New benzazepine spirocyclic derivatives

Abstract

Benzazepine spirocyclic derivatives of formula (I) and pharmaceutically acceptable salts thereof, these compounds are used for diagnosing, preventing and / or treating diseases associated with vasopressin receptors. [Formula 1] JPEG2023546527000187.jpg4054

Description

[Technical field]

[0001] This invention claims priority to the following: The application number is CN202011353057.1 and the filing date is November 26, 2020. The application number is CN202111322711.7 and the filing date is November 9, 2021.

[0002] The present invention relates to novel benzazepine spirocyclic derivatives and salts thereof. The present invention also relates to drugs comprising the benzazepine spirocyclic derivatives and salts thereof as active ingredients for diagnosing, preventing and / or treating diseases associated with vasopressin receptors. [Background technology]

[0003] Hormones play an important role in regulating homeostasis in the human body, and arginine vasopressin (AVP) is closely related to the regulation of water and sodium metabolism in the human body. Metabolic disorders of arginine vasopressin (AVP) can cause various diseases, such as hyponatremia, antidiuretic hormone insufficiency syndrome, congestive heart failure, liver cirrhosis, kidney disease, hypertension, and edema. Arginine vasopressin (AVP) receptor antagonists can inhibit the combination of AVP and receptors, thereby playing a role in treating the above diseases. Arginine vasopressin V2 receptor antagonists, such as tolvaptan, can increase free water excretion without affecting electrolyte metabolism, making them the ideal drug for treating the above diseases. However, commercially available AVP V2 receptor antagonists, such as tolvaptan, are metabolized by hepatic metabolic enzymes and produce large amounts of metabolic products in the body, causing severe drug-induced hepatotoxicity, so the FDA has placed a black box warning on the product label of the drug and restricted its use. Therefore, it is of great importance to develop novel V2 receptor antagonists that are highly efficient and have fewer side effects. Summary of the Invention

[0004] The object of the present invention is to provide a novel benzazepine spirocyclic compound or a salt thereof which has a vasopressin V2 receptor antagonistic activity, excellent metabolic stability, and / or metabolites with reduced drug-induced hepatotoxicity properties, as well as medical uses of said compound.

[0005] In one aspect, the present invention provides a compound represented by formula (X), its optical isomers and pharma- ceutically acceptable salts thereof, [ka]

[0006] Where: Ring A is selected from heterocycloalkyl and cycloalkyl, wherein the heterocycloalkyl and cycloalkyl are selected from 1, 2, 3 or 4 R A optionally replaced by; Ring B is selected from aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl, or cycloalkyl is selected from one, two, or three R 3 optionally replaced by; Ring C is selected from aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl, or cycloalkyl is selected from one, two, or three R 4 optionally replaced by; T 1 , T 2 are each independently selected from N and CH; R 1 , R 2 , R 3 , R 4 are each independently H, F, Cl, Br, I, CN, OH, or NH 2 , alkyl, heteroalkyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein said alkyl, heteroalkyl, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl is optionally substituted by 1, 2, 3, or 4 R; R and R Aare each independently H, F, Cl, Br, I, CN, OH, or NH 2 , alkyl, heteroalkyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein said alkyl, heteroalkyl, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl is optionally substituted by 1, 2, 3, or 4 R'; R' is H, F, Cl, Br, I, CN, OH, NH 2 , alkyl, and heteroalkyl; m1 and m2 are each independently selected from 1, 2, 3, or 4; L X is selected from -NH(C=O)-, -alkyl-NH(C=O)-, -NH(C=O)-alkyl-, alkyl, alkenyl and alkynyl, wherein said -alkyl-NH(C=O)-, -NH(C=O)-alkyl-, alkyl, alkenyl or alkynyl is optionally substituted by 1, 2, 3 or 4 R; Additionally, when ring A is selected from heterocycloalkyl, the compound of formula (I) is [ka]

[0007] Not selected from The heterocycloalkyl or heteroaryl are independently -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) 2 - and N.

[0008] In a further aspect, the present invention provides a compound of formula (I), its optical isomers and pharma- ceutically acceptable salts thereof, [ka]

[0009] Where: Ring A is a 3- to 6-membered heterocycloalkyl and C3-6 cycloalkyl, wherein the 3-6 membered heterocycloalkyl and C 3-6 Cycloalkyl is one or two R A optionally replaced by; Ring B is selected from phenyl and 5- to 6-membered heteroaryl, and the phenyl or 5- to 6-membered heteroaryl is selected from 1, 2 or 3 R 3 optionally replaced by; Ring C is selected from phenyl and 5- to 6-membered heteroaryl, and the phenyl or 5- to 6-membered heteroaryl is selected from 1, 2 or 3 R 4 optionally replaced by; T 1 , T 2 are each independently selected from N and CH; R 1 are each independently H, F, Cl, Br, I, CN, OH, or NH 2 and C 1-6 alkyl, 1-6 The alkyl is optionally substituted with 1, 2 or 3 R; R 2 are each independently H, F, Cl, Br, I, CN, OH, or NH 2 , C 1-6 Alkyl and C 3-6 cycloalkyl, 1-6 Alkyl or C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 R; R 3 are each independently H, F, Cl, Br, I, CN, OH, or NH 2 and C 1-6 alkyl, 1-6 The alkyl is optionally substituted with 1, 2 or 3 R; R 4 are each independently H, F, Cl, Br, I, CN, OH, or NH 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 cycloalkyl, phenyl, and 5- to 6-membered heteroaryl;1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 cycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R; R and R A are each independently H, F, Cl, Br, I, CN, OH, or NH 2 , C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkylamino, 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkylamino is optionally substituted with 1, 2 or 3 R'; R' is H, F, Cl, Br, I, CN, OH, NH 2 and C 1-6 alkyl; m1 and m2 are each independently selected from 1, 2, or 3; In addition, when ring A is selected from 3- to 6-membered heterocycloalkyl, the compound represented by formula (I) is [ka] Not selected from

[0010] The 3- to 6-membered heterocycloalkyl or 5- to 6-membered heteroaryl are independently -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) 2 - and N.

[0011] In another aspect of the present invention, there is provided a compound represented by formula (II), its optical isomers and pharma- ceutically acceptable salts thereof,

[0012] [ka]

[0013] Where: X 1 is C(R A ) 2 , NH and O; X 2 is selected from CH and N; T 1 , T 2 are each independently selected from N and CH; R 1 are each independently H, F, Cl, Br, I, CN, OH, or NH 2 and C 1-6 alkyl, 1-6 The alkyl is optionally substituted with 1, 2 or 3 R; R 2a and R 2b are each independently H, F, Cl, Br, I, CN, OH, or NH 2 , C 1-6 Alkyl and C 3-6 cycloalkyl, 1-6 Alkyl or C 3-6 Cycloalkyl is optionally substituted with 1, 2 or 3 R; R 3 are H, F, Cl, Br, I, CN, OH, and NH. 2 and C 1-6 alkyl, 1-6 The alkyl is optionally substituted with 1, 2 or 3 R; R 4 are each independently H, F, Cl, Br, I, CN, OH, or NH 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 cycloalkyl, phenyl, and 5- to 6-membered heteroaryl; 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 cycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R; R is H, F, Cl, Br, I, CN, OH, NH2 , C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkylamino, 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkylamino is optionally substituted with 1, 2 or 3 R'; R' is H, F, Cl, Br, I, CN, OH, NH 2 and C 1-6 alkyl; n1 is selected from 0, 1 or 2; n2 is selected from 1, 2 or 3; Also, X 1 When is selected from O, the compound of formula (II) is [ka]

[0014] Not selected from.

[0015] In another aspect of the present invention, there is also provided a compound represented by formula (III), its optical isomers and pharma- ceutically acceptable salts thereof, [ka]

[0016] Where: R 1 are each independently H, F, Cl, Br, I, CN, OH, or NH 2 and C 1-6 alkyl, 1-6 The alkyl is optionally substituted with 1, 2 or 3 R; R 3 are H, F, Cl, Br, I, CN, OH, and NH. 2 and C 1-6 alkyl, 1-6 The alkyl is optionally substituted with 1, 2 or 3 R; R 4are each independently H, F, Cl, Br, I, CN, OH, or NH 2 , C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 cycloalkyl, phenyl, and 5- to 6-membered heteroaryl; 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Alkylamino, C 3-6 cycloalkyl, phenyl or 5-6 membered heteroaryl is optionally substituted by 1, 2 or 3 R; R is H, F, Cl, Br, I, CN, OH, NH 2 , C 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkylamino, 1-6 Alkyl, C 1-6 Alkoxy and C 1-6 alkylamino is optionally substituted with 1, 2 or 3 R'; R' is H, F, Cl, Br, I, CN, OH, NH 2 and C 1-6 alkyl; X 2 is selected from CH and N.

[0017] In some embodiments of the invention, R is H, F, Cl, Br, I, CN, OH, NH 2 , C.H. 3 , C.F. 3 , [ka] and the other variables are as defined herein.

[0018] In some embodiments of the present invention, R A H, OH and NH 2 and the other variables are as defined herein.

[0019] In some embodiments of the present invention, R 4 are H, F, Cl, Br, I, CN, OH, and NH. 2 , C.H. 3 , C.F. 3 , [ka] It is selected from cyclopropyl, cyclobutyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl, thienyl and thiazolyl, the other variables being as defined herein.

[0020] In some aspects of the invention, ring A is selected from cyclopropyl, cyclobutyl, cyclopentyl, aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, and tetrahydrofuranyl, wherein said cyclopropyl, cyclobutyl, cyclopentyl, aziridinyl, oxiranyl, azetidinyl, oxetanyl, pyrrolidinyl, or tetrahydrofuranyl is selected from one or two R A and other variables are as defined in the present invention.

[0021] In some aspects of the invention, Ring A is [ka] and the other variables are as defined herein.

[0022] In some embodiments of the present invention, the structural unit [ka] teeth, [ka] and the other variables are as defined herein.

[0023] In some embodiments of the invention, Ring B is selected from phenyl and pyridyl, said phenyl or pyridyl being selected from one, two or three R 3 and other variables are as defined in the present invention.

[0024] In some aspects of the invention, Ring C is [ka] and the other variables are as defined herein.

[0025] In a further aspect of the present invention, the present invention also provides compounds of the following formula selected from the following formulae, their optical isomers and pharma- ceutically acceptable salts:

[0026] [ka] [ka]

[0027] In a further aspect, the present invention also provides the use of said compounds, their optical isomers and pharma- ceutically acceptable salts thereof in the manufacture of a medicament for the prophylaxis or treatment of a disease associated with the arginine vasopressin V1a receptor, the arginine vasopressin V1b receptor, the arginine vasopressin V2 receptor, the sympathetic nervous system or the renin-angiotensin-aldosterone system.

[0028] In some embodiments of the invention, the disease associated with arginine vasopressin V1a receptor, arginine vasopressin V1b receptor, arginine vasopressin V2 receptor, the sympathetic nervous system or the renin-angiotensin-aldosterone system comprises hypertension, Reye's syndrome, painful menstruation, premature labor, inappropriate secretion of corticotropin-releasing hormone, adrenal hyperplasia, depression, chronic congestive heart failure, cirrhosis, syndrome of inappropriate secretion of antidiuretic hormone, hyponatremia due to chronic heart failure / cirrhosis / inappropriate secretion of antidiuretic hormone, or polycystic kidney disease.

[0029] [Definitions and Explanations] Unless otherwise stated, the following terms and phrases as used herein are intended to have the following meanings: Certain terms or phrases should not be considered indefinite or indefinite without a specific definition, but should be understood in their ordinary sense. When trade names are mentioned herein, it is intended to refer to the corresponding product or its active ingredients.

[0030] For the purposes of the present invention, the phrase "at least one" when used in reference to a list of one or more elements should be understood to mean at least one element selected from any one or more elements in said list of elements, but not necessarily including at least one of each of the elements specifically named in said list of elements, and not excluding any combination of elements in said list of elements. This definition also allows for the optional presence of elements other than those specifically identified in the list of elements to which the phrase "at least one" refers, whether related to the specifically identified elements or not.

[0031] As used herein, the term "pharmacologically acceptable" refers to those compounds, materials, compositions and / or dosage forms which, within the scope of sound medical judgment, may be applied in contact with the tissues of humans and animals and which are free of excessive toxicity, irritation, allergic response or other problem or complication and are commensurate with a reasonable benefit / risk ratio.

[0032] The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention made with a compound having a specific substituent discovered by the present invention and a relatively non-toxic acid or base. When a compound of the present invention contains a relatively acidic functional group, a base addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of base in a pure solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When a compound of the present invention contains a relatively basic functional group, an acid addition salt can be obtained by contacting the neutral form of such a compound with a sufficient amount of acid in a pure solution or in a suitable inert solvent. Examples of pharma- ceutically acceptable acid addition salts include inorganic acid salts including hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, hydrogen sulfate, hydroiodic acid, phosphorous acid, and the like, and organic acid salts including acetic acid, propionic acid, isobutyric acid, trifluoroacetic acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid, and the like, and further include salts of amino acids (e.g., arginine, etc.) and salts of organic acids such as glucuronic acid. Certain compounds of the present invention contain basic and acidic functional groups and can therefore be converted into any base or acid addition salt.

[0033] The pharma- ceutically acceptable salts of the present invention can be synthesized from a parent compound that contains an acidic or basic group by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of an appropriate base or acid in water or an organic solvent, or a mixture of both.

[0034] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic and other mixtures thereof, such as mixtures enriched in enantiomers or diastereomers, and all such mixtures are included within the scope of the present invention. Other asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers and any mixtures thereof are included within the scope of the invention as claimed.

[0035] The compounds of the present invention can exist in a specific form. Unless otherwise stated, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can be rapidly converted between each other. Tautomers can reach chemical equilibrium of tautomers if possible (e.g., in solution). For example, proton tautomers (also called prototropic tautomers) include interconversions via the transfer of protons, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions by recombination of some bond electrons. Among them, a specific example of keto-enol tautomerization is the interconversion between the two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.

[0036] The compounds of the present invention may contain unnatural atomic isotopes at one or more atoms that constitute the compounds. For example, tritium ( 3 H), iodine-125( 125 I) or C-14( 14Compounds can be labeled with radioisotopes such as C). Also, for example, deuterium can be replaced with hydrogen to form deuterated drugs, and the bond formed between deuterium and carbon is stronger than the bond formed between normal hydrogen and carbon, and compared with non-deuterated drugs, deuterated drugs have the advantages of reduced toxic side effects, increased drug stability, improved therapeutic effect, and extended biological half-life. All variations in the isotopic composition of the compounds of the present invention, whether radioactive or not, are within the scope of the present invention. "Optional" or "optionally" means that the following items or circumstances are possible but not necessarily appear, and the description includes cases where the items or circumstances described therein are not multiplied by the items or circumstances when they occur.

[0037] [ka] The valence bonds of the groups are dotted like this: [ka] When present, the dotted line indicates the point at which the group is attached to the remainder of the molecule. [ka] As a single bond, [ka] where present, the dotted line represents a single bond or the absence of a single bond; and [ka] is a single bond [ka] or double bond [ka] is meant to represent.

[0038] The term "substituted" or "substituted by" refers to the replacement of any one or more hydrogen atoms at a particular atom with a substituent, and may include deuterium and hydrogen variants, provided that the particular valence state is correct and the compound is stable after substitution. The term "optionally substituted" or "optionally substituted by" may or may not be substituted, and unless otherwise defined, the type and number of substituents are any that are chemically stable and feasible.

[0039] When any variable (e.g., R) occurs more than one time in a composition or structure of a compound, its definition is independent at each occurrence. So, for example, if a group is substituted with one, two or three R', then said group is optionally substituted with one, two or three R', and each occurrence of R is independently optional. Also, combinations of substituents and / or variables thereof are permissible only if such combinations result in stable compounds.

[0040] If one of the variables is a single bond, the two groups connected by it are directly linked, e.g. [ka] L in 1 If represents a single bond, this structure is actually [ka] become.

[0041] If a given substituent does not specify through which atom the substituted substituent is linked, then such substituent may be linked through any atom thereof; for example, a pyridyl group as a substituent may be linked to the substituent through any carbon atom of the pyridine ring.

[0042] If the listed linking group does not specify another linking direction, then the linking direction is arbitrary, for example: [ka] The linking group L in is -CH 2 O-, and in this case -CH 2 O- is a link between phenyl and cyclopentyl in the same direction as reading from left to right. [ka] The phenyl and cyclopentyl groups can be linked in the reverse order of reading from left to right. [ka] Combinations of the above linking groups, substituents and / or variables are permissible only if such combinations result in stable compounds.

[0043] Unless otherwise defined, the number of atoms in a ring is generally defined as the number of ring members, for example, a "3- to 6-membered ring" refers to a "ring" having 3 to 6 atoms arranged around it.

