Novel tetrahydroisoquinoline compound, preparation method therefor, pharmaceutical composition containing said compound, and use thereof

Abstract

Provided are a novel tetrahydroisoquinoline compound, a preparation method therefor, a pharmaceutical composition containing said compound, and a use thereof. Specifically, provided are a nitrogen-containing heterocyclic compound as represented by general formula (I), a pharmaceutically acceptable salt, an enantiomer, a diastereoisomer, or a racemate thereof. The compound may be used for preparing a pharmaceutical composition for treating a disease or condition related to the activity or expression levels of relaxin family receptor 4.

Description

Novel tetrahydroisoquinoline compounds, preparation methods thereof, pharmaceutical compositions containing such compounds and uses thereof Technical Field

[0001] The present invention relates to novel nitrogen-containing heterocyclic compounds, methods for preparing the same, pharmaceutical compositions containing the same, and uses thereof, and belongs to the field of pharmaceutical technology. The invention relates to novel nitrogen-containing heterocyclic compounds represented by general formula (I), pharmaceutically acceptable salts, isomers, solvates, metabolites, metabolic precursors thereof, pharmaceutical compositions containing the same, and uses of the compounds in preventing and / or treating diseases or conditions associated with RXFP4 agonist activity, such as constipation, anorexia, diabetes, and non-alcoholic steatohepatitis. Background Art

[0002] The human relaxin (R) / insulin (INS) superfamily includes INS, insulin-like growth factor (IGF) 1, IGF2, R1, R2, INSL3, INSL4, INSL5, INSL6, and INSL7 (R3). Relaxin and related hormone peptides have diverse functions and are involved in various physiological and pathological processes, including reproduction, neural signaling, wound healing, collagen metabolism, and tumorigenesis. Insulin-like peptide 5 (INSL5) is a member of the relaxin / insulin superfamily. Its structure consists of a signal peptide, an A chain, a B chain, and a connecting C chain. The A and B chains are connected by two disulfide bonds, and there is also a disulfide bond within the A chain. INSL5 is activated and biologically active only after the C peptide chain is hydrolyzed and removed by enzymes. Northern blot analysis revealed that INSL5 was expressed in the human uterus and digestive tract, with the highest expression in the rectum and also in the ascending and descending colon. Quantitative reverse transcription polymerase chain reaction (RT-PCR) analysis revealed that human INSL5 was present in a variety of peripheral tissues, especially the colon, rectum, and uterus, and also in the human brain, primarily in the pituitary gland.

[0003] Relaxin family peptides further induce biological signaling by binding to G protein-coupled receptors. Four relaxin receptors have been discovered, designated RXFP 1-4. In 2003, Liu et al. first discovered RXFP4 in the human genome database. Originally named GPR100, it was initially described as a bradykinin receptor. A 2005 study revealed that GPR100 is a receptor for INSL5, leading to its subsequent renaming as RXFP4, also known as G protein-coupled receptor 142 (GPCR142). INSL5 is a specific agonist of RXFP4. Human RXFP4 consists of 374 amino acids, encoded by a single exon, and belongs to the class A neuropeptide-like G protein-coupled receptor (rhodopsin-like receptor). It consists of a short N-terminal extracellular domain, seven α-helical transmembrane domains, and an intracellular C-terminal domain. After INSL5 binds to RXFP4, the conformation of the RXFP4-coupled Gi protein changes, the α subunit is activated, and Giα-guanosine diphosphate (GDP) is exchanged with guanosine triphosphate (GTP) to generate Giα-GTP; Giα-GTP then separates from the β and γ subunits and moves to the adjacent adenylate cyclase (AC), inhibiting AC and thus inhibiting the production of intracellular cyclic adenosine monophosphate (cAMP), causing the cAMP concentration in tissues expressing RXFP4 to decrease. Northern blotting revealed that human RXFP4 is expressed in the heart, skeletal muscle, kidney, liver, and placenta, with peak expression in the pancreas. RT-PCR revealed that human RXFP4 is expressed in the heart, skeletal muscle, kidney, liver, and placenta, as well as in the colon, thyroid, salivary glands, prostate, thymus, testis, and brain. Western blotting revealed that human RXFP4 is expressed in the hypothalamus, pituitary gland, testis, epididymis, ovary, uterus, pancreas, and liver. Immunohistochemistry revealed that human RXFP4 is expressed in pancreatic islet B cells, as well as in the pituitary gland, testis, and ovary. RXFP4 is expressed only in certain species. The RXFP4 gene in rats and dogs is a pseudogene, and the RXFP4 gene in mice is less conserved than that in humans. Further studies of RXFP4 in monkeys, cattle, and pigs confirmed that these species share a high degree of homology with human RXFP4 and behave similarly to the human receptor in vitro.

[0004] Appetite regulation is one of the main issues of concern in the current medical field. Gastrointestinal hormones have multiple physiological functions outside the intestine and play a key role in food intake behavior, appetite changes, and nutrient metabolism. INSL5 is a gastrointestinal hormone secreted by intestinal L cells and is the second appetite-stimulating hormone discovered after ghrelin. INSL5 and RXFP4 are mainly expressed and distributed in the colon. Therefore, compared with ghrelin receptors, which are mainly distributed in the pituitary gland in the brain, INSL5 and its analogs do not need to pass through the blood-brain barrier and can directly exert physiological functions by affecting the enteric nervous system. This also makes its receptor RXFP4 have potential advantages as a drug treatment target.

[0005] Constipation refers to a condition in which bowel movements are difficult or difficult to pass due to hard or dry stool. Constipation often has many causes, including slow bowel movements due to stool, irritable bowel syndrome, or ostial disease. Related underlying medical conditions include hypothyroidism, diarrhea, Parkinson's disease, colon cancer, diverticulitis, and inflammatory bowel disease. Recent studies have shown that RXFP4 agonists can promote intestinal motility and significantly reduce defecation time in constipated mouse models, suggesting that the discovery of RXFP4 agonists may provide a new class of safe and effective drug treatments for constipation.

[0006] In summary, the RXFP4 target is closely related to important physiological functions of the human body, such as appetite regulation and intestinal motility. The design and discovery of related agonists can provide strong support for subsequent research on the INSL5-RXFP4 system, and is also expected to provide a new class of drugs for the treatment of metabolic-related diseases.

[0007] Summary of the Invention

[0008] One object of the present invention is to provide a nitrogen-containing heterocyclic compound represented by general formula (I), and a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof.

[0009] Another object of the present invention is to provide a method for preparing the compound represented by the above general formula (I).

[0010] Another object of the present invention is to provide a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds represented by the above general formula (I) or pharmaceutically acceptable salts thereof.

[0011] Another object of the present invention is to provide the use of the compound represented by the above general formula (I) in the preparation of drugs for treating glycolipid metabolic diseases such as constipation, anorexia, diabetes, and non-alcoholic steatohepatitis.

[0012] The compounds of the present invention are useful for agonizing relaxin family receptor type 4 (RXFP4).

