-3. MS-ESI calculated value [M+H-56] + 308, actual value 307.8.

[0348] Step 3: Synthesis of compound 33-4 Acetic anhydride (8 mL) was placed in a reaction flask, and concentrated nitric acid (200 mg, 65% concentration) was slowly added at -78 °C. Next, compound 33-3 (500 mg) was dissolved in acetic anhydride (5 mL) and slowly added dropwise to the reaction flask at -78 °C. After the addition was complete, the reaction mixture was warmed to 0 °C and stirred for 1 h. The reaction mixture was slowly poured into stirring ice water (100 mL) and stirred for 10 min. After filtration, the solid was dissolved in ethyl acetate (50 mL), washed twice with water (50 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-30%) to give compound 33-4. 1 H NMR (400MHz, DMSO-d6) δ: 9.23 (s, 1H), 7.84 (s, 1H), 6.29 (s, 2H), 1.38 (s, 9H).

[0349] Step 4: Synthesis of compound 33-5 Compound 33-4 (0.2 g) was dissolved in N,N-dimethylformamide (4 mL), followed by the addition of tris(dibenzylideneacetone)dipalladium (44.8 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (23.3 mg), and zinc cyanide (115 mg). The reaction mixture was stirred at 100 °C for 14 hours under a nitrogen atmosphere. Water (10 mL) and ethyl acetate (15 mL) were added to the reaction mixture, which was then filtered. The filtrate was extracted with ethyl acetate (15 mL x 2). The organic phase was washed with saturated brine (30 mL x 3). The combined organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-50%) to give compound 33-5. 1 H NMR (400MHz, DMSO-d6) δ: 8.21 (s, 1H), 7.55 (s, 2H), 6.34 (s, 2H).

[0350] Step 5: Synthesis of compound 33-6 A mixture of copper chloride (90.8 mg) and acetonitrile (5 mL) was heated to 60 °C, and t-butyl nitrite (87.1 mg) was added in one portion. Compound 33-5 (70 mg) was dissolved in acetonitrile (5 mL) and added to the reaction mixture in several portions. The reaction mixture was stirred at 60 °C for 30 minutes. After the reaction was completed, the reaction mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (15 mL × 2). The organic phase was washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate / petroleum ether = 0-30%) to obtain compound 33-6. 1 H NMR (400MHz, DMSO-d6) δ: 8.31 (s, 1H), 6.51 (s, 2H).

[0351] Step 6: Synthesis of compound 33-7 Compound 33-6 (760 mg) was dissolved in tetrahydrofuran (15 mL), triethylamine (1.02 g) and 3-aminopropanol (756 mg) were added, and the reaction mixture was heated to 60 °C and stirred for 14 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with ethyl acetate (35 mL × 2). The organic phase was washed with saturated brine (50 mL × 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 0-5%) to give compound 33-7. MS-ESI calculated value [M+H] + 266, actual value 266.

[0352] Step 7: Synthesis of compound 33-8 Compound 33-7 (330 mg) was dissolved in ethanol (10 mL), and palladium / carbon (300 mg, 10% purity) was added. The reaction mixture was stirred under hydrogen (15 psi) at room temperature for 14 hours. After completion of the reaction, the reaction mixture was filtered, the filter cake was washed with ethanol, and the filtrate was collected and concentrated under reduced pressure to give compound 33-8, which was used directly in the next step. MS-ESI calculated value [M+H]+ 236, actual value 235.9.

[0353] Step 8: Synthesis of compound 33-9 Compound 33-8 (260 mg) was dissolved in aqueous hydrochloric acid (6 M, 10 mL), and a solution of sodium nitrite (114 mg) in water (4 mL) was added dropwise at 0 °C. The reaction mixture was stirred at 15 °C for 2 h. After completion of the reaction, the mixture was partitioned between dichloromethane (20 mL) and water (15 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give compound 33-9, which was used directly in the next step. MS-ESI calculated value [M+H] + 247, actual value 246.8.

[0354] Step 9: Synthesis of compound 33-10 Compound 33-9 (250 mg) was dissolved in formic acid (20 mL, 75% purity) and nickel-aluminum alloy (434 mg) was added. The reaction mixture was heated to 90 °C and stirred for 14 h. The reaction mixture was filtered, the filtrate was collected, and concentrated to dryness under reduced pressure. Ethanol (8 mL) and aqueous sodium hydroxide solution (4 M, 8 mL) were added to the concentrate. The reaction mixture was stirred at 15 °C for 1 h. After completion of the reaction, the reaction mixture was extracted with dichloromethane (30 mL × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 0-5%) to obtain compound 33-10. MS-ESI calculated value [M+H] + 250, actual value 249.9.

[0355] Step 10: Synthesis of compound 33-11 Compound 31-10 (110 mg) was dissolved in dichloromethane (6 mL), and triethylamine (223 mg) and methanesulfonyl chloride (101 mg) were added. The reaction mixture was stirred at 15°C for 1 hour. After completion of the reaction, the reaction mixture was partitioned between dichloromethane (15 mL) and water (10 mL). The organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. The residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 0-5%) to obtain compound 33-11. MS-ESI calculated value [M+H] + 328, actual value 327.9.

[0356] Step 11: Synthesis of compound 33-12 Compound 33-11 (50 mg) was dissolved in acetonitrile (20 mL), and diisopropylethylamine (59.2 mg), potassium iodide (126 mg), and compound 1-13 (53.7 mg) were added. The reaction mixture was heated to 90°C and stirred for 14 hours. After the reaction was completed, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 0-5%) to obtain compound 33-12. MS-ESI calculated value [M+H] + 583, actual value 583.