[0044] Unless otherwise defined, the term "alkyl" refers to a straight or branched chain saturated aliphatic hydrocarbon group consisting of 1 to 20 carbon atoms, preferably an alkyl group containing 1 to 12 carbon atoms, more preferably an alkyl group containing 1 to 6 carbon atoms, and even more preferably an alkyl group containing 1 to 3 carbon atoms. Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2 ,3-dimethylpentyl, 2,4-dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, n-nonyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2,2-diethylpentyl, n-decyl, 3,3-diethylhexyl, 2,2-diethylhexyl and various branched chain isomers thereof.More preferably, it is a lower alkyl containing from 1 to 6 carbon atoms, non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, and the like. The alkyl may be substituted or unsubstituted, and when substituted, the substituents may be substituted at any available point of attachment, and said substituents are preferably one or more substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0045] Unless otherwise defined, "C 1-6 The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group of 1 to 6 carbon atoms. 1-6 Alkyl is C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl, etc., and monovalent (e.g. CH 3 ), divalent (-CH 2 -) or multivalent (e.g. [ka] ) can be. C 1-6 An example of an alkyl group is CH 3 , [ka] These include, but are not limited to:

[0046] Unless otherwise defined, "C 1-4 The term "alkyl" refers to a straight or branched chain saturated hydrocarbon group of 1 to 4 carbon atoms. 1-4 Alkyl is C 1-2 , C 1-3 , C 3-4 and C 2-3 alkyl, etc., and monovalent (e.g. CH 3 ), divalent (-CH 2 -) or multivalent (e.g. [ka] ) can be. C 1-4 An example of an alkyl group is CH 3 , [ka] These include, but are not limited to:

[0047] Unless otherwise defined, "C 2-3 "Alkenyl" refers to a straight or branched chain hydrocarbon group of 2 to 3 carbon atoms containing at least one carbon-carbon double bond, which may be located at any position in the group. 2-3 Alkenyl is C 3 and C 2 alkenyl, 2-3 Alkenyl can be monovalent, divalent or polyvalent. 2-3 Examples of alkenyl are: [ka] These include, but are not limited to:

[0048] Unless otherwise defined, "C 2-3"Alkynyl" refers to a straight or branched chain hydrocarbon group of 2 to 3 carbon atoms containing at least one carbon-carbon triple bond, which may be located in any position of the group. It may be monovalent, divalent or polyvalent. 2-3 Alkynyl is C 3 and C 2 Contains alkynyl. 2-3 Examples of alkynyl are: [ka] These include, but are not limited to:

[0049] Unless otherwise defined, the term "heteroalkyl," by itself or in combination with other terms, refers to a stable linear or branched alkyl group or combinations thereof consisting of the specified number of carbon atoms and at least one heteroatom or heteroatom group. In some embodiments, the heteroatom is selected from B, O, N, and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. In other embodiments, the heteroatom group is selected from -C(=O)O-, -C(=O)-, -C(=S)-, -S(=O), -S(=O) 2 -, -C(=O)N(H)-, -N(H)-, -C(=NH)-, -S(=O) 2 In some embodiments, the heteroalkyl is selected from -N(H)- and -S(=O)N(H)-. 1-6 heteroalkyl, in another embodiment, the heteroalkyl is C 1-3 Heteroalkyl. The heteroatom or heteroatom group can be placed at any interior position of the heteroalkyl, including the position at which the alkyl is attached to the remainder of the molecule, although the term "alkoxy" is a convention and refers to an alkyl attached to the remainder of the molecule via an oxygen atom. An example of a heteroalkyl is -OCH 3 , -OCH 2 CH 3 , -OCH 2 CH 2 CH 3 , -OCH 2 (CH 3) 2 , -CH 2 -CH 2 -O-CH 3 , -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )(CH 2 CH 3 ), -CH 2 -CH 2 -NH-CH 3 , -CH 2 -CH 2 -N(CH 3 )-CH 3 , -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 , -CH 2 -S-CH 2 -CH 3 , -CH 2 -CH 2 , -S(=O)-CH 3 , -CH 2 -CH 2 -S(=O) 2 -CH 3 and up to two heteroatoms may be consecutive, for example, -CH 2 -NH-OCH 3 It is.

[0050] Unless otherwise defined, "C 1-6 The term "alkoxy" refers to an alkyl group containing 1 to 6 carbon atoms attached to the remainder of the molecule through an oxygen atom. 1-6 Alkoxy is C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3Alkoxy and the like. C 1-6 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutoxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, and the like.

[0051] Unless otherwise defined, "C 1-3 The term "alkoxy" refers to an alkyl group containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom. 1-3 Alkoxy is C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 Alkoxy and the like. C 1-3 Examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.

[0052] Unless otherwise defined, "C 1-6 The term "alkylamino" refers to an alkyl group containing 1 to 6 carbon atoms attached to the remainder of the molecule through an amino group. 1-6 Alkylamino is C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3 and C 2 Alkylamino etc. C 1-6 An example of an alkylamino is -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -N(CH 2 CH 3 )(CH2 CH 3 ), -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 , -NHCH 2 CH 2 CH 2 CH 3 These include, but are not limited to:

[0053] Unless otherwise defined, "C 1-3 The term "alkylamino" refers to an alkyl group containing 1 to 3 carbon atoms attached to the remainder of the molecule through an amino group. 1-3 Alkylamino is C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 Alkylamino etc. C 1-3 An example of an alkylamino is -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 These include, but are not limited to:

[0054] Unless otherwise defined, "C 1-6 The term "alkylthio" refers to an alkyl group containing 1 to 6 carbon atoms attached to the remainder of the molecule through a sulfur atom. 1-6 Alkylthio is C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 , C 3and C 2 Includes alkylthio. C 1-6 An example of an alkylthio group is -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 These include, but are not limited to:

[0055] Unless otherwise defined, "C 1-3 The term "alkylthio" refers to an alkyl group containing 1 to 3 carbon atoms attached to the remainder of the molecule through a sulfur atom. 1-3 Alkylthio is C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 Includes alkylthio. C 1-3 An example of an alkylthio group is -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 These include, but are not limited to:

[0056] Unless otherwise defined, the term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing 3 to 20 carbon atoms, preferably 3 to 12 carbon atoms (either at the specified endpoints or between any two endpoints, e.g., 3, 4, 5, 6 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms, etc.), more preferably 3 to 8 carbon atoms, and most preferably 3 to 6 (e.g., 3, 4, 5, or 6) carbon atoms. Non-limiting examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, etc., preferably cycloalkyl, and polycyclic cycloalkyls include spirocycloalkyls, fused cycloalkyls, and bridged cycloalkyls.

[0057] The term "spirocycloalkyl" refers to a 5-20 membered polycyclic group sharing one carbon atom (called a spiro atom) between the rings, which may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. It is preferably 6-14 membered, more preferably 7-10 membered. According to the number of spiro atoms shared between the rings, spirocycloalkyls can be classified as monocyclic spirocycloalkyls, bicyclic spirocycloalkyls or polycyclic spirocycloalkyls, preferably monocyclic spirocycloalkyls and bicyclic spirocycloalkyls. More preferably, it is 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monocyclic spirocycloalkyls. Non-limiting examples of spirocycloalkyls are: [ka] etc.

[0058] The term "fused cycloalkyl" refers to a 5-20 member all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with another ring in the system, and one or more rings may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. It is preferably 6-14 membered, more preferably 7-10 membered. According to the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic cycloalkyl. Non-limiting examples of fused cycloalkyl are: [ka] etc.

[0059] The term "bridged cycloalkyl" refers to a 5-20 member all-carbon polycyclic group having any two rings sharing two carbon atoms that are not directly bonded, containing one or more double bonds, but neither ring having a completely conjugated π-electron system. It is preferably 5-14 membered, more preferably 7-10 membered. According to the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged cycloalkyl are: [ka] etc.

[0060] The cycloalkyl includes the above cycloalkyls fused to an aryl, heteroaryl, or heterocycloalkyl ring (e.g., monocyclic cycloalkyls, fused cycloalkyls, spirocycloalkyls, and bridged cycloalkyls) where the ring attached to the parent structure is a cycloalkyl, non-limiting examples include indanyl, tetrahydronaphthyl, benzocycloheptyl, and the like; preferably benzocyclopentyl, tetrahydronaphthyl.

[0061] Cycloalkyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0062] The term "heterocyclyl" refers to a heterocyclic ring containing 3 to 20 ring atoms, one or more of which is nitrogen, oxygen, or S(O). m (m is an integer of 0 to 2), but the remaining ring atoms, except for the ring portion of -OO-, -OS-, or -SS-, are carbon. The heterocyclyl preferably contains 3 to 12 ring atoms (which may be a specific end point or the interval between any two end points, for example, 3, 4, 5, or 6 ring atoms, 4 to 11 ring atoms, 6 to 12 ring atoms, etc.), of which 1 to 4 are heteroatoms, preferably 3 to 8 ring atoms, of which 1 to 3 are heteroatoms, and more preferably 3 to 6 ring atoms, of which 1 to 3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyls include azetidinyl, pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like, preferably tetrahydropyranyl, piperidinyl, pyrrolidinyl. Polycyclic heterocyclyls include spiroheterocyclyl, fused heterocyclyl, and bridged heterocyclyl.

[0063] The term "spiroheterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclic group that shares one atom (called a spiro atom) between the monocyclic rings, where one or more of the ring atoms is nitrogen, oxygen, or S(O). m(m is an integer from 0 to 2), and the remaining ring atoms are carbon. The spiroheterocyclyl may contain one or more double bonds, but none of the rings has a completely conjugated π-electron system. It is preferably 6 to 14 members, more preferably 7 to 11 members. According to the number of spiro atoms shared between the rings, the spiroheterocyclyl can be classified into monocyclic spiroheterocyclyl, bicyclic spiroheterocyclyl or polycyclic spiroheterocyclyl, preferably monocyclic spirocycloalkyl and bicyclic spirocycloalkyl. More preferably, it is 4-membered / 4-membered, 4-membered / 5-membered, 4-membered / 6-membered, 5-membered / 5-membered or 5-membered / 6-membered monocyclic spiroheterocyclyl. Non-limiting examples of spiroheterocyclyl are: [ka] etc.

[0064] The term "fused heterocyclyl" refers to a 5- to 20-membered polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with another ring in the system, one or more of the rings may contain one or more double bonds, but none of the rings has a completely conjugated pi-electron system, and one or more of the ring atoms is nitrogen, oxygen, or S(O) m (m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14-membered, more preferably 7 to 11-membered. According to the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyl are: [ka] JPEG0007627343000039.jpg1884 etc.

[0065] The term "bridged heterocyclyl" refers to a 5-14 membered polycyclic heterocyclic group having two rings sharing two atoms that are not directly bonded together, where either ring contains one or more double bonds, but neither ring has a completely conjugated pi-electron system, and where one or more of the ring atoms is nitrogen, oxygen, or S(O). m (m is an integer of 0 to 2), and the remaining ring atoms are carbon. It is preferably 6 to 14-membered, more preferably 7 to 11-membered. According to the number of rings, it can be classified as bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclyl, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic. Non-limiting examples of bridged heterocyclyl are: [ka] etc.

[0066] The heterocyclyls include the above heterocyclyls fused to an aryl, heteroaryl, or cycloalkyl ring (e.g., monocyclic heterocyclyls, fused heterocyclyls, spiroheterocyclyls, and bridged heterocyclyls), where the ring attached to the parent structure is a heterocyclyl, non-limiting examples of which are: [ka] etc.

[0067] The heterocyclyl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, and oxo.

[0068] The term "aryl" refers to an all-carbon monocyclic or fused polycyclic (i.e., rings sharing adjacent pairs of carbon atoms) group having a conjugated pi-electron system of 6 to 20 members, preferably 6 to 10 members, more preferably 6 members, such as phenyl and naphthyl. The aryl includes the above aryls fused to a heteroaryl, heterocyclyl, or cycloalkyl ring, where the ring attached to the parent structure is an aryl ring, non-limiting examples of which are: [ka] etc.

[0069] Aryl can be substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0070] The term "heteroaryl" refers to a heteroaromatic system containing 1-4 heteroatoms and 5-20 ring atoms, the heteroatoms being selected from oxygen, sulfur and nitrogen. Heteroaryl is preferably 5-10 membered and contains 1-3 heteroatoms, more preferably 5 or 6 membered and contains 1-3 heteroatoms, non-limiting examples include pyrazolyl, imidazolyl, furanyl, thienyl, thiazolyl, oxazolyl, pyrrolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazole, pyrazinyl, and the like. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, where the ring attached to the parent structure is a heteroaryl ring, non-limiting examples of which are: [ka] Includes.

[0071] Heteroaryl may be optionally substituted or unsubstituted, and when substituted, the substituents are preferably one or more substituents independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, mercapto, hydroxyl, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, and heterocycloalkylthio.

[0072] Unless otherwise defined, "C 3-6 "Cycloalkyl" refers to a saturated cyclic hydrocarbon group of 3 to 6 carbon atoms, including monocyclic and bicyclic ring systems, 3-6 Cycloalkyl is C 3-5 , C 4-5 and C 5-6 C includes cycloalkyl, and may be monovalent, divalent or polyvalent. 3-6 Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0073] Unless otherwise defined, the term "3- to 6-membered heterocycloalkyl", by itself or in combination with other terms, refers to a saturated cyclic group of 3 to 6 ring atoms, each of which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is preferably optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)). pand p is 1 or 2. This includes monocyclic and bicyclic ring systems, where bicyclic ring systems include spiro, fused, and bridged rings. Additionally, for "3- to 6-membered heterocycloalkyl," a heteroatom can occupy the position at which the heterocycloalkyl is attached to the remainder of the molecule. Said 3- to 6-membered heterocycloalkyl includes 4- to 6-membered, 5- to 6-membered, 4-membered, 5-membered, and 6-membered heterocycloalkyl, and the like. Examples of 3-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl (including tetrahydrothien-2-yl and tetrahydrothien-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl, and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, or homopiperidinyl.

[0074] Unless otherwise defined, the terms "5- to 6-membered heteroaromatic ring" and "5- to 6-membered heteroaryl" of the present invention can be used interchangeably, and the term "5- to 6-membered heteroaryl" refers to a monocyclic group having a conjugated π-electron system consisting of 5 to 6 ring atoms, of which 1, 2, 3, or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms can be optionally oxidized (i.e., NO and S(O)). pand p is 1 or 2. The 5-6 membered heteroaryl can be attached to the remainder of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of 5-6 membered heteroaryl include pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5-oxazolyl, etc.), triazolyl (including 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1,2,4-triazolyl, etc.), and the like. aryl and the like), tetrazolyl, isoxazolyl (including 3-isoxazolyl, 4-isoxazolyl, and 5-isoxazolyl, and the like), thiazolyl (including 2-thiazolyl, 4-thiazolyl, and 5-thiazolyl, and the like), furanyl (including 2-furanyl and 3-furanyl, and the like), thienyl (including 2-thienyl and 3-thienyl, and the like), pyridyl (including 2-pyridyl, 3-pyridyl, and 4-pyridyl, and the like), pyrazinyl, or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, and the like).

[0075] Unless otherwise defined, C n-n+m Or C n -C n+m includes any one of the specific cases of n to n+m carbons, for example, C 1-12 is C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 Including any range of n to n+m, for example, C 1-12 is C 1-3 , C 1-6 , C 1-9 , C 3-6 , C3-9 , C 3-12 , C 6-9 , C 6-12 and C 9-12 Similarly, n-membered to n+m-membered rings indicate that the number of atoms on the ring is n to n+m, and for example, a 3- to 12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, a 9-membered ring, a 10-membered ring, an 11-membered ring, and a 12-membered ring, and also includes any range of n to n+m, and for example, a 3- to 12-membered ring includes a 3- to 6-membered ring, a 3- to 9-membered ring, a 5- to 6-membered ring, a 5- to 7-membered ring, a 5- to 10-membered ring, a 6- to 7-membered ring, a 6- to 8-membered ring, a 6- to 9-membered ring, and a 6- to 10-membered ring.

[0076] The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., an affinity substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate esters such as methanesulfonate, toluenesulfonate, p-bromobenzenesulfonate, p-toluenesulfonate, and the like; acyloxy such as acetoxy, trifluoroacetoxy, and the like.

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

[0078] The compounds of the present invention can be prepared by a variety of synthetic methods familiar to those skilled in the art, including the specific embodiments listed below, embodiments in combination with other chemical synthetic methods, and equivalent alternative methods familiar to those skilled in the art, and preferred embodiments include, but are not limited to, the examples of the present invention.

[0079] The solvents used in the present invention can be obtained commercially.

[0080] Compounds were named according to art-conventional names or ChemDraw® software; for commercially available compounds, manufacturer's catalog names were used. [Brief description of the drawings]

[0081] [Figure 1] 1 shows the results of an experiment on inhibiting the proliferation of LLC-PK1 cells according to an embodiment of the present invention. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0082] The present application will be specifically described below by examples, but is not intended to limit the present invention in any way. The present application has been described in detail herein, and specific embodiments thereof have been disclosed, and it is obvious to those skilled in the art that various changes and modifications can be made in the specific embodiments of the present application without departing from the spirit and scope of the present application.

[0083] Experimental materials and reagents used in the following examples are commercially available unless otherwise specified.

[0084] Preparation of intermediates Reference Example 1: Preparation of Intermediate I-1

[0085] [ka]

[0086] At room temperature, p-toluenesulfonyl chloride (21.9 g, 115 mmol) was added to a solution of 7-chloro-1,2,3,4-tetrahydrobenzo[B]azepin-5-one (15 g, 76.7 mmol) in pyridine (150 mL). The reaction solution was reacted at room temperature for 16 hours. The reaction solution was concentrated under reduced pressure, poured into water (200 mL), extracted with ethyl acetate (100 mL x 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, and the residue was separated and purified by silica gel chromatography to obtain intermediate I-1.

[0087] LC-MS (ESI) [M+H] + 349.9.

[0088] 1H NMR (400 MHz, CDCl 3 ) δ 7.66 (d, J = 2.4 Hz, 1H), 7.58 (d, J = 8.3 Hz, 2H), 7.47 (dd, J = 8.6, 2.5 Hz, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 8.0 Hz, 2H), 3.83 (t, J = 6.5 Hz, 2H), 2.43 (s, 3H), 2.40 - 2.35 (m, 2H), 2.00 - 1.91 (m, 2H).

[0089] Reference Example 2: Preparation of Intermediate I-2

[0090] [ka]

[0091] At room temperature, intermediate I-1 (20.0 g, 57.2 mmol) was added to cyclohexane (250 mL), and n-butylamine (8.49 mL, 85.8 mmol) and trifluoroacetic acid (1.00 mL) were added. The reaction mixture was refluxed under argon gas protection for 48 hours to separate water, and concentrated under reduced pressure to obtain a residue. A mixed solution of ethyl acetate / petroleum ether (volume ratio 1:15, 64 mL) was added to the residue while stirring, and the mixture was stirred for 10 minutes, then filtered with suction, and the obtained solid was dried under reduced pressure to obtain intermediate I-2.