[0013] In a first aspect, the present invention provides a nitrogen-containing heterocyclic compound represented by general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof:

[0014] in,

[0015] The chiral carbon atom C* is independently S-type, R-type, racemic, or a combination thereof;

[0016] n = 0, 1, or 2;

[0017] X1 and X2 are each independently selected from the group consisting of O or NH;

[0018] X3 is a chemical bond, CHR6 or (CHR6)2;

[0019] R1 and R2 are each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, hydroxyl, carboxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C1-C6 alkylphenyl, substituted or unsubstituted C1-C6 alkyl 5-7 membered heteroaryl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, amino, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 amide, -SOR5, -OSOR5, -OCOR5, C(=NH)NH2, Fmoc, allyloxycarbonyl (Alloc);

[0020] When n=0, R1 and R2 are not methyl at the same time; when n=1, R1 and R2 are not hydrogen at the same time;

[0021] or said R1 and R2 and adjacent (CH2) n O and C=C together constitute a substituted or unsubstituted 5-7 membered heterocycle, wherein the heterocycle is a fully saturated heterocycle, a partially unsaturated heterocycle or an aromatic heterocycle;

[0022] X is selected from the group consisting of O, S, CHR6, C2H4 (i.e., forming a cyclopropyl group at the X substitution position) or NR6; wherein R6 is selected from the group consisting of H, CN, C1-C6 alkyl, C1-C6 alkoxy;

[0023] Y is a linking group selected from the group consisting of: a chemical bond, a C1-C6 straight or branched alkyl group, -CH2NH-, a C2-C6 straight or branched alkenyl group, -CH2O-, -CH2S-, -CONH-, -NHCO-, -COO-, -OOC-,

[0024] Ring A is a substituted or unsubstituted group selected from the following group: a 5-12 membered nitrogen-containing heterocyclic group (including a monocyclic, fused polycyclic, bridged or spirocyclic ring, wherein the connection point is preferably located on the nitrogen atom), a C6-C12 aryl group (preferably a C6-C10 aryl group), a 5-12 membered heteroaryl group (preferably a 5-7 membered heteroaryl group); wherein the heterocyclic group or heteroaryl group includes a heteroatom selected from the following group as the ring skeleton: N, NH, S, O, S(O)2;

[0025] R4 is selected from the following groups which are unsubstituted or substituted with 1-3 substituents: C3-C7 cycloalkyl, 5-12 membered heterocyclic group, C6-C12 aryl, 5-12 membered heteroaryl (preferably 5-7 membered heteroaryl, or benzo 5-7 membered heteroaryl); wherein each of the heterocyclic group or heteroaryl contains 1-3 heteroatoms selected from oxygen, sulfur and nitrogen; and the substituents are each independently selected from halogen, C1-C6 straight or branched alkyl, C2-C6 straight or branched alkyl, C3-C7 cycloalkyl, C1-C7 straight or branched alkyl, C2-C6 straight or branched alkyl, C3-C7 cycloalkyl, C1-C7 straight or branched alkyl, C3 ... a C2-C6 straight-chain or branched alkenyl group, a C2-C6 straight-chain or branched alkynyl group, a C1-C6 straight-chain or branched alkoxy group, a C1-C6 straight-chain or branched alkylcarbonyloxy group, a cyano group, a nitro group, a hydroxyl group, an amino group, a hydroxymethyl group, a trifluoromethyl group, a trifluoromethoxy group, a carboxyl group, a mercapto group, a C1-C4 acyl group, an amide group, a sulfonyl group, an aminosulfonyl group, a C1-C4 alkyl-substituted sulfonyl group, or two substituents on adjacent ring atoms together with the carbon atom to which they are attached form a 5-7 membered ring;

[0026] R3 and R5 are each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, C1-C6 alkyl unsubstituted or substituted by 1-3 halogens, or C3-C6 cycloalkyl unsubstituted or substituted by 1-3 halogens, C6-C10 aryl unsubstituted or substituted by 1-3 halogens, C1-C3 alkyl-C6-C10 aryl unsubstituted or substituted by 1-3 halogens, 5-7 membered heteroaryl unsubstituted or substituted by 1-3 halogens;

[0027] Unless otherwise specified, the term "substituted" refers to the replacement of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: C1 to C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Cycloalkyl, C1~C 10 Alkoxy, 5-12 membered heterocyclic group, halogen, hydroxyl, carboxyl (-COOH), C1~C 10 Aldehyde, C2~C 10 Acyl, C2~C 10 Ester group, cyano group, amino group, phenyl group; the phenyl group includes unsubstituted phenyl group or substituted phenyl group having 1-3 substituents, the substituents are selected from: halogen, C1-C 10Alkyl, cyano, hydroxyl, nitro, C3~C 10 Cycloalkyl, C1~C 10 Alkoxy, amino;

[0028] And the compound is not a structure selected from the following group:

[0029] In another preferred embodiment, the compound has a structure shown in the following formula:

[0030] in,

[0031] The chiral carbon atom C* is independently S-type, R-type, racemic, or a combination thereof;

[0032] n = 0, 1, or 2;

[0033] R1 and R2 are each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, hydroxyl, carboxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C1-C6 alkylphenyl, substituted or unsubstituted C1-C6 alkyl 5-7 membered heteroaryl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, amino, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 amide, -SOR5, -OSOR5, -OCOR5;

[0034] When n=0, R1 and R2 are not methyl at the same time; when n=1, R1 and R2 are not hydrogen at the same time;

[0035] or said R1 and R2 and adjacent (CH2) n O and C=C together constitute a substituted or unsubstituted 5-7 membered heterocycle, wherein the heterocycle is a fully saturated heterocycle, a partially unsaturated heterocycle or an aromatic heterocycle;

[0036] X is O or S;

[0037] Y is a linking group selected from the group consisting of: a chemical bond, a C1-C6 straight or branched alkyl group, -CH2NH-, a C2-C6 straight or branched alkenyl group, -CH2O-, -CH2S-, -CONH-, -NHCO-, -COO-, -OOC-,

[0038] Ring A is a substituted or unsubstituted group selected from the group consisting of a 5- to 12-membered nitrogen heterocyclic group (wherein the attachment site is preferably located on the nitrogen atom), a C6-C12 aryl group (preferably a C6-C10 aryl group), or a 5- to 12-membered heteroaryl group (preferably a 5- to 7-membered heteroaryl group); wherein the heterocyclic group or heteroaryl group includes a heteroatom selected from the group consisting of N, NH, S, O, and S(O)2 as the ring backbone;

[0039] R4 is selected from the following groups which are unsubstituted or substituted with 1-3 substituents: C3-C7 cycloalkyl, 5-12 membered heterocyclic group, C6-C12 aryl, 5-12 membered heteroaryl (preferably 5-7 membered heteroaryl, or benzo 5-7 membered heteroaryl); wherein each of the heterocyclic group or heteroaryl contains 1-3 heteroatoms selected from oxygen, sulfur and nitrogen; and the substituents are each independently selected from halogen, C1-C6 straight or branched alkyl, C2-C6 straight or branched alkyl, C3-C7 cycloalkyl, C1-C7 straight or branched alkyl, C2-C6 straight or branched alkyl, C3-C7 cycloalkyl, C1-C7 straight or branched alkyl, C3 ... a C2-C6 straight-chain or branched alkenyl group, a C2-C6 straight-chain or branched alkynyl group, a C1-C6 straight-chain or branched alkoxy group, a C1-C6 straight-chain or branched alkylcarbonyloxy group, a cyano group, a nitro group, a hydroxyl group, an amino group, a hydroxymethyl group, a trifluoromethyl group, a trifluoromethoxy group, a carboxyl group, a mercapto group, a C1-C4 acyl group, an amide group, a sulfonyl group, an aminosulfonyl group, a C1-C4 alkyl-substituted sulfonyl group, or two substituents on adjacent ring atoms together with the carbon atom to which they are attached form a 5-7 membered ring;

[0040] R3 and R5 are each independently selected from the following groups: hydrogen, deuterium, tritium, halogen, C1-C6 alkyl which is unsubstituted or substituted by 1-3 halogens, or C3-C6 cycloalkyl which is unsubstituted or substituted by 1-3 halogens, C6~C10 aryl which is unsubstituted or substituted by 1-3 halogens, C1-C3 alkyl-C6~C10 aryl which is unsubstituted or substituted by 1-3 halogens, 5-7 membered heteroaryl which is unsubstituted or substituted by 1-3 halogens.