[0357] Step 12: Synthesis of compound 33-13 Compound 1-15 (44 mg, acetate salt) and compound 33-12 (64.9 mg) were dissolved in methanol (4 mL) and tetrahydrofuran (2 mL). Diisopropylethylamine (28.8 mg) and sodium triacetylborohydride (118.2 mg) were added, and the reaction mixture was stirred at 20 °C for 12 hours. Sodium triacetylborohydride (118.2 mg) was added, and the reaction mixture was stirred at 20 °C for another 5 hours. 5% aqueous sodium bicarbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 2). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 33-13, which was used directly in the next step. MS-ESI calculated value [M+H] + 901, actual measured value 901.

[0358] Step 13: Synthesis of the formate salt of compound 33 Compound 33-13 (62 mg) was dissolved in tetrahydrofuran (4 mL), triethylamine trihydrofluoride (55.4 mg) was added, and the reaction mixture was stirred at 15 °C for 14 h. After the reaction was complete, the mixture was allowed to stand, the supernatant was discarded, and the solid was washed with 5 mL of tetrahydrofuran. The residue was then separated by high-performance liquid chromatography (column type: Phenomenex Gemini-NX C18, length x inner diameter: 75 mm x 30 mm, 3 μm). Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.225% formic acid). Gradient elution method: acetonitrile was gradient eluted from 0% to 30%, with an elution time of 7 min) to obtain the formate salt of compound 33. 1 H NMR(400MHz,DMSO-d6)δ:8.17(s,1H),8.15~8.10(m,1H),7.58(s,1H),7.48~7.44(m,2H),7.23 (s,1H),7.07~7.03(m,3H),6.99~6.95(m,2H),6.92~6.88(m,1H),6.45~6.40(m,1H),6.22~6.1 8(m,2H),5.10~5.04(m,1H),4.67~4.59(m,3H),3.85(s,2H),2.76~2.70(m,2H),2.42~2.32(m, 3H), 2.12(s, 3H), 2.06~2.01(m, 2H), 1.92~1.86(m, 2H), 1.66~1.60(m, 2H), 1.31~1.24(m, 4H). MS-ESI calculated value [M+H] + 787, actual value 787.2.

[0359] (Examples 34 and 35) [ka] Synthetic Route: [ka]

[0360] Step 1: Synthesis of compound 34-1 Compound 33-11 (31 mg) was dissolved in acetonitrile (10 mL), and diisopropylethylamine (36.7 mg), potassium iodide (78.6 mg), and compound 13-3 (34.6 mg) were added. The reaction mixture was heated to 90°C and stirred for 14 hours. After the reaction was completed, the reaction mixture was concentrated to dryness under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 0-5%) to obtain compound 34-1. MS-ESI calculated value [M+H] + 597, actual value 597.

[0361] Step 2: Synthesis of compound 34-2 Compound 1-15 (30 mg, acetate salt) and compound 34-1 (45.3 mg) were dissolved in methanol (4 mL) and tetrahydrofuran (2 mL). Diisopropylethylamine (19.6 mg) and sodium triacetylborohydride (80.5 mg) were added, and the reaction mixture was stirred at 20 °C for 12 hours. Sodium triacetylborohydride (80.5 mg) was added, and the reaction mixture was stirred at 20 °C for another 5 hours. 5% aqueous sodium bicarbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 2). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 34-2, which was used directly in the next step. MS-ESI calculated value [M+H] + 915, actual measured value 915.

[0362] Step 3: Synthesis of the formate salt of compound 34 Compound 34-2 (60 mg) was dissolved in tetrahydrofuran (4 mL), triethylamine trihydrofluoride (52.8 mg) was added, and the reaction mixture was stirred at 15 °C for 14 h. After the reaction was complete, the mixture was allowed to stand, the supernatant was discarded, and the solid was washed with 5 mL of tetrahydrofuran. The residue was separated by high-performance liquid chromatography (column type: Phenomenex Gemini-NX C18, length x inner diameter: 75 mm x 30 mm, 3 μm). Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.225% formic acid). Gradient elution method: acetonitrile was gradient eluted from 0% to 30%, with an elution time of 7 min) to obtain the formate salt of compound 34. 1 H NMR(400MHz,DMSO-d6)δ:8.18(s,1H),8.15~8.10(m,1H),7.57(s,1H),7.46~7.42(m,2H),7.07~7.04 (m,2H),6.98~6.94(m,1H),6.92~6.88(m,1H),6.83~6.80(m,1H),6.64~6.62(m,1H),6.45~6.40(m,1 H),6.22~6.19(m,2H),5.08~5.05(m,1H),4.66~4.60(m,3H),3.85(s,2H),2.76~2.68(m,2H),2.42~2 .33(m,6H),2.11(s,3H),2.06~2.00(m,2H),1.90~1.86(m,2H),1.66~1.61(m,2H),1.35~1.26(m,4H). MS-ESI calculated value [M+H] + 801, actual measured value 801.

[0363] The synthesis of the formate salt of compound 35 was carried out by a three-step reaction using compounds 33-11 and 14-1 as starting materials, following the synthesis route for the formate salt of compound 34.

[0364] Formate salt of compound 35: 1H NMR(400MHz,DMSO-d6)δ:8.17(s,1H),8.15~8.10(m,1H),7.58(s,1H),7.46~7.42(m,2H),7.07~7.04 (m,2H),6.98~6.94(m,1H),6.92~6.88(m,1H),6.83~6.80(m,1H),6.64~6.62(m,1H),6.45~6.40(m,1 H),6.22~6.19(m,2H),5.08~5.05(m,1H),4.66~4.60(m,3H),3.86(s,2H),2.76~2.68(m,2H),2.42~2 .33(m,6H),2.11(s,3H),2.06~2.00(m,2H),1.90~1.86(m,2H),1.66~1.61(m,2H),1.35~1.26(m,4H). MS-ESI calculated value [M+H] + 801, actual measured value 801.