[0092] 1 H NMR (400 MHz, CDCl 3) δ 7.56 - 7.51 (m, 2H), 7.45 (d, J = 2.2 Hz, 1H), 7.41 - 7.38 (m, 1H), 7.37 - 7.34 (m, 1H), 7.22 (d, J = 8.0 Hz, 2H), 3.76 (t, J = 6.2 Hz, 2H), 2.93 (t, J = 7.2 Hz, 2H), 2.40 (s, 3H), 2.10 - 2.06 (m, 2H), 1.76 - 1.69 (m, 2H), 1.65 - 1.58 (m, 2H), 1.41 - 1.35 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H).

[0093] Reference Example 3: Preparation of intermediate I-3

[0094] [ka]

[0095] At room temperature, a selective fluorine reagent (26.2 g, 74.0 mmol) was added to acetonitrile (200 mL), and intermediate I-2 (15.0 g, 37.0 mmol) was added in five portions every 40 minutes. After the addition was completed, the reaction mixture was stirred at room temperature for 72 hours to react. Ice water (200 mL) was added, and concentrated hydrochloric acid (15.0 mL) was slowly added dropwise while stirring. After stirring for 5 minutes, the mixture was filtered with suction, and the resulting solid was dried under reduced pressure to obtain intermediate I-3.

[0096] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.79 - 7.63 (m, 4H), 7.44 (d, J = 8.0 Hz, 2H), 7.37 - 7.32 (m, 1H), 4.07 - 3.98 (m, 2H), 2.67 - 2.53 (m, 2H), 2.41 (s, 3H).

[0097] Reference Example 4: Preparation of intermediate I-4

[0098] [ka]

[0099] At 0°C, intermediate I-3 (12.0g, 31.1mmol) was added to concentrated sulfuric acid (15.0mL), and the reaction mixture was stirred at room temperature for 4 hours. It was poured into ice water, the pH was adjusted to 11 with 50% aqueous sodium hydroxide solution, and extracted with ethyl acetate (100mL x 3). The organic phases were combined, washed with saturated brine (200mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-4.

[0100] LCMS (ESI) [M+H] + 232.1.

[0101] 1 H NMR (400 MHz, DMSO) δ 7.45 (dd, J = 8.4, 3.6 Hz, 2H), 7.34 (dd, J = 8.9, 2.6 Hz, 1H), 6.91 (d, J = 8.9 Hz, 1H), 3.29 - 3.21 (m, 2H), 2.70 - 2.56 (m, 2H).

[0102] Reference Example 5: Preparation of Intermediate I-5

[0103] [ka]

[0104] At room temperature, methyltriphenylphosphonium bromide (18.5 g, 51.8 mmol) was added to tetrahydrofuran (120 mL), cooled to 0°C, potassium tert-butoxide (5.81 g, 51.8 mmol) was added, and the reaction mixture was stirred at 0°C for 1 hour, and then a solution of intermediate I-4 (6.00 g, 25.9 mmol) in tetrahydrofuran (20 mL) was added at 0°C. After the dropwise addition was completed, the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was poured into ice water (200 mL), extracted with ethyl acetate (100 mL x 3), the organic phase was combined, washed with saturated saline (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-5.

[0105] LCMS (ESI) [M+H] + 230.1.

[0106] Reference Example 6: Preparation of Intermediate I-6

[0107] [ka]

[0108] At room temperature, 6-aminonicotinic acid methyl ester (1.0 g, 6.57 mmol) was dissolved in pyridine (20 mL), and 2-trifluoromethylbenzoyl chloride (1.51 g, 7.25 mmol) was added, and the reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water (100 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with water (50 mL x 5), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography to obtain intermediate I-6.

[0109] LC-MS (ESI) [M+H] + 325.0.

[0110] Reference Example 7: Preparation of intermediate I-7

[0111] [ka]

[0112] At room temperature, intermediate I-6 (1.35 g, 4.16 mmol) was dissolved in tetrahydrofuran (10 mL), and a solution of sodium hydroxide (499 mg, 12.5 mmol) in water (2 mL) was added. The reaction mixture was stirred at 70° C. for 1 hour, and after the reaction was completed, 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5-6. The mixture was filtered and the solid was dried to obtain intermediate I-7.

[0113] LC-MS (ESI) [M+H] + 311.0.

[0114] Reference Example 8: Preparation of Intermediate I-8

[0115] [ka]

[0116] At room temperature, intermediate I-7 (244 mg, 0.785 mmol) was dissolved in N,N-dimethylacetamide (6.00 mL), cooled to 0 ° C., thionyl chloride (125 mg, 1.05 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. Then, a solution of intermediate I-5 (120 mg, 0.523 mmol) in N,N-dimethylacetamide (3 mL) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (20 mL × 3), the organic phases were combined, washed with saturated aqueous sodium bicarbonate solution (50 mL) and saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-8.

[0117] LCMS (ESI) [M+H] + 522.2.

[0118] Reference Example 9: Preparation of Intermediate I-9

[0119] [ka]

[0120] At room temperature, o-toluoyl chloride (5.00 g, 32.3 mmol) was dissolved in chloroform (80 mL), and 4-amino-2-methylbenzoic acid (4.88 g, 32.3 mmol) and triethylamine (9.81 g, 96.9 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated saline (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-9.

[0121] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.53 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.73 - 7.62 (m, 2H), 7.51 - 7.45 (m, 1H), 7.44 - 7.37 (m, 1H), 7.36 - 7.25 (m, 2H), 2.53 (s, 3H), 2.39 (s, 3H).

[0122] Reference Example 10: Preparation of Intermediate I-10

[0123] [ka]

[0124] At room temperature, intermediate I-9 (211 mg, 0.785 mmol) was dissolved in N,N-dimethylacetamide (6.00 mL), cooled to 0 ° C., and under the protection of argon gas, thionyl chloride (125 mg, 1.05 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours, and then a solution of intermediate I-5 (120 mg, 0.523 mmol) in N,N-dimethylacetamide (3 mL) was added. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was poured into water (30 mL), extracted with ethyl acetate (20 mL × 3), the organic phase was combined, washed with saturated aqueous sodium bicarbonate solution (50 mL) and saturated saline (50 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-10.

[0125] LCMS (ESI) [M+H] + 481.1.

[0126] Reference Example 11: Preparation of Intermediate I-11

[0127] [ka]

[0128] At room temperature, 6-amino-4-methylnicotinic acid methyl ester (500 mg, 3.01 mmol) was dissolved in pyridine (20 mL), and 2-trifluoromethylbenzoyl chloride (628 mg, 3.01 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water (100 mL), extracted with ethyl acetate (50 mL x 3), the organic phases were combined, washed with water (50 mL x 5), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated and purified by silica gel chromatography to obtain intermediate I-11.

[0129] LC-MS (ESI) [M+H] + 339.1.

[0130] Reference Example 12: Preparation of Intermediate I-12

[0131] [ka]

[0132] Intermediate I-11 (700 mg, 2.07 mmol) was dissolved in tetrahydrofuran (10 mL) at room temperature, and a solution of sodium hydroxide (414 mg, 10.35 mmol) in water (5 mL) was added, and the reaction mixture was stirred at 70° C. for 1 hour to react. 1N hydrochloric acid was added to the reaction solution to adjust the pH to 5-6, and the solution was filtered and the solid was dried to obtain intermediate I-12.

[0133] Reference Example 13: Preparation of intermediate I-13

[0134] [ka]

[0135] At 0° C., intermediate I-12 (200 mg, 0.617 mmol) was dissolved in dichloromethane (10 mL), and oxalyl chloride (165 mg, 1.30 mmol) and N,N-dimethylformamide (1 drop) were added, and the reaction mixture was stirred at 0° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product of intermediate I-13. The crude product was used directly in the next reaction without further purification.

[0136] Reference Example 14: Preparation of intermediate I-14

[0137] [ka]

[0138] 7-Chloro-1,2,3,4-tetrahydrobenzo[B]azepin-5-one (26.0 g, 0.133 mol) and di-tert-butyl dicarbonate (200 g) were heated to 100° C. and reacted for 16 hours. After the reaction solution was cooled to room temperature, most of the di-tert-butyl dicarbonate was removed under reduced pressure using an oil pump, and the residue was separated and purified by silica gel chromatography to obtain intermediate I-14.

[0139] LC-MS (ESI) [M+H-56] + 239.9.

[0140] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.66 - 7.58 (m, 2H), 7.48 (d, J = 8.4 Hz, 1H), 3.66 (s, 2H), 2.64 (t, J = 6.6 Hz, 2H), 2.07 - 1.96 (m, 2H), 1.40 (d, J = 13.8 Hz, 9H).

[0141] Reference Example 15: Preparation of Intermediate I-15

[0142] [ka]

[0143] Under the protection of argon gas, methyltriphenylphosphonium bromide (47.9 g, 0.134 mol) was added to a solution of potassium tert-butoxide (18.9 g, 0.168 mol) in tetrahydrofuran (500 mL) at 0 °C, and the reaction solution was stirred at 0 °C for 30 minutes. Next, intermediate I-14 (33.0 g, 0.112 mol) was added to the reaction system. The reaction solution was stirred at room temperature for 16 hours. The reaction solution was diluted with water (500 mL) and extracted with ethyl acetate (500 mL × 2). The organic phases were combined, washed with water (500 mL) and saturated saline (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain a crude product, which was separated and purified by silica gel chromatography to obtain intermediate I-15.

[0144] LC-MS (ESI) [M+H-56] + 238.0.

[0145] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.36 (s, 1H), 7.30 (dd, J = 8.5, 2.5 Hz, 1H), 7.22 (d, J = 8.5 Hz, 1H), 5.20 (d, J = 11.7 Hz, 2H), 3.51 (s, 2H), 2.37 (t, J = 6.1 Hz, 2H), 1.81 (s, 2H), 1.45 - 1.28 (m, 9H).

[0146] Reference Example 16: Preparation of Intermediate I-16

[0147] [ka]

[0148] Intermediate I-15 (6.10 g, 20.8 mmol) was dissolved in a mixture of trifluoroacetic acid / dichloromethane (20.0 mL / 40.0 mL) at room temperature, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into saturated sodium bicarbonate solution (200 mL), extracted with dichloromethane (50 mL x 4), the organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was separated and purified by silica gel chromatography to obtain intermediate I-16.

[0149] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.11 (d, J = 2.5 Hz, 1H), 7.00 (dd, J = 8.6, 2.5 Hz, 1H), 6.69 (d, J = 8.6 Hz, 1H), 5.17 (d, J = 1.6 Hz, 1H), 4.99 - 4.93 (m, 1H), 3.18 - 3.07 (m, 2H), 2.50 - 2.45 (m, 2H), 1.88 - 1.76 (m, 2H).

[0150] Reference Example 17: Preparation of intermediate I-17

[0151] [ka]

[0152] Intermediate I-13 (150 mg) was dissolved in pyridine (10 mL) at room temperature, and intermediate I-16 (60 mg, 0.310 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography to obtain intermediate I-17.

[0153] LC-MS (ESI) [M+H] + 500.1.

[0154] Reference Example 18: Preparation of intermediate I-18

[0155] [ka]

[0156] At room temperature, o-toluoyl chloride (6.11 g, 39.5 mmol) was added to a solution of methyl 6-aminonicotinate (5.00 g, 32.9 mmol) in pyridine (40.0 mL). The reaction mixture was stirred at room temperature for 2 hours, then poured into water (300 mL), suction filtered, and the obtained solid was dried to obtain intermediate I-18.

[0157] LC-MS (ESI) [M+H] + 271.0.

[0158] Reference Example 19: Preparation of Intermediate I-19

[0159] [ka]

[0160] Sodium hydroxide (2.66 g, 66.6 mmol) was added to a solution of intermediate I-18 (6.00 g, 22.2 mmol) in methanol / water (60 mL / 30 mL) at room temperature. The reaction mixture was stirred at 70° C. for 30 minutes. The mixture was cooled to room temperature, adjusted to pH 5-6 with 3N dilute hydrochloric acid in an ice-water bath, and extracted with ethyl acetate (50 mL×6). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to give intermediate I-19.

[0161] LC-MS (ESI) [M+H] + 257.1.

[0162] Reference Example 20: Preparation of Intermediate I-20

[0163] [ka]

[0164] At room temperature, intermediate I-19 (1.50 g, 5.85 mmol) and N,N-dimethylformamide (0.10 mL) were added to dichloromethane (20.0 mL), the reaction system was cooled to 0° C., and oxalyl chloride (1.49 g, 11.7 mmol) was added. The reaction solution was stirred at 0° C. for 1 hour, and concentrated to dryness to obtain the crude product of intermediate I-20. The crude product was used directly in the next reaction without further purification.

[0165] Reference Example 21: Preparation of Intermediate I-21

[0166] [ka]

[0167] At room temperature, intermediate I-16 (378 mg, 1.95 mmol) was added to pyridine (5.00 mL), and intermediate I-20 (500 mg) was added in one portion. The reaction solution was stirred at room temperature for 16 hours, then poured into water (30 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-21.

[0168] LC-MS (ESI) [M+H] + 432.1.

[0169] Reference Example 22: Preparation of Intermediate I-22

[0170] [ka]

[0171] At 0° C., intermediate I-7 (200 mg, 0.65 mmol) was dissolved in dichloromethane (10 mL), and oxalyl chloride (165 mg, 1.30 mmol) and N,N-dimethylformamide (1 drop) were added, and the reaction mixture was stirred at 0° C. for 1 hour. The reaction solution was concentrated under reduced pressure to obtain the crude product of intermediate I-22. The crude product was used directly in the next reaction without further purification.

[0172] Reference Example 23: Preparation of intermediate I-23

[0173] [ka]

[0174] Intermediate I-22 (214 mg, 0.65 mmol) was dissolved in pyridine (10 mL) at room temperature, and intermediate I-16 (97 mg, 0.501 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was separated and purified by silica gel chromatography to obtain intermediate I-23.

[0175] LC-MS (ESI) [M+H] + 486.2.

[0176] Reference Example 24: Preparation of Intermediate I-24

[0177] [ka]

[0178] At room temperature, copper(I) cyanide (24.0 g, 0.268 mol) was added to a solution of 2-amino-5-bromo-4-methylpyridine (25.0 g, 0.134 mol) in N,N-dimethylacetamide (230 mL). The reaction mixture was stirred at 170° C. for 16 hours under the protection of argon gas. After cooling to 0° C., ethylenediamine (50 mL) and water (500 mL) were added to the reaction solution and stirred for 15 minutes to quench the reaction. Extraction was performed with ethyl acetate (300 mL×3), and the organic phases were combined, washed with water (300 mL×3) and saturated saline (500 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, obtaining the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-24.

[0179] LC-MS (ESI) [M+H] + 134.1.

[0180] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.23 ​​(s, 1H), 6.89 (s, 2H), 6.35 (s, 1H), 2.25 (s, 3H).

[0181] Reference Example 25: Preparation of Intermediate I-25

[0182] [ka]

[0183] At room temperature, intermediate I-24 (10.2 g, 76.6 mmol) was added to a solution of sodium hydroxide aqueous solution (90 mL, 10 mol / L) and ethanol (90 mL), and the reaction mixture was refluxed for 16 hours. After cooling to room temperature, the pH was adjusted to neutral with hydrochloric acid (6 mol / L), and the solid was precipitated, filtered, and the filter cake was washed with water and dried to obtain intermediate I-25.

[0184] LC-MS (ESI) [M+H] + 153.3.

[0185] Reference Example 26: Preparation of Intermediate I-26

[0186] [ka]

[0187] At room temperature, thionyl chloride (15 mL) was added to a solution of intermediate I-25 (7.8 g, 51.3 mmol) in methanol (80 mL). The reaction mixture was refluxed for 16 hours. It was cooled to room temperature, most of the methanol solvent was removed under reduced pressure, and water (100 mL) was added to dilute the mixture, and the pH was adjusted to 13 with aqueous sodium hydroxide (2 mol / L) to precipitate a solid, which was filtered with suction. The filter cake was washed with water and dried to obtain intermediate I-26.

[0188] LC-MS (ESI) [M+H] + 167.1.

[0189] Reference Example 27: Preparation of intermediate I-27

[0190] [ka]

[0191] At room temperature, o-toluoyl chloride (5.14 g, 33.2 mmol) was added to a solution of intermediate I-26 (4.6 g, 27.7 mmol) in pyridine (35 mL), and the reaction mixture was stirred at room temperature for 3 hours to react. Ice water (70 mL) was added to the reaction solution to precipitate a solid, which was then filtered. The filter cake was washed with a large amount of water and petroleum ether, and dried to obtain intermediate I-27.

[0192] LC-MS (ESI) [M+H] + 285.2.

[0193] Reference Example 28: Preparation of intermediate I-28

[0194] [ka]

[0195] At room temperature, 5% aqueous sodium hydroxide solution (48 mL) was added to a solution of intermediate I-27 (4.1 g, 14.4 mmol) in methanol (60 mL), and the reaction mixture was reacted at 70° C. for 30 minutes. The mixture was cooled to room temperature, diluted with water (50 mL), and the pH was adjusted to weak acidity with hydrochloric acid (3 mol / L), and the solid was precipitated, filtered, and the filter cake was washed with a large amount of water and freeze-dried to obtain intermediate I-28.

[0196] LC-MS (ESI) [M+H] + 271.1.

[0197] 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.04 (s, 1H), 10.99 (s, 1H), 8.75 (s, 1H), 8.16 (s, 1H), 7.48 (d, J = 7.6 Hz, 1H), 7.43 - 7.35 (m, 1H), 7.32 - 7.24 (m, 2H), 2.60 (s, 3H), 2.39 (s, 3H).