[0041] In another preferred embodiment, the A ring is selected from the following group: aziridine, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, piperazinyl, homopiperazinyl, thiomorpholinyl, thiomorpholinyl with ring sulfur replaced by sulfoxide or sulfone, imidazolidinyl, pyrazinyl, hexahydropyrimidinyl or The A ring is optionally substituted by 1-2 groups selected from hydrogen, C1-C3 straight or branched alkyl, halogen, hydroxyl and C1-C4 alkoxycarbonyl.

[0042] In another preferred embodiment, the A ring is selected from the following group: The A ring is optionally substituted by 1-2 groups selected from hydrogen, C1-C3 straight or branched alkyl, halogen, hydroxyl and C1-C4 alkoxycarbonyl.

[0043] In another preferred embodiment, R1 and R2 are each independently selected from the following group: hydrogen, deuterium, tritium, halogen, hydroxyl, carboxyl, phenyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C1-C6 alkyl 5-7 membered heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, amino, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 amide, -SOR5, -OSOR5, -OCOR5.

[0044] In another preferred embodiment, X is O;

[0045] Y is selected from the group consisting of -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2NH-, -CH2O-, or -CH2S-.

[0046] In another preferred embodiment, R4 is selected from the following groups which are unsubstituted or substituted with 1-3 substituents: C6-C10 aryl, 5-7 membered heteroaryl, or benzo 5-7 membered heteroaryl; preferably, the heterocyclic ring and heteroaromatic ring moieties in the group are selected from the group formed by indole, benzodioxole, isoxazole, pyridine, pyrazole, dihydroimidazopyridine, imidazopyridine, benzothiophene, dihydrobenzodioxane, quinoxaline, pyrrole, benzofuran, indazole, benzimidazole, quinoline, and 1,3-dioxoisoindoline.

[0047] In another preferred embodiment, it is hydrogen, deuterium, tritium, halogen, C1-C6 alkyl which is unsubstituted or substituted by 1-3 halogens, or C3-C6 cycloalkyl which is unsubstituted or substituted by 1-3 halogens.

[0048] In another preferred embodiment, the chiral carbon atom C* is S-type.

[0049] The second aspect of the present invention provides a method for preparing the compound of formula (I) as described in the first aspect of the present invention, the method comprising the steps of:

[0050] (1) In an inert solvent, in the presence of a condensing agent, a compound of formula II and a compound of formula I c Compound reaction to obtain formula I d Compound; preferably, the condensing agent is EDCI (1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride);

[0051] (2) In an inert solvent, use formula I d The compound is subjected to Bischler-Napieralski ring closure reaction to obtain formula I eCompound; preferably, phosphorus oxychloride is used as Lewis acid in the ring-closure reaction;

[0052] (3) In an inert solvent, use formula I e The compound is subjected to reduction reaction to obtain formula I f Compound; preferably, the reduction reaction uses borohydride as a reducing agent or Noyori catalyst as an asymmetric reduction catalyst;

[0053] (4) In an inert solvent, f Compounds and Carrying out a condensation reaction to obtain a compound of formula (I);

[0054] In the above formulae, the definitions of the groups are as described in the first aspect of the present invention.

[0055] The third aspect of the present invention provides a pharmaceutical composition, which comprises: a therapeutically effective amount of the compound of formula (I) as described in the first aspect of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0056] In a fourth aspect, the present invention provides a use of a compound of formula (I) as described in the first aspect of the present invention, characterized in that it is used to prepare a pharmaceutical composition for treating a disease or condition associated with the activity or expression of type 4 relaxin family receptors; preferably, the compound is used to prepare a pharmaceutical composition for treating a disease or condition selected from the group consisting of constipation, anorexia, or a disease related to glucose and lipid metabolism.

[0057] In another preferred embodiment, the compound is used to prepare a pharmaceutical composition for treating diseases or conditions caused by low activity or expression of relaxin type 4 family receptors.

[0058] In another preferred embodiment, the glucose and lipid metabolism-related diseases are selected from the following group: diabetes and non-alcoholic steatohepatitis.

[0059] It should be understood that within the scope of the present invention, the above-mentioned technical features of the present invention and the technical features described in detail below (such as in the embodiments) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be listed here one by one. BRIEF DESCRIPTION OF THE DRAWINGS

[0060] Figure 1. The intestinal motility-promoting effects of different doses of compounds on constipation model mice. A, fecal water content; B, fecal weight; C, fecal pellet count; D, bead elimination time;

[0061] Figure 2. Compounds improve colon histopathological changes in constipation model mice. A, Colonic muscularis thickness; B, Colonic mucosal thickness; C, Liberkunst gland number; D, Goblet cell number;

[0062] Figure 3. Regulatory effects of compounds on the expression levels of AQP3, TRPV1, and CGRP in mouse colon;

[0063] Figure 4. Effects of compounds on serum 5-HT, NO and VIP levels in mice. DETAILED DESCRIPTION

[0064] After extensive and in-depth research, the present inventors have developed a class of compounds of Formula I that can activate relaxin family receptor type 4 (RXFP4). Compared to prior art relaxin family receptor type 4 (RXFP4) inhibitors, these compounds exhibit higher inhibitory activity and selectivity. Based on these findings, the present invention was completed.

[0065] the term

[0066] In this document, unless otherwise specified, the term "substituted" refers to one or more hydrogen atoms on a group being replaced by a substituent selected from the group consisting of: C1 to C 10 Alkyl, C3~C 10 Cycloalkyl, C1~C 10 Alkoxy, halogen, hydroxyl, carboxyl (-COOH), C1~C 10 Aldehyde, C2~C 10 Acyl, C2~C 10 Ester group, amino group, phenyl group; the phenyl group includes unsubstituted phenyl group or substituted phenyl group having 1-3 substituents, the substituents are selected from: halogen, C1-C 10 Alkyl, cyano, hydroxyl, nitro, C3~C 10 Cycloalkyl, C1~C 10 Alkoxy, amino.

[0067] Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom may be optionally in the R configuration or the S configuration, or a mixture of the R configuration and the S configuration.

[0068] The term "C1-C6 alkyl" refers to a straight or branched chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or the like.

[0069] The term "3-8 membered heterocyclic group" refers to a group formed by losing a hydrogen atom from a 3- to 8-membered saturated ring having 1-3 heteroatoms selected from the group consisting of N, S, and O; for example, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or similar groups.

[0070] The term "6-10 membered aryl group" refers to a group formed by losing a hydrogen atom from a 6- to 10-membered aryl group; for example, phenyl, naphthyl, or the like.

[0071] The term "5-10 membered heteroaryl" refers to a group formed by losing a hydrogen atom from a 5- to 8-membered aromatic group having 1-3 heteroatoms selected from the group consisting of N, S, and O, wherein the ring system of each heteroaryl group may be monocyclic or polycyclic; for example, pyrrolyl, pyridyl, thienyl, furanyl, imidazolyl, pyrimidinyl, benzothienyl, indolyl, imidazopyridinyl, quinolinyl or the like.

[0072] The term "C1-C6 alkoxy" refers to a straight or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, or the like.

[0073] The term "C2-C6 ester group" refers to a ROC(=O)- group having 2 to 6 carbon atoms, such as -COOCH3, -COOC2H5, -COOC3H7, -COOC4H9, or the like.

[0074] The term "C2-C6 alkenyl" refers to a group formed by losing one or two hydrogen atoms from an olefin having 2 to 6 carbon atoms, which may be a monoolefin, diolefin or triolefin, such as -CH=CH2, -C2H4=CH2, -CH=C2H4, or a similar group.

[0075] The term "halogen" refers to F, Cl, Br and I.

[0076] Unless otherwise specified, the structural formulas described in the present invention are intended to include all isomeric forms (such as enantiomers, diastereomers and geometric isomers (or conformers): for example, R, S configurations containing asymmetric centers, (Z), (E) isomers of double bonds and (Z), (E) conformers. Therefore, single stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers or geometric isomers (or conformers) are all within the scope of the present invention.