[0365] (Examples 36 and 37) [ka] Synthetic Route: [ka] [ka]

[0366] Step 1: Synthesis of compound 36-2 Compound 36-1 (1 g) was dissolved in N,N-dimethylformamide (20 mL), and N-iodosuccinimide (7.22 g) was added at 0°C. The reaction mixture was stirred at 25°C for 1 hour. After the reaction was completed, 200 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2). The organic phases were combined, washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0 to 20%) to obtain compound 36-2. 1H NMR (400MHz, CHCl3-d)δ:7.37(d,J=8.4Hz,1H),6.38(d,J=8.0Hz,1H),5.15(d,J=2.0Hz,2H),5.00(t,J=2.0Hz,2H),3.55(s,2H).

[0367] Step 2: Synthesis of compound 36-3 Compound 36-2 (3.25 g) was dissolved in tetrahydrofuran (60 mL), and triethylamine (3.15 g) and di-t-butyl dicarbonate (4.75 g) were added. The reaction mixture was stirred at 70 °C for 2 hours. After completion of the reaction, the reaction mixture was poured into 500 mL of water and extracted with ethyl acetate (500 mL × 2). The combined organic phase was washed with saturated brine (500 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0-20%) to give compound 36-3. 1 H NMR (400MHz, DMSO-d6) δ:9.04(s,1H),7.54(d,J=8.4Hz,1H),7.25(d,J=8.4Hz,1H),5.11(s,2H),4.84(s,2H),1.45(s,9H).

[0368] Step 3: Synthesis of compound 36-4 Compound 36-3 (1 g) was dissolved in acetic anhydride (15 mL) and cooled to -78 °C. Concentrated nitric acid (402.60 mg, purity 65%) was added at this temperature. The reaction mixture was stirred at 0 °C for 2 hours. Ten parallel reactions were performed. After the reaction was completed, the reaction mixture was poured into 2000 mL of water and extracted with ethyl acetate (500 mL × 2). The combined organic phases were washed with saturated brine (500 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0-5%) to give compound 36-4. 1 H NMR (400MHz, DMSO-d6) δ: 9.46 (s, 1H), 8.15 (s, 1H), 5.18 (s, 2H), 4.95 (s, 2H), 1.40 (s, 9H).

[0369] Step 4: Synthesis of compound 36-5 Compound 36-4 (1.02 g) was dissolved in ethyl acetate (10 mL), and a hydrochloric acid / ethyl acetate solution (4 M, 31.39 mL) was added. The reaction mixture was stirred at 20 °C for 4 hours. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure. The pH of the residue was adjusted to 7 with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (100 mL × 2). The combined organic phase was washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 36-5, which was used directly in the next step. 1 H NMR (400MHz, DMSO-d6) δ: 8.23 ​​(s, 1H), 7.35 (s, 2H), 5.11 (t, J = 2.4 Hz, 2H), 4.89 (t, J = 2.8 Hz, 2H).

[0370] Step 5: Synthesis of compound 36-6 Compound 36-5 (1.12 g) was dissolved in N,N-dimethylformamide (25 mL) and, under nitrogen protection, tris(dibenzylideneacetone)dipalladium (167.85 mg), 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (174.77 mg), and zinc cyanide (516.60 mg) were added. The reaction mixture was heated to 80 °C under a nitrogen atmosphere and stirred for 16 h. After completion of the reaction, the mixture was cooled to room temperature, poured into 250 mL of water, and extracted with ethyl acetate (100 mL × 2). The combined organic phases were washed with saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash silica gel chromatography (eluent: ethyl acetate / petroleum ether = 0-50%) to give compound 36-6.

[0371] Step 6: Synthesis of compound 36-7 A mixture of cuprous chloride (897.78 mg) and acetonitrile (50 mL) was heated to 65 °C, and t-butyl nitrite (860.72 mg) was added in one portion, followed by compound 36-6 (685 mg) in several portions. The reaction mixture was stirred at 65 °C for 30 min. After completion of the reaction, the reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. Ethyl acetate (75 mL) and hydrochloric acid solution (6 M, 30 mL) were added to the residue, and the layers were separated. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give compound 36-7, which was used directly in the next step.

[0372] Step 7: Synthesis of compound 36-8 Compound 36-7 (750 mg) was dissolved in tetrahydrofuran (45 mL), triethylamine (844.75 mg) and 3-aminopropanol (752.43 mg) were added, and the reaction mixture was heated to 65 °C and stirred for 16 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, poured into 50 mL of water, and extracted with ethyl acetate (75 mL × 2). The organic phase was washed with saturated brine (100 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 36-8, which was used directly in the next step. MS-ESI calculated value [M+H] + 264, actual value 263.9.

[0373] Step 8: Synthesis of compound 36-9 Compound 36-8 (747 mg) was dissolved in ethanol (75 mL), and palladium / carbon (75 mg, purity 10%) was added. The reaction mixture was stirred under a hydrogen atmosphere (15 psi) at 25° C. for 16 hours. After the reaction was completed, the reaction mixture was filtered, and the filter cake was washed with 100 mL of ethanol. The filtrate was collected and concentrated to dryness under reduced pressure to give compound 36-9. MS-ESI calculated value [M+H] + 234, actual value 233.9.

[0374] Step 9: Synthesis of compound 36-10 Compound 36-9 (660 mg) was dispersed in a hydrochloric acid solution (6 M, 4.72 mL), and the mixture was cooled to 0 °C. A solution of sodium nitrite (292.84 mg) in water (6 mL) was slowly added dropwise at 0 °C. The reaction mixture was stirred at 0 to 25 °C for 1 hour. After completion of the reaction, the reaction mixture was partitioned between dichloromethane (500 mL) and water (50 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 36-10 was obtained by flash silica gel chromatography (eluent: methanol / dichloromethane = 0 to 5%). MS-ESI calculated value [M+H] + 245, actual value 244.9.