[0198] Reference Example 29: Preparation of Intermediate I-29

[0199] [ka]

[0200] Oxalyl chloride (2.07 g, 16.3 mmol) and N,N-dimethylformamide (1 drop) were added to a solution of intermediate I-28 (2.2 g, 8.14 mmol) in dichloromethane (30 mL) under ice-water bath, and the reaction solution was reacted at 0° C. for 30 minutes. The solvent was concentrated to dryness at low temperature to obtain the crude product of intermediate I-29, which was used directly in the next reaction without purification.

[0201] Reference Example 30: Preparation of Intermediate I-30

[0202] [ka]

[0203] At room temperature, intermediate I-29 (1.75 g) was added to a solution of intermediate I-16 (900 mg, 4.65 mmol) in pyridine (30 mL). The reaction mixture was stirred at room temperature for 3 hours. Water (50 mL) was added and extracted with ethyl acetate (30 mL x 2). The organic phases were combined, washed with water (30 mL x 3) and saturated saline (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, giving a crude product. The crude product was separated and purified by silica gel chromatography to give intermediate I-30.

[0204] LC-MS (ESI) [M+H] + 446.2.

[0205] Reference Example 31: Preparation of intermediate I-31

[0206] [ka]

[0207] At room temperature, N-bromosuccinimide (110 mg, 0.618 mmol) was added to a solution of intermediate I-30 (230 mg, 0.516 mmol) in tetrahydrofuran / water (15 mL / 3 mL), and the reaction solution was stirred at room temperature for 16 hours. Next, aqueous sodium hydroxide solution (2 mL, 2.5 N) was added, and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, and a crude product was obtained. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-31.

[0208] LC-MS (ESI) [M+H] + 462.0.

[0209] 1H NMR (400 MHz, DMSO-d 6 ) δ 10.97 - 10.53 (m, 1H), 8.47 - 7.63 (m, 2H), 7.56 - 7.10 (m, 6H), 7.03 - 6.66 (m, 1H), 4.98 - 4.67 (m, 1H), 3.30 - 2.62 (m, 3H), 2.48 - 2.25 (m, 6H), 2.21 - 1.99 (m, 2H), 1.91 - 1.52 (m, 2H).

[0210] Reference Example 32: Preparation of intermediate I-32

[0211] [ka]

[0212] At room temperature, 2-methyl-4-nitrobenzoyl chloride (2.06 g, 10.3 mmol) and triethylamine (3.13 g, 30.9 mmol) were added to a solution of intermediate I-16 (2.0 g, 10.3 mmol) in dichloromethane (40 mL). The reaction mixture was stirred at room temperature for 1 hour, poured into water (100 mL), extracted with dichloromethane (50 mL x 3), the organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-32.

[0213] LC-MS (ESI) [M+H] + 356.9.

[0214] Reference Example 33: Preparation of intermediate I-33

[0215] [ka]

[0216] At room temperature, iron powder (282 mg, 5.05 mmol) and ammonium chloride (540 mg, 10.1 mmol) were added to a solution of intermediate I-32 (360 mg, 1.01 mmol) in methanol / water (20 mL / 5 mL). The reaction solution was stirred at 60° C. under argon gas protection for 3 hours. It was cooled to room temperature, filtered, and the filtrate was concentrated to dryness to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-33.

[0217] LC-MS (ESI) [M+H] + 327.0.

[0218] Reference Example 34: Preparation of intermediate I-34

[0219] [ka]

[0220] At room temperature, o-chlorobenzoyl chloride (225 mg, 1.29 mmol) and triethylamine (260 mg, 2.59 mmol) were added to a solution of intermediate I-33 (280 mg, 0.857 mmol) in 1,2-dichloroethane (20 mL). The reaction mixture was stirred at 50° C. for 2 hours. After cooling to room temperature, the reaction solution was diluted with dichloromethane (20 mL), washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-34.

[0221] LC-MS (ESI) [M+H] + 465.2.

[0222] Reference Example 35: Preparation of Intermediate I-35

[0223] [ka]

[0224] Intermediate I-9 (2.00 g, 7.43 mmol) was added to a solution of thionyl chloride (20.0 mL) at room temperature, and the reaction mixture was stirred at 40° C. for 4 h. The reaction was concentrated under reduced pressure to give the crude product of intermediate I-35, which was used directly in the next reaction.

[0225] Reference Example 36: Preparation of Intermediate I-36

[0226] [ka]

[0227] Intermediate I-16 (1.42 g, 7.31 mmol) was dissolved in pyridine (30.0 mL) at room temperature, and intermediate I-35 (2.00 g) was added, and the reaction mixture was stirred at room temperature for 8 hours. The reaction system was poured into water (100 mL), extracted with ethyl acetate (50 mL x 3), and the organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-36.

[0228] LC-MS (ESI) [M+H] + 445.0.

[0229] Reference Example 37: Preparation of intermediate I-37

[0230] [ka]

[0231] Intermediate I-36 (1.00 g, 2.25 mmol) was dissolved in dichloromethane (30.0 mL) at room temperature, 3-chloroperbenzoic acid (1.95 g, 11.3 mmol) was added, and the reaction system was stirred at room temperature for 10 hours. The reaction system was concentrated under reduced pressure at room temperature to obtain a crude product, which was separated and purified by C18 reverse phase chromatography to obtain intermediate I-37.

[0232] 1H NMR (400 MHz, DMSO-d 6 ) δ 10.41 - 10.23 (m, 1H), 7.77 - 7.10 (m, 9H), 6.83 - 6.63 (m, 1H), 5.04 - 3.53 (m, 1H), 3.21 - 2.68 (m, 3H), 2.37 - 2.33 (m, 6H), 2.13 - 1.56 (m, 4H).

[0233] Reference Example 38: Preparation of intermediate I-38

[0234] [ka]

[0235] At 25°C, intermediate I-1 (1.00g, 2.86mmol) was dissolved in tetrahydrofuran (10mL), tert-butylsulfinamide (415.74mg, 3.43mmol), tetraethyl titanate (1.30g, 5.72mmol) were added, and the reaction solution was stirred at 80°C for 3 hours under microwave conditions. Water (10mL) was added, filtered, the filter cake was washed with ethyl acetate (20mL), the filtrate was collected, washed with saturated brine (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-38.

[0236] LC-MS (ESI) [2M+H] + 453.0.

[0237] Reference Example 39: Preparation of Intermediate I-39

[0238] [ka]

[0239] At 25°C, zinc powder (2.01g, 30.76mmol) was suspended in tetrahydrofuran (100mL) and replaced with nitrogen gas three times. 1,2-dibromoethane (96.31mg, 0.51mmol) and trimethylchlorosilane (278.48mg, 2.56mmol) were added and stirred at 65°C for 1 hour. After adding tert-butyl bromoacetate (5.00g, 25.63mmol) dropwise, the reaction solution was stirred at 50°C for 1 hour. The mixture was cooled to obtain a tetrahydrofuran solution of intermediate 1-39 (100mL, 25.63mmol).

[0240] Reference Example 40: Preparation of Intermediate I-40

[0241] [ka]

[0242] At 25°C, a solution of intermediate I-38 (850.00 mg, 1.88 mmol) in tetrahydrofuran (20 mL) was added dropwise to a solution of intermediate I-39 in tetrahydrofuran (100 mL, 25.63 mmol), and the reaction solution was stirred at 50°C for 16 hours to react. Water (100 mL) was added, and the mixture was extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-40.

[0243] LC-MS (ESI) [M+H] + 569.2.

[0244] Reference Example 41: Preparation of Intermediate I-41

[0245] [ka]

[0246] At 25°C, intermediate I-40 (350.00 mg, 0.61 mmol) was dissolved in tetrahydrofuran (10 mL), and a solution of diisobutylaluminum hydride in toluene (2.05 mL, 3.07 mmol, 1.5 M) was added, and the reaction solution was reacted at room temperature for 16 hours. Water (0.12 mL), 15% aqueous sodium hydroxide solution (0.12 mL), and water (0.3 mL) were added in sequence, followed by anhydrous sodium sulfate, and the mixture was stirred at room temperature for 0.5 hours. After filtration, the filtrate was concentrated and separated and purified by silica gel chromatography to obtain intermediate I-41.

[0247] LC-MS (ESI) [M+H] + 499.2.

[0248] Reference Example 42: Preparation of Intermediate I-42

[0249] [ka]

[0250] At 25°C, intermediate I-41 (170.00 mg, 0.34 mmol) was dissolved in toluene (10 mL), cyanomethylenetri-n-butylphosphine (98.47 mg, 0.41 mmol) was added, and the reaction solution was stirred at 110°C for 3 hours. The mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by silica gel chromatography to obtain intermediate I-42.

[0251] LC-MS (ESI) [M+H] + 481.2.

[0252] Reference Example 43: Preparation of intermediate I-43

[0253] [ka]

[0254] Intermediate I-42 (100.00 mg, 0.21 mmol) was dissolved in concentrated hydrochloric acid (5 mL) at 25° C., and the reaction solution was reacted at 100° C. for 16 hours. The mixture was directly concentrated and dried, and separated and purified using a C18 reverse phase column to obtain intermediate I-43.

[0255] LC-MS (ESI) [M+H] + 223.0.

[0256] Reference Example 44: Preparation of Intermediate I-44

[0257] [ka]

[0258] At 25°C, intermediate I-43 (40.00 mg, 0.18 mmol) was dissolved in tetrahydrofuran (5 mL), 10% aqueous sodium bicarbonate (5 mL) and di-tert-butyl dicarbonate (47.04 mg, 0.22 mmol) were added, and the reaction solution was reacted at room temperature for 1 hour. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by silica gel chromatography to obtain intermediate I-44.

[0259] LC-MS (ESI) [M+H] + 323.2.

[0260] Reference Example 45: Preparation of Intermediate I-45

[0261] [ka]

[0262] At 25°C, intermediate I-44 (50.00mg, 0.15mmol) was dissolved in dichloromethane (10mL), triethylamine (47.02mg, 0.46mmol) and 2-methyl-4-nitrobenzoyl chloride (46.37mg, 0.23mmol) were added, and the reaction solution was stirred at room temperature for 16 hours. Water (10mL) was added, and the mixture was extracted with dichloromethane (10mL x 3). The organic phases were combined, washed with saturated saline (10mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated and separated and purified by silica gel chromatography to obtain intermediate I-45.

[0263] LC-MS (ESI) [M-100+H] + 386.2.

[0264] Reference Example 46: Preparation of Intermediate I-46

[0265] [ka]

[0266] At 25°C, intermediate I-45 (50.00 mg, 0.10 mmol) was dissolved in ethanol (4 mL), reduced iron powder (28.73 mg, 0.51 mmol) and saturated aqueous ammonium chloride solution (2 mL) were added, and the reaction solution was stirred at 80°C for 5 hours to react. It was filtered, the filter cake was washed with ethyl acetate (10 mL), the filtrate was collected, water (10 mL) was added, and the layers were separated. The organic phase was collected, concentrated, and separated and purified by silica gel chromatography to obtain intermediate I-46.

[0267] LC-MS (ESI) [M-100+H] + 356.2.

[0268] Reference Example 47: Preparation of Intermediate I-47

[0269] [ka]

[0270] At 25°C, intermediate I-46 (30.00 mg, 0.066 mmol) was dissolved in dichloromethane (5 mL), triethylamine (19.97 mg, 0.20 mmol) and 2-methylbenzoyl chloride (12.21 mg, 0.079 mmol) were added in sequence, and the reaction solution was reacted at room temperature for 1 hour. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness, and separated and purified by silica gel chromatography to obtain intermediate I-47.

[0271] LC-MS (ESI) [M-100+H] + 474.2.

[0272] Reference Example 48: Preparation of intermediate I-48

[0273] [ka]

[0274] At room temperature, cesium carbonate (82.7 g, 254 mmol) and tetrakis(triphenylphosphine)palladium (2.93 g, 2.54 mmol) were added to a solution of 2-bromo-4-chloro-1-nitrobenzene (20.0 g, 84.6 mmol) and 3,6-dihydro-2H-pyran-4-boronic acid pinacol ester (21.3 g, 101.4 mmol) in dioxane / water (600 mL / 200 mL), and the reaction mixture was stirred under argon gas protection at 100 °C for 5 hours. The mixture was cooled to room temperature, most of the solvent was removed under reduced pressure, and extracted with ethyl acetate (100 mL x 3), and the organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, giving the crude product. The crude product was separated and purified by silica gel chromatography to give intermediate I-48.

[0275] LC-MS (ESI) [M+H] + 240.0.

[0276] 1 H NMR (400 MHz, CD 3 OD) δ 7.92 (d, J = 8.7 Hz, 1H), 7.52 (dd, J = 8.7, 2.3 Hz, 1H), 7.44 (d, J = 2.3 Hz, 1H), 5.75 - 5.71 (m, 1H), 4.26 - 4.21 (m, 2H), 3.89 (t, J = 5.3 Hz, 2H), 2.36 - 2.31 (m, 2H).

[0277] Reference Example 49: Preparation of Intermediate I-49

[0278] [ka]

[0279] At room temperature, 3-chloroperbenzoic acid (16.2 g, 93.9 mmol) was added to a solution of intermediate I-48 (15.0 g, 62.6 mmol) in dichloromethane (100 mL). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with dichloromethane (100 mL), washed with saturated aqueous sodium thiosulfate solution (100 mL x 3), saturated aqueous sodium carbonate solution (100 mL x 3) and saturated saline (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, obtaining a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-49.

[0280] LC-MS (ESI) [M+H] + 256.0.

[0281] 1 H NMR (400 MHz, DMSO-d 6) δ 8.17 (d, J = 8.7 Hz, 1H), 7.77 - 7.68 (m, 2H), 4.01 - 3.88 (m, 2H), 3.69 - 3.61 (m, 1H), 3.53 - 3.45 (m, 1H), 3.37 (s, 1H), 2.20 - 2.11 (m, 1H), 2.03 - 1.95 (m, 1H).

[0282] Reference Example 50: Preparation of Intermediate I-50

[0283] [ka]

[0284] Boron trifluoride etherate (4.37 g, 30.8 mmol) was added to a solution of intermediate I-49 (7.5 g, 29.3 mmol) in dichloromethane (70 mL) under ice-water bath. The reaction mixture was stirred at 0°C for 30 minutes. The reaction mixture was washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-50.

[0285] LC-MS (ESI) [M+H] + 256.0.

[0286] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.56 (s, 1H), 8.07 (d, J = 8.7 Hz, 1H), 7.72 (dd, J = 8.7, 2.2 Hz, 1H), 7.65 (d, J = 3.6 Hz, 1H), 4.31 (d, J = 9.8 Hz, 1H), 4.05 (d, J = 9.9 Hz, 1H), 4.00 - 3.86 (m, 2H), 2.69 - 2.60 (m, 1H), 2.40 - 2.31 (m, 1H).

[0287] Reference Example 51: Preparation of Intermediate I-51

[0288] [ka]

[0289] Under the protection of argon gas in an ice-water bath, sodium hydride (278 mg, 60%wt, 6.95 mmol) was added to triethylphosphonoacetate (1.18 g, 5.26 mmol) in tetrahydrofuran (30 mL), and the mixture was stirred in an ice-water bath for 30 minutes. Intermediate I-50 (890 mg, 3.48 mmol) was then added, and the reaction mixture was reacted at room temperature for 2 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, and the crude product was obtained. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-51.

[0290] LC-MS (ESI) [M+H] + 326.1.

[0291] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.91 - 7.84 (m, 1H), 7.70 - 7.63 (m, 2H), 7.08 (d, J = 15.9 Hz, 1H), 5.68 (d, J = 15.9 Hz, 1H), 4.18 - 4.06 (m, 3H), 3.92 - 3.81 (m, 3H), 2.48 - 2.43 (m, 1H), 2.36 - 2.27 (m, 1H), 1.19 (t, J = 7.1 Hz, 3H).

[0292] Reference Example 52: Preparation of Intermediate I-52

[0293] [ka]

[0294] At room temperature, platinum dioxide (50 mg) was added to a solution of intermediate I-51 (720 mg, 2.21 mmol) in tetrahydrofuran (50 mL). The reaction mixture was hydrogenated under a hydrogen balloon atmosphere at room temperature for about 6 hours. After filtration, the filtrate was concentrated under reduced pressure to remove the organic solvent to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-52.

[0295] LC-MS (ESI) [M+H] + 298.1.

[0296] Reference Example 53: Preparation of intermediate I-53

[0297] [ka]

[0298] Sodium hydroxide (88.7 mg, 2.22 mmol) was added to a solution of intermediate I-52 (220 mg, 0.739 mmol) in tetrahydrofuran / water (10 mL / 3 mL) at room temperature. The reaction solution was stirred at 40° C. for 16 hours. After cooling to room temperature, the reaction solution was adjusted to pH 7 by adding dilute hydrochloric acid (1N), and concentrated under reduced pressure to remove the organic solvent to obtain a crude product of intermediate I-53, which was used directly in the next reaction without purification.

[0299] LC-MS (ESI) [M+H] + 270.1.

[0300] Reference Example 54: Preparation of intermediate I-54

[0301] [ka]

[0302] At room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (283 mg, 1.48 mmol) and 4-dimethylaminopyridine (135 mg, 1.11 mmol) were added to a solution of intermediate I-53 (300 mg) in tetrahydrofuran (60 mL), and the reaction solution was reacted at room temperature for 16 hours. Water (60 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, and a crude product was obtained. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-54.

[0303] LC-MS (ESI) [M+H] + 252.1.

[0304] 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.57 (d, J = 30.6 Hz, 1H), 7.40 - 7.29 (m, 2H), 7.04 - 6.97 (m, 1H), 3.90 - 3.78 (m, 3H), 3.73 - 3.65 (m, 1H), 2.31 - 2.05 (m, 6H).