[0077] The term "tautomer" refers to structural isomers of different energies that can interconvert across a low energy barrier. For example, proton tautomers (i.e., prototropy) include interconversions via proton migration, such as 1H-indazole and 2H-indazole, and 1H-benzo[d]imidazole and 3H-benzo[d]imidazole. Valence tautomers include interconversions via reorganization of some of the bonding electrons.

[0078] Herein, the form "C1-C6" indicates that the group may have 1 to 6 carbon atoms, such as 1, 2, 3, 4 or 5 carbon atoms.

[0079] Tetrahydroisoquinoline compounds represented by formula (I)

[0080] The present invention provides a tetrahydroisoquinoline compound represented by general formula (I), its enantiomers, diastereomers, racemates and mixtures thereof or pharmaceutically acceptable salts thereof.

[0081] Here, the definitions of the groups are as described above.

[0082] In another preferred embodiment, n, X, Y, R1, R2, R3, and R4 are each independently the corresponding groups corresponding to the specific compounds in the examples. In particular, the tetrahydroisoquinoline compounds of the present invention are preferably selected from the compounds shown in Table A below:

[0083] Preparation of compounds of formula (I)

[0084] The present invention also provides a method for synthesizing a compound of formula I. Specifically, the compound of formula I is prepared by the following process:

[0085] Step a: I c Dissolve in a solvent and react with II with the aid of a condensing agent to obtain compound I d ; The solvent is dichloromethane;

[0086] Step b: I d Dissolve in a solvent, add excess phosphorus oxychloride, reflux and stir to obtain compound I e ; The solvent is anhydrous acetonitrile;

[0087] Step c: I e Dissolve in a solvent, add excess sodium borohydride, stir until the reaction is complete, and spin dry the solvent to obtain compound I f, the solvent is methanol; or Noyori catalyst is added and stirred until the reaction is complete, and the solvent is a mixed solvent of water and methanol.

[0088] Step d: I f Dissolve in a solvent and react with the corresponding raw material to obtain compound I g ; The solvent is dichloromethane;

[0089] X, Y, R1, R2, R3, and R4 are the same as defined in the above requirements.

[0090] Pharmaceutical composition containing a compound of formula (I)

[0091] The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of one or more nitrogen-containing heterocyclic compounds represented by formula (I), pharmaceutically acceptable salts thereof, prodrugs thereof, and hydrates and solvates thereof, and optionally, a pharmaceutically acceptable carrier, which can be used to treat autoimmune diseases such as psoriasis. The pharmaceutical composition can be prepared in various forms according to different administration routes.

[0092] One or more of the aldehyde compounds represented by formula (I) of the present invention, their pharmaceutically acceptable salts, their prodrugs, and their hydrates and solvates, or the pharmaceutical composition comprising a therapeutically effective amount of one or more of the tetrahydroisoquinoline compounds represented by formula (I), their pharmaceutically acceptable salts, their prodrugs, and their hydrates and solvates can be used as phosphodiesterase 4 (PDE4) inhibitors for the treatment of glycolipid metabolic diseases such as constipation, anorexia, diabetes, and non-alcoholic steatohepatitis.

[0093] Pharmaceutically acceptable salts of the compounds of the present invention can be prepared by direct salt-forming reaction of the free base of the compound with an inorganic or organic acid. The inorganic or organic acid can be selected from hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, hydrofluoric acid, hydrobromic acid, formic acid, acetic acid, picric acid, citric acid, maleic acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonic acid.

[0094] Because the compounds of the present invention have excellent inhibitory activity against relaxin family receptor 4 (RXFP4), the compounds of the present invention, their various crystalline forms, pharmaceutically acceptable inorganic or organic salts, hydrates, or solvates, and pharmaceutical compositions containing the compounds of the present invention as the primary active ingredient can be used to treat and alleviate diseases associated with relaxin family receptor 4 (RXFP4). According to prior art, the compounds of the present invention can be used to treat the following diseases: constipation, anorexia, diabetes, non-alcoholic steatohepatitis, and other glycolipid metabolic diseases.

[0095] The pharmaceutical composition of the present invention comprises a safe and effective amount of a compound of the present invention or a pharmacologically acceptable salt thereof, and a pharmacologically acceptable excipient or carrier. "Safe and effective amount" means an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Typically, the pharmaceutical composition contains 1-2000 mg of the compound of the present invention per dose, more preferably 5-200 mg of the compound of the present invention per dose. Preferably, "one dose" is one capsule or tablet.

[0096] "Pharmaceutically acceptable carriers" refer to: one or more compatible solid or liquid fillers or gel substances, which are suitable for human use and must have sufficient purity and sufficiently low toxicity. "Compatibility" here means that the components in the composition can be mixed with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable carriers include cellulose and its derivatives (such as sodium carboxymethyl cellulose, sodium ethyl cellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid, magnesium stearate), calcium sulfate, vegetable oils (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (such as propylene glycol, glycerol, mannitol, sorbitol, etc.), emulsifiers (such as ), wetting agents (such as sodium lauryl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0097] There is no particular limitation on the administration of the compound or pharmaceutical composition of the present invention. Representative administrations include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous) and topical administration.

[0098] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or with the following ingredients: (a) fillers or extenders, for example, starches, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose, and acacia; (c) humectants, for example, glycerol; (d) disintegrants, for example, agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain complex silicates, and sodium carbonate; (e) solubilizers, for example, paraffin; (f) absorption accelerators, for example, quaternary ammonium compounds; (g) wetting agents, for example, cetyl alcohol and glyceryl monostearate; (h) adsorbents, for example, kaolin; and (i) lubricants, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents.

[0099] Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared using coatings and shell materials, such as enteric coatings and other materials known in the art. They may contain opacifying agents, and the release of the active compound or compounds in such compositions can be delayed in a certain portion of the digestive tract. Examples of useful encapsulating components are polymeric substances and waxes. If desired, the active compound can also be microencapsulated with one or more of the above-mentioned excipients.

[0100] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or tinctures. In addition to the active compound, the liquid dosage form may contain an inert diluent conventionally used in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butylene glycol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil, or mixtures thereof.

[0101] Besides such inert diluents, the composition may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.

[0102] Suspensions, in addition to the active compounds, may contain suspending agents such as, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar, or mixtures of these substances.

[0103] Compositions for parenteral injection may comprise physiologically acceptable sterile aqueous or anhydrous solutions, dispersions, suspensions or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Suitable aqueous and non-aqueous carriers, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof.

[0104] Dosage forms for topical administration of the compounds of this invention include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or propellants that may be required.

[0105] The compounds of the present invention may be administered alone or in combination with other pharmaceutically acceptable compounds.

[0106] The compounds according to the present invention as described above can be used clinically in mammals, including humans and animals, and can be administered through the mouth, nose, skin, lungs, or gastrointestinal tract, and more preferably orally. The daily dose is preferably 0.01 to 200 mg / kg body weight, taken as a single dose, or 0.01 to 100 mg / kg body weight, taken in divided doses. Regardless of the method of administration, the optimal dose for an individual should be determined based on the specific treatment. Generally, the dose is started with a small dose and gradually increased until the most suitable dose is found. Of course, the specific dose should also take into account factors such as the route of administration and the patient's health status, which are all within the skill of a skilled physician.

[0107] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are intended to illustrate the present invention only and are not intended to limit the scope of the invention. The experimental methods in the following examples, for which specific conditions are not specified, are generally based on conventional conditions or the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0108] The present invention is further illustrated in the following examples. These examples are intended to illustrate the present invention only and are not intended to limit the present invention in any way. All parameters in the examples and the remaining descriptions, unless otherwise stated, are based on mass.