[0375] Step 10: Synthesis of compound 36-11 Compound 36-10 (645.00 mg) was dissolved in formic acid (40 mL, 75% purity) and nickel-aluminum alloy (1.13 g) was added. The reaction mixture was heated to 90 °C and stirred for 16 h. The reaction mixture was filtered, and the filtrate was collected, concentrated to dryness under reduced pressure, and dissolved in 30 mL of ethanol. An aqueous solution of sodium hydroxide (1 M, 13.22 mL) was added with stirring. The reaction mixture was stirred at 15 °C for 1 h. After completion of the reaction, most of the methanol was removed under reduced pressure and the mixture was extracted with ethyl acetate (250 mL × 2). The organic phase was concentrated to dryness under reduced pressure to give compound 36-11, which was used directly in the next step. MS-ESI calculated value [M+H] + 248, actual value 247.9.

[0376] Step 11: Synthesis of compound 36-12 Compound 36-11 (650 mg) was dissolved in dichloromethane (50 mL), and triethylamine (1.33 g) and methanesulfonyl chloride (619.48 mg) were added. The reaction mixture was stirred at 25°C for 30 minutes. After completion of the reaction, the reaction mixture was partitioned between dichloromethane (100 mL) and water (50 mL). The organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 36-12 was obtained by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-5%). MS-ESI calculated value [M+H] + 326, actual value 325.8.

[0377] Step 12: Synthesis of compound 36-13 Compound 13-3 (60 mg) was dissolved in acetonitrile (10 mL), and diisopropylethylamine (50.92 mg), potassium iodide (65.40 mg), and compound 36-12 (47.00 mg) were added. The reaction mixture was heated to 90 °C and stirred for 16 hours. After completion of the reaction, the reaction mixture was poured into 50 mL of water, extracted with dichloromethane (50 mL × 2), and the layers were separated. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 36-13 was obtained by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-5%). MS-ESI calculated value [M+H] + 595, actual value 595.1.

[0378] Step 13: Synthesis of compound 36-14 Compound 36-13 (50.5 mg) and compound 1-15 (28.40 mg, acetate salt) were dissolved in methanol (3 mL) and tetrahydrofuran (2 mL). Sodium triacetylborohydride (89.98 mg) was added, and the reaction mixture was stirred at 25°C for 16 hours. Sodium triacetylborohydride (89.98 mg) was further added, and the reaction mixture was stirred at 25°C for 24 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 36-14 was isolated and purified by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-5%) to give compound 36-14. MS-ESI calculated value [M+H] + 913, actual value 913.4.

[0379] Step 14: Synthesis of the formate salt of compound 36 Compound 36-14 (30 mg) was dissolved in tetrahydrofuran (5 mL), and triethylamine trihydrofluoride (26.48 mg) was added. The reaction mixture was stirred at 25 °C for 16 h. After the reaction was complete, the mixture was allowed to stand. The supernatant was discarded, and the solid was washed with 10 mL of tetrahydrofuran. The resulting mixture was purified by high-performance liquid chromatography (HPLC) (formic acid method: preparative column: Phenomenex C18, length x inner diameter: 150 mm x 40 mm, 5 μm. Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. Mobile phase: acetonitrile / water (containing formic acid). Gradient elution: acetonitrile was gradient eluted from 1% to 30%, with an elution time of 10 min). The formate salt of compound 36 was obtained by lyophilization. 1H NMR(400MHz,DMSO-d6)δ:10.32(s,1H),8.15(s,1H),8.11(d,J=10.0Hz,1H),7.88(s,1H),7.48~7.48(m,1H),7.13(s,1H), 7.07~7.01(m,2H),6.98~6.94(m,1H),6.89(d,J=8.4Hz,1H),6.81(d,J=3.6Hz,1H),6.63(d,J=2.4Hz,1H),6.39(d,J=10.0 Hz,1H),5.45(s,2H),5.13(s,2H),5.11~5.05(m,1H),4.64(s,1H),4.59(t,J=6.8Hz,2H),3.86(s,2H),2.84~2.68(m,2H), 2.54(s,1H),2.47~2.43(m,4H),2.37(s,3H),2.16(s,3H),2.04~1.95(m,2H),1.89(s,2H),1.66(s,2H),1.38~1.28(m,4H). MS-ESI calculated value [M+H] + 799, actual value 799.6.

[0380] The synthesis of the formate salt of compound 37 was carried out in a three-step reaction using compounds 36-12 and 14-1 as starting materials, following the synthesis route for the formate salt of compound 36.

[0381] Formate salt of compound 37: 1H NMR(400MHz,DMSO-d6)δ:10.31(s,1H),8.16(s,1H),8.11(d,J=10.0Hz,1H),7.87(s,1H),7.44(d,J=5.2Hz,1H),7.12(s,1H) ),7.06~6.99(m,2H),6.98~6.92(m,1H),6.89(d,J=8.0Hz,1H),6.81(d,J=3.2Hz,1H),6.63(d,J=2.8Hz,1H),6.39(d,J=10. 0Hz,1H),5.44(s,2H),5.13(s,2H),5.11~5.05(m,1H),4.64(s,1H),4.59(t,J=6.8Hz,2H),3.85(s,2H),2.84~2.67(m,2H), 2.54(s,1H),2.47~2.43(m,4H),2.37(s,3H),2.15(s,3H),2.03~1.96(m,2H),1.89(s,2H),1.66(s,2H),1.38~1.28(m,4H). MS-ESI calculated value [M+H] + 799, actual value 799.3.