[0305] Reference Example 55: Preparation of Intermediate I-55

[0306] [ka]

[0307] At room temperature, borane-tetrahydrofuran solution (2.09 mL, 1 M) was added to intermediate I-54 (105 mg, 0.417 mmol) in tetrahydrofuran (20 mL), and the reaction solution was reacted at 40° C. for 2 hours. The mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, yielding a crude product. The crude product was separated and purified by silica gel chromatography to yield intermediate I-55.

[0308] LC-MS (ESI) [M+H] + 238.1.

[0309] 1 H NMR (400 MHz, CDCl 3 ) δ 7.21 (d, J = 2.3 Hz, 1H), 7.00 (dd, J = 8.3, 2.4 Hz, 1H), 6.65 (d, J = 8.3 Hz, 1H), 4.10 (d, J = 8.8 Hz, 1H), 3.97 - 3.89 (m, 2H), 3.81 - 3.74 (m, 1H), 3.14 - 3.05 (m, 1H), 3.00 - 2.93 (m, 1H), 2.40 - 2.32 (m, 1H), 2.18 - 2.09 (m, 1H), 1.89 - 1.83 (m, 2H), 1.75 - 1.69 (m, 2H).

[0310] Reference Example 56: Preparation of Intermediate I-56

[0311] [ka]

[0312] At room temperature, 2-methyl-4-nitrobenzoyl chloride (42.4 mg, 0.212 mmol) was added to a solution of intermediate I-55 (42 mg, 0.177 mmol) and pyridine (42.0 mg, 0.531 mmol) in tetrahydrofuran (5 mL). The reaction solution was reacted at 50° C. for 5 hours. The mixture was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (10 mL×2). The organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-56.

[0313] LC-MS (ESI) [M+H] + 401.0.

[0314] Reference Example 57: Preparation of Intermediate I-57

[0315] [ka]

[0316] At room temperature, iron powder (31.3 mg, 0.560 mmol) and ammonium chloride (59.9 mg, 1.12 mmol) were added to a solution of intermediate I-56 (45 mg, 0.112 mmol) in methanol / water (10 mL / 3 mL). The reaction solution was reacted at 50° C. for 2 hours under the protection of argon gas. It was cooled to room temperature, filtered, and the filtrate was concentrated to remove most of the solvent, diluted with water (5 mL), and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-57.

[0317] LC-MS (ESI) [M+H] + 371.0.

[0318] Reference Example 58: Preparation of intermediate I-58

[0319] [ka]

[0320] At room temperature, trimethylsulfoxonium iodide (370 mg, 1.68 mmol) and potassium tert-butoxide (189 mg, 1.68 mmol) were added to dimethylsulfoxide (6.00 mL), and the reaction mixture was stirred for 30 minutes under the protection of argon gas, and then intermediate I-4 (130 mg, 0.561 mmol) was added at room temperature, and the reaction mixture was stirred for 3 hours at room temperature. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3), and the organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-58.

[0321] LCMS (ESI) [M+H] + 260.0.

[0322] 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.57 (d, J = 2.6 Hz, 1H), 7.17 (dd, J = 8.4, 2.6 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 5.65 (d, J = 4.9 Hz, 1H), 4.57 - 4.40 (m, 2H), 3.22 - 3.05 (m, 2H), 2.73 (t, J = 12.4 Hz, 1H), 2.41 - 2.32 (m, 1H), 2.20 - 2.04 (m, 1H).

[0323] Reference Example 59: Preparation of Intermediate I-59

[0324] [ka]

[0325] At room temperature, N-bromosuccinimide (395 mg, 2.22 mmol) was added to a solution of intermediate I-21 (800 mg, 1.85 mmol) in tetrahydrofuran / water (15 mL / 3 mL), and the reaction solution was stirred at room temperature for 24 hours. Then, 10% aqueous sodium hydroxide solution (3.70 mL, 9.25 mmol) was added. The reaction solution was stirred at room temperature for 1 hour. The reaction solution was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, and the crude product was obtained. The crude product was separated and purified by a C18 reverse phase column to obtain intermediate I-59.

[0326] LC-MS (ESI) [M+H] + 448.1.

[0327] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.87 (m, 2H), 8.20 - 6.90 (m, 10H), 4.94 - 4.81 (m, 1H), 3.13 - 2.78 (m, 3H), 2.35 (s, 3H), 2.15 - 1.93 (m, 2H), 1.66 (m, 2H).

[0328] Reference Example 60: Preparation of Intermediate I-60

[0329] [ka]

[0330] At room temperature, 2-phenylbenzoic acid (14.0 g, 70.6 mmol) was dissolved in dichloromethane (200 mL), thionyl chloride (16.8 g, 141 mmol) was added to the reaction system, and the reaction mixture was stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure to obtain the crude product of intermediate I-60, which was directly used in the next reaction.

[0331] Reference Example 61: Preparation of Intermediate I-61

[0332] [ka]

[0333] Intermediate I-60 (10.0 g) was dissolved in pyridine (80.0 mL) at room temperature, methyl 6-aminonicotinate (7.03 g, 46.2 mmol) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was poured into water (500 mL) and extracted with ethyl acetate (100 mL x 3). The organic phases were combined, washed with saturated saline (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified using a C18 reverse phase column to obtain intermediate I-61.

[0334] LC-MS (ESI) [M+H] + 333.0.

[0335] Reference Example 62: Preparation of Intermediate I-62

[0336] [ka]

[0337] At room temperature, intermediate I-61 (10.0 g, 30.1 mmol) was dissolved in methanol / water (100 mL / 20 mL), sodium hydroxide (3.61 g, 90.3 mmol) was added to the reaction system, and the reaction mixture was stirred at room temperature for 3 hours. Dilute hydrochloric acid (1.0 mol / L) was added to the reaction system to adjust the pH to 6-7, and a large amount of solid was precipitated. The solid was collected by filtration and dried under reduced pressure to obtain intermediate I-62.

[0338] LC-MS (ESI) [M+H] + 319.0.

[0339] Reference Example 63: Preparation of Intermediate I-63

[0340] [ka]

[0341] Intermediate I-62 (2.00 g, 6.28 mmol) was dissolved in dichloromethane (30.0 mL) at room temperature, thionyl chloride (2.24 g, 18.8 mmol) was added, and the reaction mixture was stirred at 50° C. for 3 hours. The reaction was concentrated under reduced pressure to give the crude product of intermediate I-63, which was used directly in the next reaction.

[0342] Reference Example 64: Preparation of Intermediate I-64

[0343] [ka]

[0344] Intermediate I-16 (633 mg, 3.27 mmol) was dissolved in pyridine (10.0 mL) at room temperature, and intermediate I-63 (1.10 g) was added, and the reaction mixture was stirred at room temperature for 3 hours. The reaction system was poured into water (50.0 mL), extracted with ethyl acetate (20 mL x 3), and the organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-64.

[0345] LC-MS (ESI) [M+H] + 494.2.

[0346] Reference Example 65: Preparation of Intermediate I-65

[0347] [ka]

[0348] Intermediate I-64 (500 mg, 1.01 mmol) was dissolved in tetrahydrofuran / water (25 mL / 5 mL) at room temperature, N-bromosuccinimide (360 mg, 2.02 mmol) was added, and the reaction mixture was stirred at room temperature for 24 hours. 25% aqueous sodium hydroxide solution (1.00 mL) was added to the reaction system, and the reaction mixture was stirred at room temperature for 1 hour. The reaction system was poured into water (20 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, washed with saturated saline (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-65.

[0349] LC-MS (ESI) [M+H] + 510.1.

[0350] Reference Example 66: Preparation of Intermediate I-66

[0351] [ka]

[0352] In an ice-water bath, N-methylurea (5.0 g, 67.5 mmol) was dissolved in water (40 mL), and sodium nitrite (5.12 g, 74.2 mmol) was added. In an ice-water bath, concentrated hydrochloric acid (8.9 mL) was slowly added dropwise over about 30 minutes while stirring, and the reaction solution was reacted in an ice-water bath for 30 minutes. The precipitate was filtered, and the filter cake was washed with water and dried by oil pump suction to obtain intermediate I-66, which was directly used in the next reaction without further purification.

[0353] Reference Example 67: Preparation of Intermediate I-67

[0354] [ka]

[0355] In an ice-water bath, 40% potassium hydroxide aqueous solution (40 mL) and ethyl ether (54 mL) were added to a smooth reaction flask, and intermediate I-66 (4.2 g, 40.7 mmol) was added to the above reaction system in several portions. The reaction flask was gently shaken several times, and after reacting for 30 minutes, the upper layer of the ethyl ether solution was transferred to another smooth flask containing potassium hydroxide solid and dried. An ethyl ether solution (0.75 M) of intermediate I-67 was obtained and used directly in the next reaction.

[0356] Reference Example 68: Preparation of Intermediate I-68

[0357] [ka]

[0358] In an ice-water bath, an ethyl ether solution (40 mL, 0.75 M) of intermediate I-67 was slowly added to an ethyl ether (10 mL) solution of intermediate I-15 (300 mg, 1.02 mmol) and palladium acetate (50 mg), and the reaction solution was stirred in an ice-water bath for 1 hour. The reaction solution was quenched by adding acetic acid (1 mL), diluted with water (30 mL), extracted with ethyl ether (20 mL x 3), and the organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, and a crude product was obtained. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-68.

[0359] LC-MS (ESI) [M+H-56] + 252.1.

[0360] Reference Example 69: Preparation of Intermediate I-69

[0361] [ka]

[0362] Trifluoroacetic acid (1 mL) was added to a solution of intermediate I-68 (90 mg, 0.292 mmol) in dichloromethane (5 mL) at room temperature. The reaction solution was stirred at room temperature for 5 hours. Concentration under reduced pressure gave the crude product of intermediate I-69, which was used directly in the next reaction.

[0363] LC-MS (ESI) [M+H] + 208.1.

[0364] Reference Example 70: Preparation of Intermediate I-70

[0365] [ka]

[0366] At room temperature, 2-methyl-4-nitrobenzoyl chloride (115 mg, 0.576 mmol) was added to a solution of intermediate I-69 (60 mg) and pyridine (68.6 mg, 0.867 mmol) in 1,2-dichloroethane (10 mL), and the reaction solution was stirred at 50° C. for 16 hours. The mixture was cooled to room temperature, diluted with dichloromethane (20 mL), washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to remove the organic solvent, and a crude product was obtained. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-70.

[0367] LC-MS (ESI) [M+H] + 371.1.

[0368] Reference Example 71: Preparation of Intermediate I-71

[0369] [ka]

[0370] At room temperature, iron powder (30.2 mg, 0.541 mmol) and ammonium chloride (57.8 mg, 1.08 mmol) were added to a solution of intermediate I-70 (40 mg, 0.108 mmol) in methanol / water (10 mL / 3 mL), and the reaction solution was stirred at 50° C. for 3 hours under argon gas protection. It was cooled to room temperature, filtered, and the filtrate was concentrated to dryness to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-71.

[0371] LC-MS (ESI) [M+H] + 341.1.

[0372] Reference Example 72: Preparation of Intermediate I-72

[0373] [ka]

[0374] At room temperature, diethyl malonate (10.0 g, 62.5 mmol) was dissolved in dimethyl sulfoxide (150 mL), and sodium hydride (2.92 g, 60% wt, 72.9 mmol) was slowly added. The reaction mixture was stirred at room temperature for 30 minutes, after which 2,4-dichloronitrobenzene (10.0 g, 52.1 mmol) was added to the reaction solution. After the addition was completed, the reaction solution was heated to 80°C and stirred for 5 hours. It was cooled to room temperature, water (300 mL) was added, and extracted with ethyl acetate (300 mL x 3). The organic phases were combined, washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, yielding a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-72.

[0375] LC-MS (ESI) [M+H] + 316.0.

[0376] Reference Example 73: Preparation of Intermediate I-73

[0377] [ka]

[0378] At room temperature, intermediate I-72 (10.0 g, 31.68 mmol) was dissolved in dimethyl sulfoxide (100 mL) and water (1 mL), and lithium chloride (6.65 g, 158.4 mmol) was added. After the addition was completed, the reaction solution was heated to 100° C. and stirred for 5 hours. The mixture was cooled to room temperature, diluted with water (200 mL), and extracted with ethyl acetate (200 mL×3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was separated and purified by silica gel chromatography to yield intermediate I-73.

[0379] 1 H NMR (400 MHz, CDCl 3 ) δ 8.08 (d, J = 8.8 Hz, 1H), 7.44 (dd, J = 8.8, 2.3 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 3.99 (s, 2H), 1.25 (t, J = 7.1 Hz, 3H).

[0380] Reference Example 74: Preparation of Intermediate I-74

[0381] [ka]

[0382] At 0°C, intermediate I-73 (3.5 g, 14.4 mmol) was dissolved in N,N-dimethylformamide (100 mL) and slowly added to a solution of sodium hydride (860 mg, 60% wt, 21.5 mmol) in N,N-dimethylformamide (10 mL). The reaction mixture was stirred for 30 minutes, after which 1,3-diiodopropane (5.1 g, 17.2 mmol) was added to the reaction solution. After the addition was completed, the reaction solution was stirred at room temperature overnight. Water (200 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (200 mL x 3). The organic phases were combined, washed with saturated brine (200 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, giving the crude product. The crude product was separated and purified by silica gel chromatography to give intermediate I-74.

[0383] 1 H NMR (400 MHz, CDCl 3 ) δ 7.88 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H), 7.37 (dd, J = 8.6, 2.2 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 2.85 - 2.76 (m, 2H), 2.46 - 2.31 (m, 3H), 1.92 - 1.80 (m, 1H), 1.22 (t, J = 7.1 Hz, 3H).

[0384] Reference Example 75: Preparation of Intermediate I-75

[0385] [ka]

[0386] At room temperature, intermediate I-74 (1.3 g, 4.58 mmol) was dissolved in methanol (10 mL) and water (10 mL), sodium hydroxide (916 mg, 22.9 mmol) was added, and the reaction solution was heated to 100° C. and stirred for 3 hours. After cooling to room temperature and concentrating the reaction solution to remove most of the methanol, the reaction solution was acidified with 1N hydrochloric acid and extracted with ethyl acetate (50 mL×3). The organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, to obtain intermediate I-75.

[0387] 1 H NMR (400 MHz, DMSO-d 6 ) δ 12.52 (s, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.65 - 7.55 (m, 2H), 2.67 - 2.58 (m, 2H), 2.39 (m, 2H), 2.17 (dt, J = 19.4, 8.9 Hz, 1H), 1.85 - 1.72 (m, 1H).

[0388] Reference Example 76: Preparation of Intermediate I-76

[0389] [ka]

[0390] At room temperature, borane-tetrahydrofuran solution (19.5 mL, 1 M) was added to intermediate I-75 (1.0 g, 3.91 mmol) in tetrahydrofuran (50 mL), and the reaction solution was stirred at room temperature overnight. Water (50 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (50 mL x 2). The organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, and the crude product was obtained. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-76.

[0391] Reference Example 77: Preparation of Intermediate I-77

[0392] [ka]

[0393] Intermediate I-76 (800 mg, 3.31 mmol) was dissolved in dichloromethane (10 mL) at room temperature, and Dess-Martin oxidant (4.21 g, 9.93 mmol) was added. After the addition was completed, the reaction solution was stirred at room temperature for 2 hours. The reaction solution was filtered, and the filtrate was diluted with water (20 mL) and extracted with dichloromethane (20 mL x 3). The organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, yielding the crude product. The crude product was separated and purified by silica gel chromatography to yield intermediate I-77.

[0394] Reference Example 78: Preparation of Intermediate I-78

[0395] [ka]

[0396] At 0°C under argon gas protection, sodium hydride (157mg, 60%wt, 3.92mmol) was added to triethylphosphonoacetate (659mg, 2.94mmol) in tetrahydrofuran (30mL), and the mixture was stirred in an ice-water bath for 30 minutes, after which intermediate I-77 (470mg, 1.96mmol) was added. The reaction mixture was reacted at room temperature for 2 hours. The reaction solution was concentrated to remove most of the tetrahydrofuran, water (50mL) was added, and the mixture was extracted with ethyl acetate (50mL x 3). The aqueous phase was acidified by adding 1N hydrochloric acid, extracted with ethyl acetate (50mL x 3), the organic phases were combined, washed with saturated saline (50mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, to obtain intermediate I-78.

[0397] 1 H NMR (400 MHz, DMSO-d 6) δ 12.22 (s, 1H), 7.88 (d, J = 8.7 Hz, 1H), 7.59 (dd, J = 8.7, 2.3 Hz, 1H), 7.47 (d, J = 2.3 Hz, 1H), 7.30 (d, J = 15.7 Hz, 1H), 5.65 (d, J = 15.7 Hz, 1H), 2.43 - 2.33 (m, 4H), 2.05 (dd, J = 20.5, 10.1 Hz, 1H), 1.79 - 1.70 (m, 1H).

[0398] Reference Example 79: Preparation of Intermediate I-79

[0399] [ka]

[0400] Intermediate I-78 (360 mg, 1.28 mmol) was dissolved in tetrahydrofuran (20 mL) at room temperature, and Raney nickel (300 mg) was added. After the addition was complete, the reaction solution was stirred under a hydrogen gas atmosphere for 16 hours. After filtration, the filtrate was concentrated under reduced pressure to remove the organic solvent, yielding a crude product of intermediate I-79. The crude product was used directly in the next reaction.

[0401] LC-MS (ESI) [M+H] + 254.3.

[0402] Reference Example 80: Preparation of Intermediate I-80

[0403] [ka]

[0404] At room temperature, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (331 mg, 1.73 mmol) and 4-dimethylaminopyridine (211 mg, 1.73 mmol) were added to a solution of intermediate I-79 (220 mg) in tetrahydrofuran (60 mL), and the reaction solution was stirred at room temperature for 16 hours. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, and a crude product was obtained. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-80.