[0109] The analytical data of the samples were measured by the following instruments: nuclear magnetic resonance was measured by GEMINI-300, Bruker AMX-400 and INVOA-600 nuclear magnetic resonance instruments, with TMS (tetramethylsilane) as the internal standard, the chemical shift unit was ppm, and the coupling constant unit was Hz; mass spectra were measured by Finnigan MAT-711, MAT-95 and LCQ-DECA mass spectrometers and IonSpec 4.7 Tesla mass spectrometer.

[0110] Column chromatography used silica gel 200-300 mesh (produced by Qingdao Ocean Chemical Plant); TLC silica gel plates were HSGF-254 thin-layer chromatography preformed plates produced by Yantai Chemical Plant; petroleum ether had a boiling range of 60-90°C; and color development was performed using an ultraviolet lamp and an iodine flask. Unless otherwise noted, all conventional reagents and chemicals used in the following examples were purchased from Sinopharm Group. Reagents and solvents used in the experiments were prepared according to the specific reaction conditions.

[0111] Example A1: Synthesis of Compound A1

[0112] Synthesis route:

[0113] Synthesis of compound 1-3:

[0114] Dissolve 1-1 in acetone, add potassium carbonate, and then dropwise add 1-2. Stir under reflux overnight under argon. Filter the reaction mixture, evaporate to dryness, dilute with dichloromethane, add water, and stir for 10 minutes. Allow to stand and separate. Evaporate the organic layer to dryness to obtain a yellow solid 1-3, which is used directly in the next step without purification.

[0115] Synthesis of compound 1-4:

[0116] 1-3 was dissolved in nitromethane, and ammonium acetate was added and refluxed for 2 hours. The solvent was evaporated and added to ice water, stirred for 2 hours, allowed to stand, filtered, and the filter cake was washed with ethyl acetate to obtain a yellow solid with a yield of 90%. 1 H NMR(500MHz, CDCl3)δ7.95(s,2H),7.41(dd,J=8.5,2.0Hz,1H),7.21(d,J=1.9Hz,1H),6 .99(d,J=8.4Hz,1H),4.09(q,J=7.0Hz,2H),3.87(s,2H),1.43(t,J=6.9Hz,3H).ESI-MS m / z 224.2[M+H] + .

[0117] Synthesis of compound 1-5:

[0118] Lithium aluminum tetrahydride was added portionwise to argon-protected tetrahydrofuran under ice-cooling. The tetrahydrofuran solution of 1-4 was added dropwise with stirring. After addition, the mixture was stirred at room temperature for 2 hours. Water was slowly added under ice-cooling to quench the reaction. The mixture was filtered, and the filter cake was washed with ethyl acetate and methanol. The mixture was evaporated to dryness to obtain a slightly yellowish transparent oil. This was used in the next step without further purification.

[0119] Synthesis of compound 2-3:

[0120] Compounds 2-1 and 2-2 were dissolved in toluene and refluxed for 18 hours. The mixture was cooled, the solvent was evaporated, and the mixture was purified by column chromatography (dichloromethane:methanol 100:1) to obtain a white solid with a yield of 85%. 1 H NMR (500MHz, CDCl3) δ9.49(d,J=2.5Hz,1H),8.10(d,J=15.9Hz,1H),7.83(d,J=2.7Hz,1H),7.47(d,J=2.7Hz,1H ),7.08(d,J=8.4Hz,1H),6.80(dd,J=8.4,2.7Hz,1H),6.39(d,J=15.9Hz,1H),3.86(s,3H),3.75(s,3H).ESI-MS m / z 232.2[M+H] + .

[0121] Synthesis of compound 2-4:

[0122] Compound 2-3 was dissolved in methanol, and palladium hydroxide on carbon was added. The mixture was reacted at 60°C for 6 hours. The palladium on carbon was removed by filtration, and the solvent was dried to obtain a white solid. The solid was used directly in the next reaction without purification.

[0123] Synthesis of compound 2-5:

[0124] Compound 2-4 was dissolved in methanol and added with 1M aqueous sodium hydroxide solution. The reaction was allowed to proceed at 50°C for 2 hours. Most of the methanol was removed by rotary evaporation, and most impurities were washed away with dichloromethane. The aqueous phase was adjusted to pH 1-2 with 1M hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to obtain a white solid. This solid was used directly in the next reaction.

[0125] Synthesis of compound 3-6:

[0126] 2-5 was dissolved in dichloromethane, and EDCI, HOBT, and TEA were added and stirred for 30 minutes. The dichloromethane solution of 1-5 was slowly added and stirred overnight. The product was diluted with dichloromethane and washed with saturated sodium bicarbonate, saturated ammonium chloride, and saturated sodium chloride, dried over anhydrous sodium sulfate, evaporated to dryness, and purified by column chromatography with petroleum ether / ethyl acetate = 1:1 to obtain 1.2 g of an off-white solid in a yield of 92%. 1 H NMR (500MHz, CDCl3) δ9.48 (t, J=2.3Hz, 1H), 7.22 (dd, J=8.4, 2.0Hz, 1H), 7.04 (dd, J=1 2.4,2.6Hz,2H),6.87–6.81(m,1H),6.80–6.70(m,2H),6.66(dt,J=9.1,0.9Hz,2H),4.0 8(q,J=7.0Hz,2H),3.84(d,J=7.9Hz,6H),3.42(td,J=5.6,4.4Hz,2H),3.06(t,J=7.8Hz ,2H),2.74(tt,J=5.6,1.0Hz,2H),2.65(t,J=7.8Hz,2H),1.43(t,J=7.0Hz,3H).ESI-MS m / z 397.2[M+H] + .

[0127] Synthesis of compound 3-7:

[0128] Dissolve 1 g of compound 3-6 in 100 mL of anhydrous acetonitrile, add phosphorus oxychloride, and reflux under argon. After completion of the reaction, monitor by TLC, evaporate to dryness under reduced pressure. Add icy saturated sodium bicarbonate to adjust the mixture to a weak base. Extract with dichloromethane, dry over anhydrous sodium sulfate, and evaporate to dryness to obtain an orange oil, which was used directly in the next reaction without purification.

[0129] Synthesis of compound 3-8:

[0130] Compound 3-7 was dissolved in methanol, and sodium borohydride was added portionwise under ice bath. The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated ammonium chloride solution and extracted with dichloromethane. The mixture was washed with saturated sodium bicarbonate and saturated sodium chloride. The organic layer was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography (dichloromethane:methanol 20:1) to obtain a yellow solid. The yield for the two steps was 70%. 1 H NMR (500MHz, CDCl3) δ9.74(t,J=2.4Hz,1H),7.22(dd,J=8.4,2.1Hz,1H),7.08(d,J=2.6Hz,1H),7.03(d,J=2.9Hz,1H ),6.86(d,J=1.1Hz,1H),6.72(dd,J=8.4,2.7Hz,1H),6.62(t,J=1.0Hz,1H),4.19–4.01(m,2H),3.85(d,J=11.5Hz,5 H),3.78(dtd,J=7.3,5.3,1.0Hz,1H),3.44(dddd,J=14.2,5.7,4.7,3.8Hz,1H),3.41–3.31(m,1H),2.98(dt,J=14.6 ,7.2Hz,1H),2.97–2.81(m,3H),2.33(dtd,J=13.6,7.3,5.2Hz,1H),2.26–2.13(m,2H),1.42(t,J=6.9Hz,3H).ESI-MS m / z 381.3[M+H] + .