[0382] (Examples 38 and 39) [ka] Synthetic Route: [ka]

[0383] Step 1: Synthesis of compound 38-1 Compound 1-9 (698 mg) was dissolved in toluene (25 mL), and trimethyl orthoformate (480.38 mg) and p-toluenesulfonic acid (77.95 mg) were added. The reaction mixture was stirred at 120°C for 16 hours. After the reaction was completed, the reaction mixture was concentrated to dryness under reduced pressure, and 50 mL of acetonitrile was added to dissolve the solid. The solid was filtered off. The organic phase was concentrated to dryness under reduced pressure and purified by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-5%) to obtain compound 38-1. MS-ESI calculated value [M+H] +242, actual value 241.9.

[0384] Step 2: Synthesis of compound 38-2 Compound 38-1 (304 mg) was dissolved in formic acid (50 mL, 75% purity) and nickel-aluminum alloy (539.71 mg) was added. The reaction mixture was heated to 90 °C and stirred for 16 h. The reaction mixture was filtered, and the filtrate was collected and concentrated to dryness under reduced pressure. The filtrate was dissolved in 30 mL of ethanol, and an aqueous solution of sodium hydroxide (1 M, 6.24 mL) was added with stirring. The reaction mixture was stirred at 15 °C for 1 h. After completion of the reaction, the reaction mixture was concentrated to dryness under reduced pressure, and 100 mL of methanol was added to dissolve the solid. The solid was filtered off. The organic phase was concentrated to dryness under reduced pressure and purified by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-5%) to obtain compound 38-2. MS-ESI calculated value [M+H] + 245, actual value 244.9.

[0385] Step 3: Synthesis of compound 38-3 Compound 38-2 (138 mg) was dissolved in dichloromethane (25 mL), and triethylamine (285.81 mg) and methanesulfonyl chloride (133.11 mg) were added. The reaction mixture was stirred at 25°C for 30 minutes. After completion of the reaction, the reaction mixture was partitioned between dichloromethane (50 mL) and water (50 mL). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 38-3 was obtained by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-5%). MS-ESI calculated value [M+H] + 323, actual value 322.9.

[0386] Step 4: Synthesis of compound 38-4 Compound 13-3 (60 mg) was dissolved in acetonitrile (10 mL), and diisopropylethylamine (50.92 mg), potassium iodide (65.40 mg), and compound 38-3 (46.57 mg) were added. The reaction mixture was heated to 90 °C and stirred for 16 hours. After completion of the reaction, the reaction mixture was poured into 50 mL of water, extracted with dichloromethane (50 mL × 2), and the layers were separated. The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 38-4 was isolated and purified by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-5%) to give compound 38-4. MS-ESI calculated value [M+Na] + 614, actual value 614.1.

[0387] Step 5: Synthesis of compound 38-5 Compound 38-4 (46.9 mg) and compound 1-15 (26.51 mg, acetate salt) were dissolved in methanol (3 mL) and tetrahydrofuran (2 mL). Sodium triacetylborohydride (83.98 mg) was added, and the reaction mixture was stirred at 25°C for 16 hours. Sodium triacetylborohydride (83.98 mg) was further added, and the reaction mixture was stirred at 25°C for 24 hours. 50 mL of water was added to the reaction mixture, and the mixture was extracted with dichloromethane (50 mL × 2). The organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. Compound 38-5 was obtained by flash silica gel chromatography (eluent: methanol / dichloromethane = 0-5%). MS-ESI calculated value [M+H] + 910, actual value 910.5.

[0388] Step 6: Synthesis of the formate salt of compound 38 Compound 38-5 (33.5 mg) was dissolved in tetrahydrofuran (5 mL), and triethylamine trihydrofluoride (29.66 mg) was added. The reaction mixture was stirred at 25 °C for 16 h. After the reaction was complete, the mixture was allowed to stand. The supernatant was discarded, and the solid was washed with 10 mL of tetrahydrofuran. The resulting mixture was purified by high-performance liquid chromatography (HPLC) (formic acid method: preparative column: Phenomenex C18, length x inner diameter: 150 mm x 40 mm, 5 μm. Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. Mobile phase: acetonitrile / water (containing formic acid). Gradient elution: acetonitrile was gradient eluted from 1% to 30%, with an elution time of 10 min). The formate salt of compound 38 was obtained by lyophilization. 1 H NMR(400MHz,DMSO-d6)δ:10.39(s,1H),8.20(s,2H),8.09(d,J=10.0Hz,1H),8.06(s,1H),7.48(s,1H),7.44(dd,J=1.2,5.2Hz,1H) ,7.11~7.03(m,2H),6.98~6.94(m,1H),6.91(d,J=8.0Hz,1H),6.81(d,J=3.6Hz,1H),6.63(d,J=2.4Hz,1H),6.44(d,J=9.6Hz,1H),5 .16(s,1H),4.66(s,1H),4.26(t,J=6.8Hz,2H),3.94(s,2H),3.24(t,J=7.2Hz,2H),2.92(t,J=7.2Hz,2H),2.86(s,2H),2.54(s,1H) ),2.46~2.38(m,4H),2.37(s,3H),2.14(s,3H),2.12~2.05(s,2H),1.91(s,2H),1.88~1.82(m,2H),1.69(s,2H),1.40~1.31(m,4H). MS-ESI calculated value [M+H] + 796, actual value 796.5.

[0389] The synthesis of the formate salt of compound 39 was carried out in three steps using compounds 38-3 and 14-1 as starting materials, following the synthesis route for the formate salt of compound 38.