[0405] LC-MS (ESI) [M+H] + 236.2.

[0406] Reference Example 81: Preparation of Intermediate I-81

[0407] [ka]

[0408] At room temperature, borane-tetrahydrofuran solution (1.9 mL, 1 M) was added to intermediate I-80 (90 mg, 0.382 mmol) in tetrahydrofuran (20 mL). The reaction solution was reacted at 40° C. for 2 hours. The mixture was cooled to room temperature, diluted with water (20 mL), and extracted with ethyl acetate (20 mL×2). The organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to remove the organic solvent, yielding a crude product. The crude product was separated and purified by silica gel chromatography to yield intermediate I-81.

[0409] LC-MS (ESI) [M+H] + 222.2.

[0410] Reference Example 82: Preparation of Intermediate I-82

[0411] [ka]

[0412] At room temperature, 2-methyl-4-nitrobenzoyl chloride (94.8 mg, 0.475 mmol) was added to a solution of intermediate I-81 (70 mg, 0.316 mmol) and pyridine (75.0 mg, 0.948 mmol) in tetrahydrofuran (5 mL). The reaction solution was stirred at 50° C. for 5 hours. The mixture was cooled to room temperature, diluted with water (15 mL), and extracted with ethyl acetate (10 mL×2). The organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-82.

[0413] LC-MS (ESI) [M+H] + 385.2.

[0414] Reference Example 83: Preparation of Intermediate I-83

[0415] [ka]

[0416] At room temperature, iron powder (39.2 mg, 0.700 mmol) and ammonium chloride (74.9 mg, 1.40 mmol) were added to a solution of intermediate I-82 (54 mg, 0.140 mmol) in methanol / water (10 mL / 3 mL). The reaction solution was stirred at 50° C. for 2 hours under the protection of argon gas. It was cooled to room temperature, filtered, and the filtrate was concentrated to remove most of the solvent, diluted with water (5 mL), and extracted with ethyl acetate (10 mL×3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-83.

[0417] LC-MS (ESI) [M+H] + 355.1.

[0418] Reference Example 84: Preparation of Intermediate I-84

[0419] [ka]

[0420] Intermediate I-42 (880.00 mg, 1.83 mmol) was dissolved in concentrated hydrochloric acid (5 mL) at 25°C, and the reaction solution was stirred at 80°C for 16 hours. It was directly concentrated to dryness, basified by adding ammonia in methanol (1 mL, 2 M), and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-84.

[0421] LC-MS (ESI) [M+H] + 377.2.

[0422] Reference Example 85: Preparation of Intermediate I-85

[0423] [ka]

[0424] At 25°C, intermediate I-85 (670.00mg, 1.78mmol) was dissolved in dichloromethane (10mL), Boc-L-hydroxyproline (493.30mg, 2.13mmol), N,N-diisopropylethylamine (683.57mg, 5.33mmol) and 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (809.91mg, 2.13mmol) were added, and the reaction solution was stirred at room temperature for 1 hour. Water (20mL) was added, and the mixture was extracted with dichloromethane (20mL x 3). The organic phases were combined, washed with saturated saline (20mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-85.

[0425] LC-MS (ESI) [M+H] + 590.2.

[0426] Reference Example 86: Preparation of Intermediate I-86A and 86B

[0427] [ka]

[0428] Intermediate I-85 (1.22 g) was purified twice on SFC chiral separation columns (ChiralPak AD, 250×30 mm ID, 10 μm and SS whelk O1, 250×30 mm ID, 10 μm) to give chiral intermediate I-86A (Rt=4.726 min) and chiral intermediate I-86B (Rt=5.077 min).

[0429] Chiral analysis method: Chromatography column: Chiralpak AD-3 150 x 4.6 mm ID, 3 μM

[0430] Mobile phase: A: Supercritical carbon dioxide B: Ethanol (0.05% diethylamine)

[0431] Elution gradient: 5% to 40% B, 5 min; 40% B, 2.5 min; then 5% B, 2.5 min.

[0432] Flow rate: 2.5mL / min

[0433] Chromatography column temperature: 35°C

[0434] Automatic Back Pressure Regulator (ABPR): 1500psi

[0435] Intermediate I-86A LC-MS (ESI) [M+H] + 590.4;Intermediate I-86B LC-MS (ESI) [M+H] + 590.2.

[0436] Reference Example 87: Preparation of Intermediate I-87

[0437] [ka]

[0438] Intermediate I-86A (200.00 mg, 0.34 mmol) was dissolved in concentrated hydrochloric acid (3 mL) at 25° C., and the reaction solution was stirred at 100° C. for 16 h. It was directly concentrated to remove the organic solvent to give the crude product of intermediate I-87. The crude product was used directly in the next reaction.

[0439] LC-MS (ESI) [M+H] + 223.0.

[0440] Reference Example 88: Preparation of Intermediate I-88

[0441] [ka]

[0442] At 25°C, intermediate I-87 (400.00 mg) was dissolved in tetrahydrofuran (4 mL), and saturated aqueous sodium bicarbonate (2 mL) and di-tert-butyl dicarbonate (89.05 mg, 0.41 mmol) were added, and the reaction solution was reacted at room temperature for 1 hour. Water (10 mL) was added, and extraction was performed with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-88.

[0443] LC-MS (ESI) [M+H] + 323.0.

[0444] Reference Example 89: Preparation of Intermediate I-89

[0445] [ka]

[0446] At 25°C, intermediate I-88 (60.00 mg, 0.19 mmol) was dissolved in dichloromethane (5 mL), triethylamine (56.42 mg, 0.56 mmol) and 2-methyl-4-nitrobenzoyl chloride (55.64 mg, 0.28 mmol) were added, and the reaction solution was stirred at room temperature for 16 hours. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-89.

[0447] LC-MS (ESI) [M-100+H] + 386.0.

[0448] Reference Example 90: Preparation of Intermediate I-90

[0449] [ka]

[0450] Intermediate I-89 (60.00 mg, 0.12 mmol) was dissolved in ethanol (8 mL) at 25°C, reduced iron powder (34.47 mg, 0.62 mmol) and saturated aqueous ammonium chloride solution (2 mL) were added, and the reaction solution was stirred at 80°C for 5 hours. After filtration, the filter cake was washed with ethyl acetate (20 mL), the filtrate was collected, and water (10 mL) was added and separated. The organic phase was collected, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-90.

[0451] LC-MS (ESI) [M-100+H] + 356.4.

[0452] Reference Example 91: Preparation of Intermediate I-91

[0453] [ka]

[0454] At 25°C, intermediate I-90 (50.00 mg, 0.11 mmol) was dissolved in dichloromethane (5 mL), and triethylamine (33.29 mg, 0.33 mmol) and o-toluoyl chloride (25.43 mg, 0.16 mmol) were added in sequence, and the reaction solution was stirred at room temperature for 1 hour. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-91.

[0455] LC-MS (ESI) [M-100+H] + 474.0.

[0456] Reference Example 92: Preparation of Intermediate I-92

[0457] [ka]

[0458] Intermediate I-86B (750.00 mg, 1.27 mmol) was dissolved in concentrated hydrochloric acid (8 mL) at 25° C., and the reaction solution was stirred at 100° C. for 16 h. It was directly concentrated to remove the organic solvent to give the crude product of intermediate I-92. The crude product was used directly in the next reaction.

[0459] LC-MS (ESI) [M+H] + 223.0.

[0460] Reference Example 93: Preparation of Intermediate I-93

[0461] [ka]

[0462] At 25°C, intermediate I-92 (1.40 g) was dissolved in tetrahydrofuran (20 mL), and saturated aqueous sodium bicarbonate (10 mL) and di-tert-butyl dicarbonate (332.61 mg, 1.52 mmol) were added, and the reaction solution was stirred at room temperature for 1 hour. Water (20 mL) was added, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-93.

[0463] LC-MS (ESI) [M+H] + 323.2.

[0464] Reference Example 94: Preparation of Intermediate I-94

[0465] [ka]

[0466] At 25°C, intermediate I-93 (70.00 mg, 0.22 mmol) was dissolved in dichloromethane (5 mL), triethylamine (65.77 mg, 0.65 mmol) and 2-methyl-4-nitrobenzoyl chloride (64.92 mg, 0.33 mmol) were added, and the reaction solution was stirred at room temperature for 16 hours. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-94.

[0467] LC-MS (ESI) [M-100+H] + 386.0.

[0468] Reference Example 95: Preparation of Intermediate I-95

[0469] [ka]

[0470] Intermediate I-94 (90.00 mg, 0.19 mmol) was dissolved in ethanol (8 mL) at 25°C, reduced iron powder (51.71 mg, 0.93 mmol) and saturated aqueous ammonium chloride solution (2 mL) were added, and the reaction solution was stirred at 80°C for 5 hours. After filtration, the filter cake was washed with ethyl acetate (20 mL), and the filtrate was collected and water (20 mL) was added to separate the layers. The organic phase was collected and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-95.

[0471] LC-MS (ESI) [M-100+H] + 356.2.

[0472] Reference Example 96: Preparation of Intermediate I-96

[0473] [ka]

[0474] Intermediate I-95 (70.00 mg, 0.15 mmol) was dissolved in dichloromethane (5 mL) at 25°C, and triethylamine (46.60 mg, 0.46 mmol) and o-toluoyl chloride (35.60 mg, 0.23 mmol) were added in sequence, and the reaction solution was stirred at room temperature for 1 hour. Water (10 mL) was added, and the mixture was extracted with dichloromethane (10 mL x 3). The organic phases were combined, washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-96.

[0475] LC-MS (ESI) [M-100+H] + 474.2.

[0476] Reference Example 97: Preparation of Intermediate I-97

[0477] [ka]

[0478] In an ice-water bath, thionyl chloride (311 mg, 2.61 mmol) was added to intermediate I-19 (335 mg, 1.31 mmol) in N,N-dimethylacetamide (15 mL). The reaction mixture was stirred at room temperature for 3 hours, and then intermediate I-5 (150 mg, 0.653 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours to react. Water (40 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-97.

[0479] LCMS (ESI) [M+H] + 468.1.

[0480] Reference Example 98: Preparation of Intermediate I-98

[0481] [ka]

[0482] At room temperature, o-chlorobenzoyl chloride (1.27 g, 7.23 mmol) was added to a solution of methyl 6-aminonicotinate (1.00 g, 6.57 mmol) in pyridine (20.0 mL). The reaction mixture was stirred at room temperature for 1 hour, then poured into water (100 mL), suction filtered, and the filter cake was dried to obtain intermediate I-98.

[0483] LC-MS (ESI) [M+H] + 290.9.

[0484] Reference Example 99: Preparation of Intermediate I-99

[0485] [ka]

[0486] At room temperature, aqueous sodium hydroxide solution (2 mL, 3.5N) was added to a solution of intermediate I-98 (680 mg, 2.34 mmol) in tetrahydrofuran (10 mL), and the reaction solution was stirred at 70° C. for 1 hour. Dilute hydrochloric acid (1N) was added to the reaction solution to adjust the pH to 5, and the reaction solution was filtered, and the filter cake was sucked dry to obtain intermediate I-99.

[0487] LC-MS (ESI) [M+H] + 277.0.

[0488] Reference Example 100: Preparation of Intermediate I-100

[0489] [ka]

[0490] In an ice-water bath, thionyl chloride (622 mg, 5.23 mmol) was added to intermediate I-99 (800 mg, 2.89 mmol) in N,N-dimethylacetamide (20 mL). The reaction mixture was stirred at room temperature for 3 hours, and then intermediate I-5 (300 mg, 1.31 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours to react. Water (40 mL) was added to dilute the mixture, and the mixture was extracted with ethyl acetate (20 mL x 2). The organic phases were combined, washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography to obtain intermediate I-100.

[0491] LCMS (ESI) [M+H] + 487.9.

[0492] Preparation of the Examples

[0493] Example 1: Preparation of Compound 1

[0494] [ka]

[0495] At room temperature, intermediate I-8 (150 mg, 0.287 mmol) was added to an aqueous ammonia solution (8.00 mL), and elemental iodine (728 mg, 2.87 mmol) and α-isotridecyl-ω-hydroxy-poly(oxy-1,2-ethanediyl) (1.00 mL) were added to the reaction system. The reaction mixture was stirred at room temperature for 24 hours, after which a saturated aqueous sodium thiosulfate solution (50 mL) was added and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC (ammonia water system) to obtain compound 1.

[0496] LC-MS (ESI) [M+H] + 537.0.

[0497] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.25 - 11.15 (m, 1H), 8.55 - 8.13 (m, 1H), 8.10 - 7.48 (m, 7H), 7.27 (d, J = 7.4 Hz, 1H), 7.12 - 6.86 (m, 1H), 5.09 - 4.71 (m, 1H), 3.19 - 2.94 (m, 1H), 2.88 - 2.54 (m, 2H), 2.45 - 2.16 (m, 2H).

[0498] Example 2: Preparation of Compound 2

[0499] [ka]

[0500] At room temperature, intermediate I-10 (150 mg, 0.312 mmol) was added to an ammonia (8.00 mL) solution, and elemental iodine (792 mg, 3.12 mmol) and α-isotridecyl-ω-hydroxy-poly(oxy-1,2-ethanediyl) (1.00 mL) were added to the reaction system. The reaction solution was stirred at room temperature for 24 hours, and then saturated aqueous sodium thiosulfate solution (50 mL) was added and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC (ammonia water system) to obtain compound 2.

[0501] LC-MS (ESI) [M+H] + 496.0.

[0502] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.16 - 10.48 (m, 1H), 7.55 - 7.80 (m, 2H), 7.04 - 7.50 (m, 7H), 6.59 - 6.82 (m, 1H), 4.52 - 4.98 (m, 1H), 3.54 - 3.74 (m, 1H), 3.34 - 3.49 (m, 1H), 2.96 - 3.12 (m, 1H), 2.72 - 2.84 (m, 1H), 2.13 - 2.45 (m, 8H).

[0503] Example 3: Preparation of Compound 3

[0504] [ka]

[0505] At room temperature, intermediate I-17 (40 mg, 0.080 mmol) was added to aqueous ammonia (5 mL), iodine (101.8 mg, 0.800 mmol) and α-isotridecyl-ω-hydroxy-poly(oxy-1,2-ethanediyl) (0.1 mL) were added in sequence, and after the addition was completed, the reaction mixture was stirred overnight at room temperature to react. Saturated aqueous sodium sulfite solution (10 mL) was added to dilute, and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by preparative HPLC (aqueous ammonia system) to obtain compound 3.

[0506] LC-MS (ESI) [M+H] + 515.0.

[0507] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.28 - 10.84 (m, 1H), 8.64 - 6.69 (m, 9H), 5.00 - 4.67 (m, 1H), 2.78 (dt, J = 43.7, 22.6 Hz, 1H), 2.47 (s, 3H), 2.22 - 1.74 (m, 5H), 1.54 (dd, J = 52.0, 31.2 Hz, 2H).

[0508] Example 4: Preparation of Compound 4

[0509] [ka]

[0510] At room temperature, intermediate I-21 (100 mg, 0.232 mmol) was dissolved in ammonia water (5.00 mL) solution, and elemental iodine (177 mg, 0.696 mmol) and α-isotridecyl-ω-hydroxy-poly(oxy-1,2-ethanediyl) (0.300 mL) were added to the reaction system. The reaction mixture was stirred at room temperature for 16 hours, and then water (20 mL) was added and extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated aqueous sodium thiosulfate solution (30 mL) and saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC (ammonia water system) to obtain compound 4.

[0511] LC-MS (ESI) [M+H] + 447.1.

[0512] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.86 - 10.76 (m, 1H), 8.48 - 8.01 (m, 2H), 7.61 - 7.09 (m, 7H), 6.85 (dd, J = 43.8, 8.3 Hz, 1H), 4.86 (d, J = 12.6 Hz, 1H), 2.84 - 2.71 (m, 1H), 2.35 (s, 3H), 2.13 - 1.77 (m, 5H), 1.58 - 1.48 (m, 1H).

[0513] Example 5: Preparation of Compound 5

[0514] [ka]

[0515] At room temperature, intermediate I-23 (100 mg, 0.206 mmol) was added to aqueous ammonia (5 mL), iodine (533 mg, 2.1 mmol) and α-isotridecyl-ω-hydroxy-poly(oxy-1,2-ethanediyl) (0.3 mL) were added in sequence, and after the addition was completed, the reaction mixture was stirred overnight at room temperature to react. Saturated aqueous sodium sulfite solution (10 mL) was added to dilute, and extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with water (10 mL x 3), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by preparative HPLC (ammonia water system) to obtain compound 5.

[0516] LC-MS (ESI) [M+H] + 501.0.

[0517] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.21 - 11.10 (m, 1H), 8.50 - 7.93 (m, 2H), 7.84 - 7.10 (m, 7H), 6.96 - 6.76 (m, 1H), 4.96 - 4.71 (m, 1H), 2.86 - 2.69 (m, 1H), 2.21 - 1.83 (m, 5H), 1.80 - 1.44 (m, 2H).

[0518] Example 6: Preparation of Compound 6

[0519] [ka]

[0520] At room temperature, intermediate I-30 (150 mg, 0.336 mmol) was dissolved in aqueous ammonia (5.00 mL), and elemental iodine (426 mg, 1.68 mmol) and α-isotridecyl-ω-hydroxy-poly(oxy-1,2-ethanediyl) (0.300 mL) were added to the reaction system, and the reaction mixture was stirred at room temperature for 16 hours. Water (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, washed with saturated aqueous sodium thiosulfate solution (20 mL) and saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC (ammonia water system) to obtain compound 6.

[0521] LC-MS (ESI) [M+H] + 461.1.