[0131] Synthesis of compound A1:

[0132] Dissolve 100 mg of compound 3-8 in dichloromethane, add morpholine chloride and triethylamine, and stir at room temperature for 2 hours. After the reaction is complete, as monitored by TLC, add saturated ammonium chloride and extract three times with dichloromethane. Combine the organic phases and wash with saturated sodium chloride. Dry over anhydrous sodium sulfate, evaporate the solvent, and perform column chromatography (petroleum ether:ethyl acetate 1:1) to obtain A1 as a white solid in 90% yield. 1H NMR (500MHz, CDCl3) δ9.63(t,J=2.4Hz,1H),7.22(dd,J=8.4,2.0Hz,1H),7.07(d,J=2.5Hz,1H),7.02(d,J=2.8Hz,1H),6 .94(d,J=1.1Hz,1H),6.72(dd,J=8.4,2.7Hz,1H),6.61(t,J=1.0Hz,1H),5.21(td,J=5.4,1.0Hz,1H),4.14(dq,J=10.1,6 .9Hz,1H),4.11–4.01(m,2H),3.83(d,J=1.8Hz,6H),3.63–3.51(m,5H),3.16–3.03(m,4H),2.98–2.85(m,3H),2.50(dt,J =14.7,7.2Hz,1H),2.40(dtd,J=12.6,7.3,5.3Hz,1H),2.29(dtd,J=12.6,7.2,5.3Hz,1H),1.42(t,J=7.0Hz,3H).ESI-MS m / z 494.2[M+H] + .

[0133] Example (S)-A1: Synthesis of Compound (S)-A1

[0134] 3-7 was dissolved in a small amount of methanol, and deionized water was added. (R,R)-Noyori catalyst, silver hexafluoroantimonate, lanthanum trifluoromethanesulfonate, and sodium formate dihydrate were added. The mixture was stirred at room temperature overnight under argon protection. The mixture was extracted with dichloromethane and washed with water. The organic layer was filtered with diatomaceous earth and concentrated. 4-8 was obtained by column chromatography with dichloromethane / methanol = 40:1. Referring to the synthesis method of compound A1, compound (S)-A1 was obtained. 1H NMR (500MHz, CDCl3) δ9.63(t,J=2.4Hz,1H),7.22(dd,J=8.4,2.0Hz,1H),7.07(d,J=2.5Hz,1H),7.02(d,J=2.8Hz,1H),6 .94(d,J=1.1Hz,1H),6.72(dd,J=8.4,2.7Hz,1H),6.61(t,J=1.0Hz,1H),5.21(td,J=5.4,1.0Hz,1H),4.14(dq,J=10.1,6 .9Hz,1H),4.11–4.01(m,2H),3.83(d,J=1.8Hz,6H),3.63–3.51(m,5H),3.16–3.03(m,4H),2.98–2.85(m,3H),2.50(dt,J =14.7,7.2Hz,1H),2.40(dtd,J=12.6,7.3,5.3Hz,1H),2.29(dtd,J=12.6,7.2,5.3Hz,1H),1.42(t,J=7.0Hz,3H).ESI-MS m / z 494.2[M+H] + .

[0135] Example (R)-A1: Synthesis of Compound (R)-A1

[0136] The (R,R)-Noyori catalyst in the example was replaced by the (S,S)-Noyori catalyst, and the synthesis method of compound (S)-A1 was referred to to obtain compound (R)-A1. 1H NMR (500MHz, CDCl3) δ9.63(t,J=2.4Hz,1H),7.22(dd,J=8.4,2.0Hz,1H),7.07(d,J=2.5Hz,1H),7.02(d,J=2.8Hz,1H),6 .94(d,J=1.1Hz,1H),6.72(dd,J=8.4,2.7Hz,1H),6.61(t,J=1.0Hz,1H),5.21(td,J=5.4,1.0Hz,1H),4.14(dq,J=10.1,6 .9Hz,1H),4.11–4.01(m,2H),3.83(d,J=1.8Hz,6H),3.63–3.51(m,5H),3.16–3.03(m,4H),2.98–2.85(m,3H),2.50(dt,J =14.7,7.2Hz,1H),2.40(dtd,J=12.6,7.3,5.3Hz,1H),2.29(dtd,J=12.6,7.2,5.3Hz,1H),1.42(t,J=7.0Hz,3H).ESI-MS m / z 494.2[M+H] + .

[0137] Example A2: Synthesis of Compound A2

[0138] Compound A2 was obtained by replacing the morpholine chloride in Example A1 with compound 5-1 and following the synthesis method referred to compound A1. 1H NMR (500MHz, CDCl3) δ9.63(t,J=2.4Hz,1H),7.22(dd,J=8.5,2.0Hz,1H),7.07(d,J=2.5Hz,1H),7.02(d,J=2.8Hz,1H),6.93(d,J= 1.0Hz,1H),6.72(dd,J=8.4,2.7Hz,1H),6.61(t,J=0.9Hz,1H),5.17(td,J=5.4,1.0Hz,1H),4.14(dq,J=10.1,6.9Hz,1H),4.11–3 .99(m,2H),3.83(d,J=4.2Hz,6H),3.59(ddd,J=12.1,6.3,4.4Hz,1H),3.56–3.50(m,4H),2.98–2.85(m,3H),2.83(dt,J=14.8,7. 3Hz,1H),2.41(dtd,J=12.7,7.3,5.4Hz,1H),2.28(dtd,J=12.6,7.2,5.3Hz,1H),1.67–1.57(m,6H),1.42(t,J=7.0Hz,3H).ESI-MS m / z 492.3[M+H] + .

[0139] Example A3: Synthesis of Compound A3

[0140] Compound 4-8 was dissolved in dichloromethane and saturated sodium bicarbonate was added. A dichloromethane solution of triphosgene was added to the two-phase system. After reacting at room temperature for 1 hour, the dichloromethane phase was separated. The aqueous phase was extracted twice with dichloromethane. Dried over anhydrous sodium sulfate. The solution was transferred to a single-necked flask, 6-3 and diisopropylethylamine were added, and the reaction was allowed to proceed overnight at room temperature. After TLC monitoring of the reaction was complete, saturated ammonium chloride was added, and the dichloromethane was extracted 3 times. The organic phases were combined and washed with saturated sodium chloride. Dried over anhydrous sodium sulfate, the solvent was evaporated, and column chromatography (petroleum ether: ethyl acetate 1:1) gave a white solid A3 with a yield of 90%. 1H NMR (500MHz, CDCl3) δ9.63(t,J=2.4Hz,1H),7.22(dd,J=8.4,2.1Hz,1H),7.07(d,J=2.5Hz,1H),7.02(d,J=2.8Hz,1 H),6.76–6.69(m,2H),6.61(t,J=1.0Hz,1H),5.21(td,J=5.3,1.0Hz,1H),4.69(p,J=4.2Hz,1H),4.60(p,J=4.2Hz, 1H),4.20–3.95(m,5H),3.83(d,J=1.0Hz,5H),3.60(dddd,J=13.2,10.6,7.3,4.9Hz,3H),3.00–2.78(m,4H),2.39( dtd,J=12.7,7.3,5.3Hz,1H),2.28(dtd,J=12.6,7.2,5.3Hz,1H),2.06–1.79(m,5H),1.42(t,J=6.9Hz,3H).ESI-MS m / z 510.0[M+H] + .