[0390] Compound 39 acid acid: 1 H NMR(400MHz, DMSO-d6)δ:10.35(s,1H),8.19(s,1H),8.09(d,J=10.0Hz,1H),8.04(s,1H),7.48~7.42(m,2H),7.12(s,1H),7.08~7.04(m ,2H),6.96(dd,J=3.6,5.2Hz,1H),6.91(d,J=8.4Hz,1H),6.82(d,J=3.6Hz,1H),6.64(d,J=2.4Hz,1H),6.43(d,J=10.0Hz,1H),5.12(s,1 H),4.66(s,1H),4.30~4.22(m,2H),3.92~3.85(m,2H),3.28~3.06(m,2H),2.90(t,J=7.2Hz,2H),2.84~2.78(m,2H),2.54(s,1H),2.45~ 2.39(m,2H),2.38(s,3H),2.37~2.34(m,2H),2.13(s,3H),2.10(s,2H),1.91(s,2H),1.88~1.81(m,2H),1.70(s,2H),1.41~1.31(m,4H). MS-ESI calculation value [M+H] + 796, measured value 796.4.

[0391] (Example 40)

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[0392] ステップ1: Synthesis of compound 40-1 Compound 36-12 (40 mg) was dissolved in acetonitrile (10 mL), and diisopropylethylamine (47.7 mg), potassium iodide (102 mg), and compound 1-13 (43.2 mg) were added. The reaction mixture was heated to 90°C and stirred for 14 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 0-5%) to obtain compound 40-1. MS-ESI calculated value [M+H] + 581, actual value 581.

[0393] Step 2: Synthesis of compound 40-2 Compound 1-15 (27 mg, acetate salt) and compound 40-1 (39.7 mg) were dissolved in methanol (4 mL) and tetrahydrofuran (2 mL). Diisopropylethylamine (17.7 mg) and sodium triacetylborohydride (72.5 mg) were added, and the reaction mixture was stirred at 20 °C for 12 hours. Sodium triacetylborohydride (72.5 mg) was added, and the reaction mixture was stirred at 20 °C for another 5 hours. 5% aqueous sodium bicarbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 2). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 40-2, which was used directly in the next step. MS-ESI calculated value [M+H] + 899, actual value 899.

[0394] Step 3: Synthesis of the formate salt of compound 40 Compound 40-2 (60 mg) was dissolved in tetrahydrofuran (4 mL), triethylamine trihydrofluoride (53.8 mg) was added, and the reaction mixture was stirred at 15 °C for 14 h. After the reaction was complete, the mixture was allowed to stand, the supernatant was discarded, and the precipitated solid was washed with 5 mL of tetrahydrofuran and concentrated under reduced pressure. The residue was separated by high-performance liquid chromatography (column type: Phenomenex Gemini-NX C18, length x inner diameter: 75 mm x 30 mm, 3 μm. Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.225% formic acid). Gradient elution method: acetonitrile was gradient eluted from 0% to 30%, elution time: 7 min) to obtain the formate salt of compound 40. 1 H NMR(400MHz,DMSO-d6)δ:8.18(s,2H),8.13~8.08(m,1H),7.87(s,1H),7.47~7.44(m,2H),7. 09~7.00(m,3H),6.99~6.95(m,2H),6.91~6.87(m,1H),6.41~6.37(m,1H),5.48~5.41(m,2H), 5.16~5.05(m,3H),4.68~4.56(m,3H),3.91~3.77(m,2H),2.81~2.66(m,2H),2.46~2.41(m,3 H),2.15(s,3H),2.05~1.96(m,2H),1.92~1.85(m,2H),1.69~1.63(m,2H),1.37~1.28(m,4H). MS-ESI calculated value [M+H] + 785, actual value 785.

[0395] Example 41 [ka] Synthetic Route: [ka]

[0396] Step 1: Synthesis of compound 41-1 Compound 38-3 (40 mg) was dissolved in acetonitrile (10 mL), and diisopropylethylamine (48.1 mg), potassium iodide (103 mg), and compound 1-13 (43.6 mg) were added. The reaction mixture was heated to 90°C and stirred for 14 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent: methanol / dichloromethane = 0-5%) to obtain compound 41-1. MS-ESI calculated value [M+H] + 578, actual value 578.

[0397] Step 2: Synthesis of compound 41-2 Compound 1-15 (30 mg, acetate salt) and compound 41-1 (43.9 mg) were dissolved in methanol (4 mL) and tetrahydrofuran (2 mL). Diisopropylethylamine (19.6 mg) and sodium triacetylborohydride (80.6 mg) were added, and the reaction mixture was stirred at 20 °C for 12 hours. Sodium triacetylborohydride (80.6 mg) was added, and the reaction mixture was stirred at 20 °C for another 5 hours. 5% aqueous sodium bicarbonate solution (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (15 mL × 2). The organic phase was washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give compound 41-2, which was used directly in the next step. MS-ESI calculated value [M+H] + 896, actual value 896.

[0398] Step 3: Synthesis of the formate salt of compound 41 Compound 41-2 (65 mg) was dissolved in tetrahydrofuran (4 mL), triethylamine trihydrofluoride (58.5 mg) was added, and the reaction mixture was stirred at 15 °C for 14 hours. After the reaction was complete, the mixture was allowed to stand, the supernatant was discarded, and the precipitated solid was washed with 5 mL of tetrahydrofuran and concentrated under reduced pressure. The residue was separated by high-performance liquid chromatography (column type: Phenomenex Gemini-NX C18, length x inner diameter: 75 mm x 30 mm, 3 μm. Preparation method: The crude product was dissolved in dimethyl sulfoxide and filtered through a 0.45 μm membrane filter to prepare a sample solution. Mobile phase: acetonitrile / water (containing 0.225% formic acid). Gradient elution method: acetonitrile was gradient eluted from 0% to 30%, elution time: 7 min) to obtain the formate salt of compound 41. 1 H NMR(400MHz,DMSO-d6)δ:8.24(s,2H),8.13~8.06(m,2H),7.50~7.45(m,3H),7.09~7.06( m,3H),6.99~6.95(m,2H),6.95~6.91(m,1H),6.47~6.43(m,1H),5.20~5.15(m,1H),4.71~ 4.67(m,1H),4.31~4.22(m,2H),3.95(s,2H),3.29~3.21(m,2H),2.96~2.84(m,4H),2.42~ 2.37(m,3H),2.17~2.10(m,5H),1.96~1.83(m,4H),1.74~1.68(m,2H),1.42~1.31(m,4H). MS-ESI calculated value [M+H] + 782, actual value 782.