[0522] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.97 - 10.44 (m, 1H), 8.59 - 7.03 (m, 8H), 6.75 (dd, J = 41.4, 8.3 Hz, 1H), 4.97 - 4.75 (m, 1H), 2.90 - 2.63 (m, 1H), 2.48 - 2.31 (m, 6H), 2.22 - 1.74 (m, 5H), 1.54 (dd, J = 53.9, 30.7 Hz, 2H).

[0523] Example 7: Preparation of Compound 7

[0524] [ka]

[0525] At room temperature, potassium tert-butoxide (85.3 mg, 0.760 mmol) and trimethylsulfoxonium iodide (335 mg, 1.52 mmol) were added to dimethyl sulfoxide (1.5 mL), and the reaction solution was stirred at room temperature for 10 minutes. Next, intermediate I-31 (70 mg, 0.152 mmol) was added, and the reaction solution was reacted at 50° C. for 16 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (10 mL×3), and the organic phases were combined. The organic phase was washed with saturated saline (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC (ammonium bicarbonate system) to obtain compound 7.

[0526] LC-MS (ESI) [M+H] + 476.1.

[0527] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.43 - 7.64 (m, 1H), 7.53 - 6.91 (m, 7H), 6.88 - 6.51 (m, 1H), 4.94 - 4.43 (m, 1H), 3.39 (d, J = 9.5 Hz, 1H), 3.26 (d, J = 12.6 Hz, 2H), 3.18 - 2.77 (m, 2H), 2.29 - 1.90 (m, 8H), 1.84 - 1.46 (m, 2H).

[0528] Example 8: Preparation of Compound 8

[0529] [ka]

[0530] At room temperature, intermediate I-34 (150 mg, 0.322 mmol) was dissolved in aqueous ammonia (6 mL), and elemental iodine (817 mg, 3.22 mmol) and α-isotridecyl-ω-hydroxy-poly(oxy-1,2-ethanediyl) (0.2 mL) were added to the reaction system. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was quenched by adding saturated sodium sulfite (10 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC to obtain compound 8.

[0531] LC-MS (ESI) [M+H] + 479.9.

[0532] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.66 - 10.31 (m, 1H), 7.74 - 6.99 (m, 9H), 6.78 - 6.56 (m, 1H), 4.84 - 3.63 (m, 1H), 3.14 - 2.65 (m, 1H), 2.39 (s, 3H), 2.19 - 1.72 (m, 5H), 1.69 - 1.45 (m, 2H).

[0533] Example 9: Preparation of Compound 9

[0534] [ka]

[0535] Compound I-36 (300 mg, 0.674 mmol) was dissolved in aqueous ammonia (20.0 mL) at room temperature, and elemental iodine (513 mg, 2.02 mmol) and α-isotridecyl-ω-hydroxy-poly(oxy-1,2-ethanediyl) (30 mL) were added to the reaction system, and the reaction mixture was stirred at room temperature for 8 hours. The reaction system was poured into saturated sodium hydrogen sulfite solution (100 mL) and extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated saline (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC to obtain compound 9.

[0536] LC-MS (ESI) [M+H] + 460.0.

[0537] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.49 - 10.10 (m, 1H), 7.92 - 6.91 (m, 9H), 6.79 - 6.53 (m, 1H), 4.95 - 3.61 (m, 1H), 3.10 - 2.67 (m, 1H), 2.40 - 2.33 (m, 6H), 2.12 - 1.75 (m, 4H), 1.69 - 1.43 (m, 2H).

[0538] Example 10: Preparation of Compounds 10A and 10B

[0539] [ka]

[0540] At room temperature, intermediate I-37 (220 mg, 0.477 mmol) was dissolved in tert-butanol (2.20 mL), trimethylsulfoxonium iodide (1.05 g, 4.77 mmol) and potassium tert-butoxide (268 mg, 2.39 mmol) were added in sequence, and the reaction mixture was stirred at 55°C for 18 hours. The reaction system was cooled to room temperature, poured into water (30.0 mL), extracted with ethyl acetate (10 mL x 4), the organic phases were combined, washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC to obtain compound 10A and compound 10B.

[0541] Compound 10A:

[0542] LC-MS (ESI) [M+Na] + 497.0.

[0543] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.41 - 10.28 (m, 1H), 7.83 - 7.54 (m, 3H), 7.48 - 7.22 (m, 7H), 4.74 - 4.42 (m, 2H), 3.54 (m, 1H), 3.15 - 3.01 (m, 1H), 2.96 - 2.80 (m, 1H), 2.41 - 2.31 (m, 8H), 1.87 - 1.52 (m, 3H).

[0544] Compound 10B:

[0545] LC-MS (ESI) [M+H] + 489.1.

[0546] 1 H NMR (400 MHz, DMSO-d 6 +D 2O) δ 7.70 - 7.56 (m, 1H), 7.41 (dd, J = 8.3, 2.4 Hz, 1H), 7.33 - 6.87 (m, 8H), 4.62 - 4.33 (m, 2H), 3.41 - 3.30 (m, 2H), 3.28 - 3.20 (m, 1H), 3.09 - 2.96 (m, 1H), 2.88 - 2.72 (m, 1H), 2.30 - 2.06 (m, 8H), 1.82 - 1.36 (m, 3H).

[0547] Example 11: Preparation of Compound 11

[0548] [ka]

[0549] At 25°C, intermediate I-47 (40.00 mg, 0.070 mmol) was dissolved in a solution of hydrogen chloride in dioxane (5 mL, 3 M), and the reaction solution was reacted at room temperature for 1 hour. The mixture was concentrated and dried, and separated and purified by preparative HPLC (ammonium bicarbonate system) to obtain compound 11.

[0550] LC-MS (ESI) [M+H] + 474.2.

[0551] 1 H NMR (400 MHz, Methanol-d 4) δ 7.68 - 7.51 (m, 1H), 7.48 - 7.08 (m, 5H), 6.92 (dd, J = 8.5, 2.5 Hz, 1H), 6.73 (d, J = 8.5 Hz, 1H), 6.60 (d, J = 8.4 Hz, 1H), 6.09 (dt, J = 64.2, 6.5 Hz, 1H), 4.65 - 4.55 (m, 1H), 3.71 (s, 1H), 3.46 (dt, J = 13.0, 5.2 Hz, 1H), 2.89 - 2.78 (m, 2H), 2.78 - 2.64 (m, 1H), 2.62 - 2.51 (m, 1H), 2.51 - 2.40 (m, 1H), 2.30 - 2.28 (m, 6H), 2.24 - 2.06 (m, 1H), 1.97 (m, 1H).

[0552] Example 12: Preparation of Compound 12

[0553] [ka]

[0554] At room temperature, 2-methylbenzoyl chloride (21.9 mg, 0.142 mmol) and triethylamine (28.7 mg, 0.284 mmol) were added to a dichloromethane (5 mL) solution of intermediate I-57 (35 mg, 0.0944 mmol), and the reaction solution was reacted at room temperature for 3 hours. The reaction solution was diluted with dichloromethane (10 mL), washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC (ammonium bicarbonate system) to obtain compound 12.

[0555] LC-MS (ESI) [M+H] + 489.1

[0556] 1 H NMR (400 MHz, DMSO-d 6) δ 10.41 - 10.26 (m, 1H), 7.77 - 6.58 (m, 10H), 4.37 - 4.04 (m, 1H), 3.99 - 3.47 (m, 4H), 3.06 - 2.80 (m, 1H), 2.70 - 2.51 (m, 1H), 2.45 - 2.16 (m, 7H), 2.04 - 1.93 (m, 1H), 1.86 - 1.51 (m, 3H).

[0557] Example 13: Preparation of Compound 13

[0558] [ka]

[0559] At room temperature, intermediate I-7 (54.0 mg, 0.174 mmol) was dissolved in N,N-dimethylacetamide (5.00 mL), cooled to 0 ° C., and under the protection of argon gas, thionyl chloride (20.7 mg, 0.174 mmol) was added, and the reaction mixture was stirred at 0 ° C. for 3 hours, and then intermediate I-58 (30.0 mg, 0.116 mmol) was added, and the reaction mixture was stirred at room temperature for 16 hours. It was added to water (20 mL), extracted with ethyl acetate (10 mL × 3), and the organic phase was combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC (ammonia water system) to obtain compound 13.

[0560] LCMS (ESI) [M+H] + 552.0.

[0561] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.29 - 11.19 (m, 1H), 8.41 - 7.97 (m, 2H), 7.90 - 7.63 (m, 6H), 7.45 - 6.92 (m, 2H), 4.85 - 4.49 (m, 3H), 3.54 - 2.63 (m, 4H), 2.38 - 2.15 (m, 1H).

[0562] Example 14: Preparation of Compound 14

[0563] [ka]

[0564] At room temperature, potassium tert-butoxide (175 mg, 1.56 mmol) and trimethylsulfoxonium iodide (343 mg, 1.56 mmol) were added to dimethyl sulfoxide (1.00 mL), and the reaction solution was stirred at room temperature for 5 minutes. Next, intermediate I-59 (100 mg, 0.223 mmol) was added, and the reaction solution was stirred at 70° C. for 20 hours. The reaction solution was cooled to room temperature, diluted with water (10 mL), extracted with ethyl acetate (5 mL×3), and the organic phases were combined. The organic phase was washed with saturated saline (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC (ammonia water system) to obtain compound 14.

[0565] LC-MS (ESI) [M+H] + 462.0.

[0566] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.09 - 10.74 (m, 1H), 8.56 - 8.00 (m, 2H), 7.87 - 7.17 (m, 7H), 7.06 - 6.78 (m, 1H), 4.80 - 4.33 (m, 3H), 3.11 - 2.92 (m, 1H), 2.89 - 2.54 (m, 2H), 2.47 - 2.15 (m, 4H), 2.12 - 1.55 (m, 3H).

[0567] Example 15: Preparation of Compound 15

[0568] [ka]

[0569] At room temperature, intermediate I-65 (200 mg, 0.392 mmol) was dissolved in dimethyl sulfoxide (5.00 mL), trimethylsulfoxonium iodide (863 mg, 3.92 mmol) and potassium tert-butoxide (220 mg, 1.96 mmol) were added in sequence, and the reaction mixture was stirred at 50°C for 24 hours. The reaction system was cooled to room temperature, poured into water (30 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, washed with saturated saline (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative HPLC (ammonium bicarbonate system) to obtain compound 15.

[0570] LC-MS (ESI) [M+H] + 524.0.

[0571] 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.12 - 7.65 (m, 1H), 7.64 - 7.10 (m, 10H), 7.08 - 6.01 (m, 4H), 4.88 - 4.43 (m, 1H), 3.14 - 2.86 (m, 4H), 2.83 - 2.66 (m, 1H), 2.17 - 1.51 (m, 4H).

[0572] Example 16: Preparation of Compound 16

[0573] [ka]

[0574] At room temperature, O-(7-azabenzotriazol-1-yl)-N,N,N'-tetramethyluronium hexafluorophosphate (46.8 mg, 0.123 mmol) and N,N-diisopropylethylamine (23.9 mg, 0.185 mmol) were added to a solution of intermediate I-71 (21 mg, 0.0616 mmol) and o-methylbenzoic acid (10.1 mg, 0.0742 mmol) in N,N-dimethylformamide (5 mL), and the reaction solution was stirred at 50°C for 16 hours. Water (10 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 mL x 3), and the organic phases were combined, washed with saturated saline (20 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated to dryness and purified by C18 reverse phase chromatography to obtain compound 16.

[0575] LC-MS (ESI) [M+H] + 459.2.

[0576] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.40 - 10.24 (m, 1H), 7.77 - 7.45 (m, 2H), 7.40 - 7.02 (m, 7H), 6.76 - 6.66 (m, 1H), 4.88 - 2.68 (m, 1H), 2.37 (m, 6H), 2.00 - 1.87 (m, 1H), 1.82 - 1.52 (m, 2H), 1.38 - 1.14 (m, 2H), 1.02 - 0.85 (m, 1H), 0.82 - 0.68 (m, 2H).

[0577] Example 17: Preparation of Compound 17

[0578] [ka]

[0579] At room temperature, 2-methylbenzoic acid (19.3 mg, 0.142 mmol), N,N-diisopropylethylamine (43.7 mg, 0.339 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N'-tetramethyluronium hexafluorophosphate (85.9 mg, 0.226 mmol) were added to a solution of intermediate I-83 (40 mg, 0.113 mmol) in N,N-dimethylformamide (3 mL), and the reaction solution was reacted at room temperature for 16 hours. The reaction solution was separated and purified by preparative HPLC (formic acid system) to obtain compound 17.

[0580] LC-MS (ESI) [M+H] + 473.3.

[0581] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.40 - 10.26 (m, 1H), 7.75 - 7.17 (m, 9H), 6.86 - 6.55 (m, 1H), 4.52 - 3.50 (m, 1H), 2.98 - 2.83 (m, 1H), 2.77 - 2.64 (m, 1H), 2.41 - 2.23 (m, 7H), 2.22 - 1.35 (m, 8H).

[0582] Example 18: Preparation of Compound 18

[0583] [ka]

[0584] At 25° C., intermediate I-91 (50.00 mg, 0.087 mmol) was dissolved in a solution of hydrogen chloride in dioxane (5 mL, 3 M), and the reaction solution was stirred at room temperature for 1 hour. The mixture was concentrated to dryness, and separated and purified by preparative HPLC (ammonium bicarbonate system) to obtain chiral compound 18.

[0585] LC-MS (ESI) [M+H] + 474.2.

[0586] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.31 (s, 1H), 7.58 - 7.21 (m, 6H), 7.08 (dd, J = 8.3, 2.5 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 6.69 (d, J = 8.4 Hz, 1H), 6.32 - 5.90 (m, 1H), 4.68 - 4.49 (m, 1H), 3.77 - 3.64 (m, 1H), 3.59 (s, 1H), 3.49 - 3.40 (m, 2H), 2.82 - 2.69 (m, 2H), 2.44 (d, J = 6.2 Hz, 2H), 2.39 (s, 1H), 2.34 (s, 3H), 2.29 (s, 3H), 2.22 - 2.06 (m, 1H).

[0587] Example 19: Preparation of Compound 19

[0588] [ka]

[0589] Intermediate I-96 (70.00 mg, 0.12 mmol) was dissolved in a solution of hydrogen chloride in dioxane (5 mL, 3 M) at 25° C., and the reaction solution was stirred at room temperature for 1 hour. The mixture was concentrated to dryness, and separated and purified by preparative HPLC (ammonium bicarbonate system) to obtain chiral compound 19.

[0590] LC-MS (ESI) [M+H] + 474.2.

[0591] 1 H NMR (400 MHz, DMSO-d 6) δ 10.34 (s, 1H), 7.57 - 7.23 (m, 6H), 7.11 (dd, J = 8.5, 2.4 Hz, 1H), 6.85 (d, J = 8.5 Hz, 1H), 6.66 (d, J = 8.4 Hz, 1H), 6.27 - 5.98 (m, 1H), 4.63 - 4.48 (m, 1H), 3.85 - 3.57 (m, 1H), 3.51 - 3.34 (m, 1H), 2.99 - 2.78 (m, 3H), 2.64 (q, J = 8.6, 7.7 Hz, 1H), 2.48 (d, J = 18.7 Hz, 2H), 2.39 (s, 1H), 2.34 - 2.28 (m, 6H), 2.23 - 1.90 (m, 1H).

[0592] Example 20: Preparation of Compound 20

[0593] [Chemical formula]

[0594] At room temperature, α-isotridecyl-ω-hydroxy-poly(oxy-1,2-ethanediyl) (1.00 mL) and elemental iodine (1.19 g, 4.69 mmol) were added to ammonia water (20 mL) of intermediate I-97 (220 mg, 0.470 mmol). The reaction mixture was stirred at room temperature for 16 hours (LCMS and TLC confirmed that about 10% of the product was produced and most of the raw material remained). Saturated aqueous sodium sulfite (40 mL) was added, extracted with ethyl acetate (30 mL x 2), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel chromatography to recover a mixture of the raw materials and the product (210 mg), and then re-added as above and repeated twice. A saturated aqueous solution of sodium sulfite (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography and C18 reverse phase chromatography to obtain compound 20.

[0595] LC-MS (ESI) [M+H] + 483.1.

[0596] 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.90 - 10.80 (m, 1H), 8.48 - 8.07 (m, 1H), 8.08 - 7.20 (m, 8H), 7.09 - 6.82 (m, 1H), 5.03 - 4.76 (m, 1H), 3.19 - 2.92 (m, 1H), 2.84 - 2.54 (m, 2H), 2.42 - 2.13 (m, 5H).

[0597] Example 21: Preparation of Compound 21

[0598] [ka]

[0599] At room temperature, α-isotridecyl-ω-hydroxy-poly(oxy-1,2-ethanediyl) (2.00 mL) and iodine (1.56 g, 6.15 mmol) were added to a solution of I-100 (300 mg, 0.614 mmol) in aqueous ammonia (20 mL). The reaction mixture was stirred at room temperature for 16 h (LCMS and TLC confirmed that about 10% of the product was produced and most of the raw material remained). Saturated aqueous sodium sulfite (40 mL) was added, extracted with ethyl acetate (30 mL x 2), the organic phases were combined, washed with saturated brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product, which was purified by silica gel chromatography to recover a mixture of raw materials and products (295 mg), and then added again as above. A saturated aqueous solution of sodium sulfite (30 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 mL × 2). The organic phases were combined, washed with saturated saline (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel chromatography and C18 reverse phase chromatography to obtain compound 21.

[0600] LC-MS (ESI) [M+H] + 503.0.

[0601] 1 H NMR (400 MHz, DMSO-d 6 ) δ 11.16 - 11.06 (m, 1H), 8.56 - 6.84 (m, 10H), 5.08 - 4.57 (m, 1H), 3.18 - 2.94 (m, 1H), 2.89 - 2.53 (m, 2H), 2.46 - 2.16 (m, 2H).