[0141] Example A4: Synthesis of Compound A4

[0142] Compound 7-1 was used to replace 6-10 in Example A3. The synthesis method was similar to that of compound A3 to obtain compound A4. 1H NMR (500MHz, CDCl3) δ9.63(t,J=2.4Hz,1H),7.23(dd,J=8.4,1.9Hz,1H),7.09(d,J=2.5Hz,1H),7.05(d,J=1.7Hz,1H),6.97(d,J=1.0Hz,1H ),6.75(dd,J=8.4,2.0Hz,1H),6.63(t,J=1.0Hz,1H),5.18(td,J=5.2,1.0Hz,1H),4.20–4.02(m,5H),3.83(s,5H),3.68(ddd,J=12.1,6.5,4 .2Hz,2H),3.42(ddd,J=11.9,6.5,4.1Hz,1H),3.02(dddd,J=14.5,6.4,4.2,0.9Hz,1H),2.90(dddd,J=14.6,6.6,4.1,1.0Hz,1H),2.68–2.5 8(m,1H),2.55–2.40(m,2H),2.40–2.29(m,1H),2.32–2.21(m,2H),2.14(tddd,J=21.0,14.5,6.5,4.2Hz,2H),1.42(t,J=7.0Hz,3H).ESI-MS m / z 528.3[M+H] + .

[0143] Example A5: Synthesis of Compound A5

[0144] Compound A5 was obtained by replacing 6-10 in Example A3 with compound 8-1 and following the synthesis method of compound A3. 1H NMR (500MHz, CDCl3) δ9.63(t,J=2.4Hz,1H),7.23(dd,J=8.4,1.9Hz,1H),7.09(d,J=2.6Hz,1H),7.05–6.97(m,2H),6. 74(dd,J=8.4,1.8Hz,1H),6.63(t,J=1.0Hz,1H),5.11(td,J=5.3,1.0Hz,1H),4.15(dq,J=10.1,6.9Hz,1H),4.12–3.96 (m,2H),3.83(d,J=0.7Hz,6H),3.66(dt,J=10.8,4.9Hz,2H),3.62–3.50(m,3H),3.05–2.92(m,2H),2.90(dt,J=14.6,7 .4Hz,1H),2.80(t,J=4.9Hz,4H),2.52–2.37(m,2H),2.29(dtd,J=12.6,7.4,5.3Hz,1H),1.42(t,J=7.0Hz,3H).ESI-MS m / z 526.1[M+H] + .

[0145] Example A6: Synthesis of Compound A6

[0146] Compound 9-1 was used to replace 6-10 in Example A3. The synthesis method was similar to that of compound A3 to obtain compound A6. 1H NMR (500MHz, CDCl3) δ9.63(t,J=2.4Hz,1H),7.22(dd,J=8.4,2.1Hz,1H),7.06(dd,J=13.2,2.6Hz,2H),6.85(d,J=1.1Hz,1H),6.72(dd,J=8.4,2.7H z,1H),6.63(t,J=1.0Hz,1H),5.13(td,J=5.3,0.9Hz,1H),4.20–4.01(m,3 H),3.83(s,5H),3.67(dt,J=10.8,5.0Hz,2H),3.61(dt,J=10.5,5.1Hz,2H ),3.56(ddd,J=12.1,6.4,4.2Hz,1H),3.26(t,J=5.1Hz,4H),2.97(dddd,J=14.5,6.4,4.2,0.9Hz,1H),2.91(dddd,J=14.5,6.3,4.1,0.9Hz,1H),2. 85(dt,J=14.7,7.2Hz,1H),2.68–2.58(m,1H),2.38(dtd,J=12.7,7.3,5.4 Hz,1H),2.27(dtd,J=12.6,7.3,5.5Hz,1H),1.42(t,J=7.0Hz,3H).ESI-MS m / z 542.2[M+H] + .

[0147] Example A7: Synthesis of Compound A7

[0148] Compound A7 was obtained by replacing the morpholine chloride in Example A1 with compound 10-1 and following the synthesis method referring to compound A1. 1 H NMR (500MHz, DMSO-d6) δ8.69–8.64(m,2H),7.77–7.72(m,2H),7.26(d,J=7.6Hz,1H),7.14( d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H), 6.60(t,J=1.0Hz,1H),4.93–4.86(m,1H),4.06(qd,J=8.0,1.3Hz,2H),3.83–3.73(m,8H),2 .91(tt,J=7.1,0.8Hz,2H),2.78–2.64(m,2H),2.36–2.19(m,2H),1.44–1.37(m,3H).ESI-MS m / z 486.1[M+H] + .

[0149] Example A8: Synthesis of Compound A8

[0150] Compound A8 was obtained by replacing the morpholine chloride in Example A1 with compound 11-1 and following the synthesis method referred to compound A1. 1 H NMR(500MHz,DMSO-d6)δ9.01(d,J=1.5Hz,1H),8.75(dd,J=7.5,1.6Hz,1H),8.15(dt,J=7.5,1.5Hz,1H),7. 43(t,J=7.5Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1. 5Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.93–4.86(m,1H),4.06(qd,J=8.0,1.3Hz,2H),3.84 –3.77(m,8H),2.91(tt,J=7.1,0.9Hz,2H),2.78–2.64(m,2H),2.36–2.19(m,2H),1.44–1.37(m,3H).ESI-MS m / z 486.1[M+H] + .

[0151] Example A9: Synthesis of Compound A9

[0152] Compound A9 was obtained by replacing the morpholine chloride in Example A1 with compound 12-1 and following the synthesis method referred to compound A1. 1H NMR(500MHz,DMSO-d6)δ8.64(dd,J=7.5,1.5Hz,1H),7.91(td,J=7.5,1.6Hz,1H),7.79(dd,J=7.4,1.6Hz,1H), 7.57(td,J=7.5,1.5Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7 .5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.98–4.92(m,1H),4.06(qd,J=8.0,1.3Hz,2H),3 .87–3.75(m,9H),2.91(tt,J=7.1,0.8Hz,2H),2.78–2.64(m,2H),2.36–2.19(m,2H),1.44–1.37(m,3H).ESI-MS m / z 486.2[M+H] + .

[0153] Example A10: Synthesis of Compound A10

[0154] Compound A10 was obtained by replacing the morpholine chloride in Example A1 with compound 13-1 and following the synthesis method referred to compound A1. 1 H NMR (500MHz, DMSO-d6) δ9.43(d,J=1.5Hz,1H),8.84(d,J=7.5Hz,1H),7.72(dd,J=7.5,1.6Hz,1H),7.26(d,J=7 .6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.7Hz,1H),6. 60(t,J=1.0Hz,1H),4.98–4.92(m,1H),4.06(qd,J=8.0,1.3Hz,2H),3.84–3.75(m,8H),2.91(tt,J=7.1,0.8Hz ,2H),2.78(dt,J=12.3,7.1Hz,1H),2.70(dt,J=12.3,7.0Hz,1H),2.36–2.19(m,2H),1.44–1.37(m,3H).ESI-MS m / z 487.2[M+H] + .

[0155] Example A11: Synthesis of Compound A11

[0156] Compound A11 was obtained by replacing the morpholine chloride in Example A1 with compound 14-1 and following the synthesis method of compound A1. 1 H NMR(500MHz,DMSO-d6)δ9.21(s,2H),9.07(s,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.8 Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.7Hz,1H),6.60( t,J=1.0Hz,1H),4.92–4.85(m,1H),4.06(qd,J=8.0,1.3Hz,2H),3.84–3.77(m,8H),2.91 (tt,J=7.2,1.0Hz,2H),2.78–2.64(m,2H),2.35–2.18(m,2H),1.44–1.37(m,3H).ESI-MS m / z 487.2[M+H] + .

[0157] Example A12: Synthesis of Compound A12

[0158] Compound A12 was obtained by replacing the morpholine chloride in Example A1 with compound 15-1 and following the synthesis method referred to compound A1. 1 H NMR (500MHz, DMSO-d6) δ9.22(s,1H),8.82(d,J=1.8Hz,2H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H ),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.9 5(td,J=6.9,0.6Hz,1H),4.06(qd,J=8.0,1.3Hz,2H),3.89–3.77(m,8H),2.91(tt,J=7.1,0.9Hz,2H),2 .78(dt,J=12.3,7.1Hz,1H),2.70(dt,J=12.3,7.1Hz,1H),2.36–2.19(m,2H),1.44–1.37(m,3H).ESI-MS m / z 487.2[M+H] + .