[0399] Bioactivity Tests: Test Example 1: Measurement of the agonistic effect of compounds on β1 receptors using HTRF cAMP Test purpose: The β1 receptor is a G protein-coupled receptor, which is mainly coupled to the Gs protein. When activated by binding with a ligand, the Gs protein activates adenylate cyclase, thereby increasing the intracellular cAMP level. This test uses a cAMP kit to detect the agonistic activity of compounds on the β1 receptor in vitro.

[0400] Test Method: β1 cells (expressing the human ADRB1 gene) provided by Beijing AISI Biotechnology Co., Ltd. were grown under standard conditions. Cells were harvested and diluted with 1x Stimulation Buffer. 9 μL of the cell dilution was added to a white 384-well low-volume plate, with 4,000 cells seeded per well. Compounds were serially diluted 5-fold in DMSO to obtain 10 concentrations. The compounds serially diluted in DMSO before testing were diluted 100-fold with 1x Stimulation Buffer to obtain working solutions. The concentration of the solvent, DMSO, was 0.1%. Eu-cAMP and ULight™-anti-cAMP were diluted to working concentrations in Detection Buffer and added in 5 μL aliquots to the corresponding test wells. After 1 hour of incubation at room temperature, readings were taken at 665 nm and 620 nm with an excitation wavelength of 330 nm using a Biotek microplate reader. The activity of the compound was plotted from the ratio (665 / 620) versus the compound concentration, and the EC was calculated by curve fitting using nonlinear regression with the software GraphPad Prism 7. 50 was calculated.

[0401] The test results are shown in Table 1. [Table 1]

[0402] Conclusion: The compound of the present invention has a certain agonistic effect on β1 receptors.

[0403] Test Example 2: Measurement of the agonistic effect of compounds on β2 receptors using HTRF cAMP Test purpose: The β2 receptor is a G protein-coupled receptor, which is mainly coupled to the Gs protein. When activated by binding with a ligand, the Gs protein activates adenylate cyclase, thereby increasing the intracellular cAMP level. This test uses a cAMP kit to detect the agonistic activity of compounds on the β2 receptor in vitro.

[0404] Test Method: β2 cells (expressing the human ADRB2 gene) provided by Beijing AISI Biotechnology Co., Ltd. were grown under standard conditions. Cells were harvested and diluted with 1x Stimulation Buffer. 9 μL of the cell dilution was added to a white 384-well low-volume plate, with 1,000 cells seeded per well. Compounds were serially diluted 5-fold in DMSO to a 10x concentration. Before testing, compounds serially diluted in DMSO were diluted 100-fold with 1x Stimulation Buffer to obtain working solutions. The concentration of the solvent, DMSO, was 0.1%. Eu-cAMP and ULight™-anti-cAMP were diluted to working concentrations in Detection Buffer and added in 5 μL aliquots to the corresponding test wells. After incubation at room temperature for 1 hour, readings were obtained at 665 nm and 620 nm using a Biotek microplate reader with an excitation wavelength of 330 nm. The activity of the compound was plotted from the ratio (665 / 620) versus the compound concentration, and the EC was calculated by curve fitting using nonlinear regression with the software GraphPad Prism 7. 50 was calculated.

[0405] The test results are shown in Table 2. [Table 2]

[0406] Conclusion: The compounds of the present invention have relatively strong or very strong agonistic effects on β2 receptors.

[0407] Test Example 3: M3 receptor affinity test Test purpose: The M3 receptor is a G protein-coupled receptor, and this test detects the activity of a test compound at the M3 receptor in vitro by competing for the M3 binding site with radioisotope-labeled NMS and a non-isotopically labeled test compound.

[0408] Test Method: This test was performed using radioisotope affinity detection. M3 receptor membrane protein was prepared by the Bioscience Department of Yakult Co., Ltd. at 10 μg / mL, and the compound was serially diluted 2.5-fold in DMSO to give 10 concentrations. The radioisotope 3H-NMS was prepared at 0.2 nM in test buffer (10 mM HEPES and 1 mM MgCl2, pH 7.40). For the formal test, the test system consisted of 1 μL of test compound, 100 μL of M3 receptor membrane protein, and 100 μL of radioisotope, and was incubated at 300 rpm on a shaker at room temperature for 2 hours. GF / C plates (Perkin Elmer, product number 6055690) were presoaked in 0.3% PEI, and the membrane protein in the reaction mixture was collected onto the GF / C plate by filtration. Signal values ​​were read using a Perkin Elmer Microbeta2 instrument, and the inhibition rate at each concentration point was expressed as a percentage.

[0409] The test results are shown in Table 3. [Table 3]

[0410] Conclusion: The compounds of the present invention have relatively strong or very strong binding effects on M3 receptors.

[0411] Test Example 4: M2 receptor affinity test Test purpose: The M2 receptor is a G protein-coupled receptor, and this test detects the activity of test compounds at the M2 receptor in vitro by competing for the M2 binding site with radioisotope-labeled NMS and non-isotopically labeled test compounds.