[0602] Experimental Example 1: IC of compounds for inhibition of vasopressin-induced activation of the vasopressin receptor V2R 50 test (1)Cell A HeLa cell line stably expressing human vasopressin receptor V2R (HeLa-V2R): constructed by Shanghai Genechem Co., Ltd. using lentiviral infection method, and verified by qPCR to stably express human V2R.

[0603] (2) Reagents

[0604] DMEM cell culture medium: Gibco, catalog number 11995065; fetal bovine serum: Genetimes, catalog number FND500; 0.25% trypsin: Gibco, catalog number 25200072; puromycin hydrochloride: Gibco, catalog number A1113803; cAMP-GS HIRANGE kit: Cisbio, catalog number 62AM6PEC; IBMX: Sigma, catalog number i5879; Vasopressin AVP: custom made by GL Biochem (Shanghai) Ltd.

[0605] (3) Test method

[0606] HeLa-V2R cells were cultured in DMEM medium supplemented with 10% fetal bovine serum at 37°C and 5% CO 2 The cells were incubated at 4°C for 1 h and 2 μg / mL puromycin was added to the medium to continue screening for V2R-expressing cells. On the day of the experiment, the cells were digested with trypsin, washed twice with the stimulation buffer of the cAMP-GS HIRANGE kit, resuspended, and counted to obtain 1.6 × 10 6The cells / mL were prepared, and IBMX was added to a final concentration of 0.5 mM. The cell suspension was transferred to a 384-well plate at 5 μL / well, and different concentrations of test compounds (10 μM to 3-fold dilution, 10 concentration gradients) or DMSO (minimum Min, maximum Max control) were added in 2.5 μL increments to the corresponding wells. After incubation at room temperature for 30 minutes, 2.5 μL of vasopressin AVP solution was added to the test compound wells and maximum wells to a final concentration of 2.25 nM, and 2.5 μL of stimulation buffer was added to the minimum well, followed by incubation at 25° C. for 60 minutes. At the same time, a cAMP standard sample (5.6 μM to 3-fold dilution, 10 concentration points) was prepared, and 10 μL of the cAMP standard sample was transferred to the corresponding wells of the 384-well plate. The cAMP-d2 fluorescent probe and anti-cAMP antibody probe provided in the kit were diluted 20-fold with the lysis buffer of the cAMP-GS HIRANGE kit, and 5 μL was added sequentially to each well of the 384-well plate, mixed well, centrifuged briefly, and incubated at 25°C for 2 hours for detection. Samples were detected by HTRF method on an Envision microplate reader to detect the fluorescence intensity at 615 nm and 665 nm. Two replicate wells were made for each sample tested, and 32 replicate wells were made for each Min and Max.

[0607] (4) Data processing

[0608] For each well of the sample, the fluorescence intensity ratio FI at 665 nm and 615 nm was calculated. 665 / 615 The logarithm of the standard concentration is X, and the FI is 665 / 615 The standard curve was obtained by fitting the "log(inhibitor) vs response - variable slope (four parameters)" model in Prism 8.0 software with X1000 as the Y value. 665 / 615 The cAMP concentration corresponding to each sample was calculated using Prism 8.0 software according to the above standard curve, with X1000 being the Y value.

[0609] The formula for calculating %Inhibition is as follows:

[0610]

number

[0611] Where:

number

number

[0612] A nonlinear regression was performed using the “log(inhibitor) vs response - variable slope (four parameters)” model in Prism 8.0 software, with %Inhibition as the Y value and the logarithm of the compound concentration as the X value, to calculate the IC 50 Calculate Y=Bottom+(Top-Bottom) / (1+10^((LogIC 50 -X)*Hill Slope).

[0613] The experimental results are shown in Table 1:

[0614] [Table 1]

[0615] Experimental Example 2: Pharmacokinetics of the Compound of the Present Invention In this example, the pharmacokinetics in the body following intravenous injection and oral administration was evaluated using mice.

[0616] Experimental methods and conditions: Male CD1 mice, 6-8 weeks old, all animals were allowed to freely access food and water, the test compound was intravenously injected once at 1mg / kg (solvent: 5% DMSO / 10% Solutol / 85% Saline), and the test compound was orally administered at 5min, 15min, 30min, 1hr, 2hr, 4hr, 8hr, 24hr, or 10mg / kg (solvent: 5% DMSO / 10% Solutol / 85% Saline), and blood was collected from the orbit at 15min, 30min, 1hr, 2hr, 4hr, 6hr, 8hr, 24hr after administration, each sample was 50μL or more, heparin sodium was used to prevent coagulation, and the samples were left on ice after collection, and centrifuged within 1 hour to obtain plasma for testing. The blood drug concentrations in plasma were detected by liquid phase tandem mass spectrometry (LC / MS / MS), and the measured concentrations were used to calculate the pharmacokinetic parameters with Phoenix WinNonlin software. Tolvaptan was used as control 1, and the experimental results are shown in Tables 2 and 3.

[0617] [Table 2]

[0618] [Table 3]

[0619] Experimental data show that the pharmacokinetic results of the compounds of the present invention administered intravenously and orally in mice show lower metabolic clearance Cl and higher exposure AUC 0-inf showed.

[0620] Experimental Example 3: Testing the inhibitory effect of compounds on the proliferation of LLC-PK1 cells (1) Cell Porcine kidney epithelial cells LLC-PK1: purchased from ATCC, catalog number CL-101

[0621] (2) Reagents: Medium 199, Gibco (catalog number 11150059) Fetal bovine serum (FBS), Genetimes, Australia (cat. no. FND500) Trypsin-EDTA (0.25%), Phenol Red, Gibco (Cat. No. 25200072) PBS, pH 7.4, Gibco (catalog number 10010031) DMSO (Dimethyl Sulfoxide), Sigma (Cat. No. D8418) Poly-D-lysine, Gibco (catalog number A3890401) Vasopressin AVP: Custom made by GL Biochem (Shanghai) Ltd. Verapamil hydrochloride, MCE (catalog number HY-A0064) AlamarBlue TM HS Cell Viability Reagent, Invitrogen (Cat. No. A50100)

[0622] (3) Test method: The pathogenesis of polycystic kidney disease is associated with low intracellular calcium ion concentration in renal collecting duct epithelial cells, which leads to cAMP-dependent cell hyperproliferation. Based on a research paper published in The Journal of Biological Chemistry by Tamio Yamaguchi et al. in 2004, we optimized and performed a renal epithelial cell LLC-PK1 proliferation experiment to evaluate the inhibitory effect of compounds on vasopressin-induced cell proliferation after a decrease in intracellular calcium ion concentration.

[0623] LLC-PK1 cells were cultured in M199 medium supplemented with 10% fetal bovine serum at 37°C and 5% CO 2 On the first day of the experiment, 0.01% poly-D-lysine was first coated on a 96-well plate, 100 μL was added to each well, and the plate was left at room temperature for 10 min, then aspirated and air-dried at room temperature for 1 h, and washed once with 200 μL of 1XPBS for later use. LLC-PK1 cells were digested with trypsin, resuspended in serum-free M199 after centrifugation, counted, and diluted to 1 × 10 in serum-free M199 medium. 5The cells were diluted to 100 μL / mL of cell suspension, and FBS was added to a final concentration of 1%. The cell suspension was transferred to a 96-well plate at 200 μL / well. After 24 hours of incubation, the supernatant of the preparation was aspirated, and the plate was washed once with 200 μL of PBS. Then, 160 μL of M199 medium containing 0.05% FBS and 20 μL of 10X verapamil (final concentration: 5 μM) were added in sequence, and the plate was incubated for 24 hours. On the third day, 10 μL of test compound at different concentrations (3-fold dilution from final concentration 3 μM, 8 concentration gradients) or DMSO (minimum Min, maximum Max control) was added to the corresponding wells. 10 μL of vasopressin AVP solution was added to the test compound well and maximum well to a final concentration of 10 nM, and 10 μL of serum-free M199 medium was added to the minimum well, and the plate was incubated for 48 hours. On day 5, the medium was carefully aspirated, the cells were washed once with 200 μL PBS, 90 μL serum-free M199 medium was carefully added, then 10 μL Alamar Blue reagent was added, centrifuged at 300 rpm for 1 min, and incubated at 37°C for 2 h for detection. Samples were detected by a SpectraMax instrument with an excitation wavelength of 560 nm and an emission wavelength of 595 nm. Three replicate wells were made for each sample tested, and six replicate wells were made each for Min and Max.

[0624] (4) Data processing The X value represents the concentration of the compound, and the Y value represents the average value obtained by subtracting the fluorescence intensity of the background well from the fluorescence intensity of the sample in each experimental well, and represents the number of live cells in the well at the time of detection. To reflect the dose-effect relationship of different compounds on AVP-induced cell proliferation, a bar graph was created using the Grouped-Summary data-Separated bar graph of GraphPad Prism8.0 software. Tolvaptan was used as a positive control to qualitatively evaluate the inhibitory effect of the compound on proliferation, with "+++" representing that the overall performance is better than tolvaptan, "++" representing that the performance is close to tolvaptan, "+" representing that the performance is weaker than tolvaptan, and "-" representing that there is no proliferation inhibition.

[0625] Data quality control: S / B, i.e., the average value of the Max well / the average value of the Min well, is calculated, and if it is 2 or more, it is considered to have passed QC.

[0626] The experimental results, as shown in Figure 1, showed that the inhibitory effect of compound 1 on the proliferation of LLC-PK1 cells was stronger than that of the control product 1 (tolvaptan), and that it had no proliferation-promoting effect under high concentration conditions. [1] A compound represented by formula (X), its optical isomer, and a pharma- ceutically acceptable salt thereof. [ka] (where: Ring A is selected from heterocycloalkyl and cycloalkyl, wherein the heterocycloalkyl and cycloalkyl are selected from 1, 2, 3 or 4 R A optionally replaced by; Ring B is selected from aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl, or cycloalkyl is selected from one, two, or three R 3 optionally replaced by; Ring C is selected from aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein the aryl, heteroaryl, heterocycloalkyl, or cycloalkyl is selected from one, two, or three R 4 optionally replaced by; T 1 、T 2 are each independently selected from N and CH; R 1 、R 2 、R 3 、R 4 are each independently H, F, Cl, Br, I, CN, OH, or NH 2 , alkyl, heteroalkyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein said alkyl, heteroalkyl, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl is optionally substituted by 1, 2, 3, or 4 R; R and R A are each independently H, F, Cl, Br, I, CN, OH, or NH 2 , alkyl, heteroalkyl, aryl, heteroaryl, heterocycloalkyl, and cycloalkyl, wherein said alkyl, heteroalkyl, aryl, heteroaryl, heterocycloalkyl, or cycloalkyl is optionally substituted by 1, 2, 3, or 4 R'; R' is H, F, Cl, Br, I, CN, OH, NH 2 , alkyl, and heteroalkyl; m1 and m2 are each independently selected from 1, 2, 3, or 4; L X is selected from -NH(C=O)-, -alkyl-NH(C=O)-, -NH(C=O)-alkyl-, alkyl, alkenyl and alkynyl, wherein said -alkyl-NH(C=O)-, -NH(C=O)-alkyl-, alkyl, alkenyl or alkynyl is optionally substituted by 1, 2, 3 or 4 R; Additionally, when ring A is selected from heterocycloalkyl, the compound of formula (I) is

change

change

change

change

change

change

change

change

change

[10] Structural Units

change

change

[11] Ring B is selected from phenyl and pyridyl, said phenyl or pyridyl being selected from one, two or three R 3 The compound according to the above [1] or [2], an optical isomer thereof, and a pharma- ceutically acceptable salt thereof, each of which is optionally substituted by:

[12] Ring C is

change

[13] A compound represented by the following formula, its optical isomer, and its pharma- ceutically acceptable salt, selected from the following formulas:

change

change

[14] Use of the compound according to any one of the above [1] to

[13] , an optical isomer thereof, or a pharma- ceutical acceptable salt thereof in the manufacture of a medicament for preventing or treating a disease associated with an arginine vasopressin V1a receptor, an arginine vasopressin V1b receptor, an arginine vasopressin V2 receptor, the sympathetic nervous system, or the renin-angiotensin-aldosterone system.

[15] The use according to

[14] above, wherein the disease associated with arginine vasopressin V1a receptor, arginine vasopressin V1b receptor, arginine vasopressin V2 receptor, the sympathetic nervous system, or the renin-angiotensin-aldosterone system includes hypertension, Reye's syndrome, menstrual pain, premature birth, inappropriate secretion of adrenocorticotropin-releasing hormone, adrenal hyperplasia, depression, chronic congestive heart failure, cirrhosis, syndrome of inappropriate secretion of antidiuretic hormone, hyponatremia due to chronic heart failure / cirrhosis / inappropriate secretion of antidiuretic hormone, or polycystic kidney disease.

Claims

1. A compound represented by formula (II), its optical isomer and a pharma- ceutically acceptable salt thereof. 【Chemistry 1】 (Here, X １ is C(R Ａ ) ２ and NH; X ２ is selected from CH and N; T １ , T ２ is CH; R １ are each independently H, F, Cl, Br, I, CN, OH, or NH ２ and C １－６ alkyl, １－６ Alkyl is optionally substituted with 1, 2 or 3 R; R ２ａ and R ２ｂ are each independently H, F, Cl, Br, I, CN, OH, or NH ２ , C １－６ Alkyl and C ３－６ cycloalkyl, wherein C １－６ Alkyl or C ３－６ Cycloalkyl is optionally substituted by 1, 2 or 3 R; R ３ are H, F, Cl, Br, I, CN, OH, and NH. ２ and C １－６ alkyl, １－６ Alkyl is optionally substituted with 1, 2 or 3 R; R ４ are each independently H, F, Cl, Br, I, CN, OH, or NH ２ , C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylamino, C ３－６ cycloalkyl, phenyl, and 5- to 6-membered heteroaryl; １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylamino, C ３－６ cycloalkyl, phenyl or 5- to 6-membered heteroaryl is optionally substituted by 1, 2 or 3 R, said 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) 2 -, and N; R is H, F, Cl, Br, I, CN, OH, NH ２ , C １－６ Alkyl, C １－６ Alkoxy and C １－６ alkylamino, １－６ Alkyl, C １－６ Alkoxy and C １－６ alkylamino is optionally substituted with 1, 2 or 3 R'; R A is selected from H, OH and NH 2 ; R' is H, F, Cl, Br, I, CN, OH, NH ２ and C １－６ alkyl; n1 is selected from 0, 1 or 2; n2 is selected from 1, 2, or 3.

2. A compound represented by formula (III), its optical isomer and a pharma- ceutically acceptable salt thereof. 【Chemistry 2】 (where: R １ are each independently H, F, Cl, Br, I, CN, OH, or NH ２ and C １－６ alkyl, １－６ Alkyl is optionally substituted with 1, 2 or 3 R; R ３ are H, F, Cl, Br, I, CN, OH, and NH. ２ and C １－６ alkyl, １－６ Alkyl is optionally substituted with 1, 2 or 3 R; R ４ are each independently H, F, Cl, Br, I, CN, OH, or NH ２ , C １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylamino, C ３－６ cycloalkyl, phenyl, and 5- to 6-membered heteroaryl; １－６ Alkyl, C １－６ Alkoxy, C １－６ Alkylamino, C ３－６ cycloalkyl, phenyl or 5- to 6-membered heteroaryl is optionally substituted by 1, 2 or 3 R, said 5- to 6-membered heteroaryl containing 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -N=, -S-, -C(=O)-, -C(=O)O-, -S(=O)-, -S(=O) 2 -, and N; R is H, F, Cl, Br, I, CN, OH, NH ２ , C １－６ Alkyl, C １－６ Alkoxy and C １－６ alkylamino, １－６ Alkyl, C １－６ Alkoxy and C １－６ alkylamino is optionally substituted with 1, 2 or 3 R'; R' is H, F, Cl, Br, I, CN, OH, NH ２ and C １－６ Select from alkyl And; X ２ is selected from CH and N.

3. R is independently H, F, Cl, Br, I, CN, OH, or NH ２ , C.H. ３ , C.F. ３ , 【Chemistry 3】 The compound according to claim 1 or claim 2, its optical isomer, and its pharma- ceutically acceptable salt, selected from:

4. R ４ は、H、F、Cl、Br、I、CN、OH、NH ２ 、CH ３ 、CF ３ 、 【Chemistry 4】 The compound according to any one of claims 1 to 3, which is selected from cyclopropyl, cyclobutyl, cyclopentyl, phenyl, pyridyl, pyrimidinyl, thienyl and thiazolyl, its optical isomers and its pharma- ceutically acceptable salts.

5. Structural Units 【Chemistry 5】 teeth, 【Chemistry 6】 The compound according to claim 1, its optical isomers and pharma- ceutically acceptable salts thereof, selected from:

6. A compound represented by the following formula, its optical isomer, and its pharma- ceutically acceptable salt, selected from the following formulas: 【Chemistry 7】 【Chemistry 8】

7. Use of the compound according to any one of claims 1 to 6, its optical isomer, and its pharma- ceutical acceptable salt in the manufacture of a medicament for preventing or treating a disease associated with the arginine vasopressin V1a receptor, the arginine vasopressin V1b receptor, the arginine vasopressin V2 receptor, the sympathetic nervous system, or the renin-angiotensin-aldosterone system.

8. The use according to claim 7, wherein the disease associated with arginine vasopressin V1a receptor, arginine vasopressin V1b receptor, arginine vasopressin V2 receptor, the sympathetic nervous system, or the renin-angiotensin-aldosterone system includes hypertension, Reye's syndrome, menstrual pain, premature birth, inappropriate secretion of adrenocorticotropin-releasing hormone, adrenal hyperplasia, depression, chronic congestive heart failure, liver cirrhosis, syndrome of inappropriate secretion of antidiuretic hormone, chronic heart failure, liver cirrhosis, hyponatremia due to inappropriate secretion of antidiuretic hormone, or polycystic kidney disease.

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