[0412] Test Method: M2 receptor membrane protein was prepared by the Bioscience Department of Yakult Co., Ltd. at 100 μg / mL, and the compound was serially diluted 2.5-fold in DMSO to give 10 concentrations. The radioisotope 3H-NMS was prepared at 0.2 nM in test buffer (10 mM HEPES and 1 mM MgCl2, pH 7.40). For the formal test, the test system consisted of 1 μL of test compound, 100 μL of M2 receptor membrane protein, and 100 μL of radioisotope, and the reaction mixture was incubated at 300 rpm on a shaker at room temperature for 2 hours. GF / C plates (Perkin-Elmer, product number 6055690) were presoaked in 0.3% PEI, and the membrane protein in the reaction mixture was collected onto the GF / C plate by filtration. Signal values ​​were read using a Perkin-Elmer Microbeta2 instrument, and the inhibition rate at each concentration point was expressed as a percentage.

[0413] The test results are shown in Table 4. [Table 4]

[0414] Conclusion: The compound of the present invention has a relatively strong binding effect on M2 receptors.

[0415] Test Example 5: Pharmacokinetic evaluation of compounds Test purpose: In vivo pharmacokinetics of test compounds in SD rats Test materials: SD rats (male, 200–250 g, 7–9 weeks old, provided by Beijing Weitong Lihua Laboratory Animal Technology Co., Ltd.). Test procedure: A formulation containing 10% HPβCD aqueous solution as a solvent was administered intravenously (2 mpk), and a formulation containing 10% HPβCD aqueous solution as a solvent was administered intratracheally (5 mpk) using a nebulizer. Prior to the animal study, all animals were fed normally and allowed free access to water. Blood samples were collected at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours for the intravenous administration group and at 0.083, 0.25, 0.5, 1, 2, 4, 8, and 24 hours for the nebulizer administration group.

[0416] Whole blood samples (0.25 mL) were collected from the jugular vein (or other appropriate blood collection site) at designated time points and placed in labeled plastic centrifuge tubes containing K2-EDTA anticoagulant. After blood sample collection, the plasma was centrifuged and immediately placed on dry ice for cryogenic storage. The concentrations of all samples were analyzed by LC-MS / MS with a minimum detection limit of 4 nM. Mean plasma concentrations were processed using a noncompartmental model in WinNonlin™ Version 6.3 (Pharsight, Mountain View, CA) pharmacokinetic software, and pharmacokinetic parameters were calculated using the log-linear trapezoidal method. The study results are shown in Table 5. [Table 5]

[0417] Conclusion: The compound of the present invention can significantly enhance one or some of the pharmacokinetic parameters in mice.

Claims

1. A compound of formula (III) or a pharmaceutically acceptable salt thereof: 【Chemistry 1】 (In the formula, R １ is H, halogen, C １～４ selected from alkyl groups and phenyl groups; Each R ２ are each independently H, halogen, or C １～４ alkyl groups, or Or two R ２ and the connected thiophene rings form a benzothiophene, n is selected from 1 or 2; T １ is a single bond, -NH-, or -N(CH ３ ) - selected from L １ is a single bond or -CH ２ Selected from - Structural Unit 【Chemistry 2】 teeth, 【Transformation 3】 Selected from Ring A optionally contains one or two R ｂ C substituted by ４～６ a cycloalkenyl group, a 4- to 6-membered heterocycloalkenyl group, a 5- to 6-membered heteroaryl group, or a phenyl group, wherein the 4- to 6-membered heterocycloalkenyl group contains one, two, or three heteroatoms selected from N, O, and S, and the 5- to 6-membered heteroaryl group contains one, two, or three heteroatoms selected from N, O, and S; Each R ｂ are each independently —F, —Cl, —Br, —I, or —CH ３ , or -CH ２ CH ３ Selected from Ring B is 【Chemistry 4】 Selected from.)

2. R １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is selected from H, —Cl, —Br, a methyl group, a t-butyl group, or a phenyl group.

3. Each R ２ is each independently selected from H, —Cl, —Br, a methyl group, or a t-butyl group, or a pharmaceutically acceptable salt thereof.

4. T １ is a single bond or -N(CH ３ 2. The compound of claim 1, wherein R is 1 or 2; or a pharmaceutically acceptable salt thereof;

5. Structural Unit 【Transformation 5】 teeth, 【Transformation 6】 2. The compound of claim 1, selected from the group consisting of:

6. Structural Unit 【Transformation 7】 teeth, 【Transformation 8】 2. The compound of claim 1, selected from the group consisting of:

7. Structural Unit 【Chemistry 9】 teeth, 【Chemistry 10】 2. The compound of claim 1, selected from the group consisting of:

8. R ｂ are each independently —F, —Cl, —Br, —I, or —CH ３ 2. The compound of claim 1, selected from the group consisting of:

9. Ring A optionally contains one or two R ｂ is replaced by 【Chemistry 11】 2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the aryl group is selected from the group consisting of aryl, ...

10. Ring A optionally contains one or two R ｂ is replaced by 【Chemistry 12】 2. The compound according to claim 1, wherein the aryl group is selected from the group consisting of aryl, ...

11. The compound according to any one of claims 1 to 7, which is selected from the structures represented by (III-1), (III-2), (III-3), (IV-1), (IV-2) and (V-1), or a pharmaceutically acceptable salt thereof. 【Chemistry 13】 (In the formula, R １ , R ２ , T １ , n, L １ and Ring B is as defined in any one of claims 1 to 7.

12. The compound below or a pharmaceutically acceptable salt thereof. 【Chemistry 14-1】 【Chemistry 14-2】 【Chemistry 14-3】

13. 13. The compound of claim 12, selected from the following: or a pharmaceutically acceptable salt thereof. 【Chemistry 15-1】 【Chemistry 15-2】

14. A pharmaceutical composition comprising the compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and optionally further comprising a pharmaceutically acceptable additive.

15. Use of a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 14 in the manufacture of a medicament for treating chronic obstructive pulmonary disease.

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