[0159] Example A13: Synthesis of Compound A13

[0160] Compound A13 was obtained by replacing the morpholine chloride in Example A1 with compound 16-1 and following the synthesis method referred to compound A1. 1 H NMR (500MHz, DMSO-d6) δ8.82(dd,J=7.5,1.5Hz,1H),8.13(dd,J=7.5,1.5Hz,1H),7.95(t,J=7.4Hz,1H),7.26(d,J =7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.60 (d,J=1.0Hz,1H),4.95(td,J=6.9,0.7Hz,1H),4.06(qd,J=8.0,1.3Hz,2H),3.89–3.77(m,8H),2.91(tt,J=7.1,0. 9Hz,2H),2.78(dt,J=12.3,7.1Hz,1H),2.70(dt,J=12.2,7.1Hz,1H),2.36–2.19(m,2H),1.44–1.37(m,3H).ESI-MS m / z 487.2[M+H] + .

[0161] Example A14: Synthesis of Compound A14

[0162] Compound A14 was obtained by replacing the morpholine chloride in Example A1 with compound 17-1 and following the synthesis method referred to compound A1. 1 H NMR(500MHz,DMSO-d6)δ9.46(d,J=1.5Hz,1H),9.25(d,J=7.5Hz,1H),7.97(dd,J=7.5,1.6Hz,1H),7 .26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74 (d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.93–4.86(m,1H),4.06(qd,J=8.0,1.3Hz,2H),3.84–3.71( m,9H),2.91(tt,J=7.1,0.8Hz,2H),2.78–2.64(m,2H),2.36–2.19(m,2H),1.44–1.37(m,3H).ESI-MS m / z 487.2[M+H] + .

[0163] Example A15: Synthesis of Compound A15

[0164] Compound A15 was obtained by replacing the morpholine chloride in Example A1 with compound 18-1 and following the synthesis method referred to compound A1. 1 H NMR (500MHz, DMSO-d6) δ8.19(s,1H),8.15(d,J=8.2Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1 H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.7Hz,1H),6.60(t,J=1.0Hz,1H),5 .01–4.95(m,1H),4.08(qd,J=8.0,4.6Hz,2H),3.87–3.77(m,7H),2.96(dt,J=12.3,7.1Hz,1H),2.91( tt,J=7.1,0.9Hz,2H),2.70(dt,J=12.4,7.1Hz,1H),2.36–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 475.2[M+H] + .

[0165] Example A16: Synthesis of Compound A16

[0166] Compound A16 was obtained by replacing the morpholine chloride in Example A1 with compound 19-1 and following the synthesis method referred to compound A1. 1 H NMR(500MHz, CDCl3)δ9.52(t,J=2.4Hz,1H),7.56–7.51(m,2H),7.23(dd,J=8.4,2.1Hz,1H),7.09(d,J=2 .6Hz,1H),7.02(d,J=1.8Hz,1H),6.95(d,J=0.9Hz,1H),6.75(dd,J=8.4,1.8Hz,1H),6.64(t,J=1.0Hz,1H ),5.06(td,J=5.5,1.1Hz,1H),4.19–3.96(m,3H),3.88–3.80(m,7H),3.12–3.01(m,2H),2.98–2.86(m,2 H),2.42(dtd,J=12.6,7.3,5.3Hz,1H),2.29(dtd,J=12.6,7.3,5.4Hz,1H),1.42(t,J=7.0Hz,3H).ESI-MS m / z 475.2[M+H] + .

[0167] Example A17: Synthesis of Compound A17

[0168] Compound A17 was obtained by replacing the morpholine chloride in Example A1 with compound 20-1 and following the synthesis method referred to compound A1. 1 H NMR (500MHz, DMSO-d6) δ8.34(d,J=7.5Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.09(d,J=8 .4Hz,1H),6.96(d,J=7.5Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H ),4.97(t,J=6.9Hz,1H),4.08(qd,J=8.0,4.6Hz,2H),3.87–3.77(m,7H),2.96(dt,J=12.3,7.1Hz,1H),2. 91(tt,J=7.1,0.8Hz,2H),2.70(dt,J=12.4,7.1Hz,1H),2.36–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 475.2[M+H] + .

[0169] Example A18: Synthesis of Compound A18

[0170] Compound A18 was obtained by replacing the morpholine chloride in Example A1 with compound 21-1 and following the synthesis method referred to compound A1. 1H NMR (500MHz, DMSO-d6) δ8.18(d,J=1.4Hz,1H),8.06(dd,J=5.9,1.5Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d ,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.59(d,J=1.0H z,1H),4.92–4.85(m,1H),4.08(qd,J=8.0,4.6Hz,2H),3.84–3.77(m,8H),2.96(dt,J=12.3,7.1Hz,1H),2 .91(tt,J=7.2,0.9Hz,2H),2.70(dt,J=12.3,7.1Hz,1H),2.34–2.17(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 475.2[M+H] + .

[0171] Example A19: Synthesis of Compound A19

[0172] Compound A19 was obtained by replacing the morpholine chloride in Example A1 with compound 22-1 and following the synthesis method referred to compound A1. 1 H NMR (500MHz, DMSO-d6) δ8.34(d,J=7.5Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.09(d,J =8.4Hz,1H),7.00(d,J=7.5Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(s,1H),6.59(t,J=0.9Hz,1H),4. 89–4.83(m,1H),4.08(qd,J=8.0,4.6Hz,2H),3.80(d,J=13.7Hz,5H),3.72(td,J=7.0,1.2Hz,2H),2.91 (tt,J=7.0,0.8Hz,2H),2.74(qt,J=12.5,7.1Hz,2H),2.35–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 476.2[M+H] + .

[0173] Example A20: Synthesis of Compound A20

[0174] Compound A20 was obtained by replacing the morpholine chloride in Example A1 with compound 23-1 and following the synthesis method referred to compound A1. 1 H NMR (500MHz, DMSO-d6) δ8.29(s,1H),8.05(s,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.0 9(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.7Hz,1H),6.59(t,J=0.9Hz,1H),4.89–4 .83(m,1H),4.08(qd,J=8.0,4.6Hz,2H),3.80(d,J=13.7Hz,5H),3.72(td,J=7.0,1.2Hz,2H),2.91(t t,J=7.0,0.8Hz,2H),2.74(qt,J=12.5,7.1Hz,2H),2.35–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 476.2[M+H] + .

[0175] Example A21: Synthesis of Compound A21

[0176] Compound A22 was obtained by replacing the morpholine chloride in Example A1 with compound 24-1 and following the synthesis method referred to compound A1. 1 H NMR (500MHz, DMSO-d6) δ8.07(d,J=7.5Hz,1H),7.47(d,J=7.5Hz,1H),7.26(d,J=7.6Hz,1H),7.1 4(d,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.5 9(t,J=0.9Hz,1H),4.94–4.87(m,1H),4.08(qd,J=8.0,4.6Hz,2H),3.83–3.72(m,7H),2.91(tt,J =7.1,0.8Hz,2H),2.74(qt,J=12.5,7.1Hz,2H),2.36–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 476.2[M+H] + .

[0177] Example A22: Synthesis of Compound A22

[0178] Compound A22 was obtained by replacing the morpholine chloride in Example A1 with compound 25-1 and following the synthesis method referred to compound A1. 1 H NMR (500MHz, DMSO-d6) δ8.93(d,J=7.5Hz,1H),7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.09( d,J=8.4Hz,1H),6.85–6.76(m,2H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.95(td,J=6.9, 0.6Hz,1H),4.08(qd,J=8.0,4.6Hz,2H),3.87–3.77(m,7H),2.91(tt,J=7.1,0.9Hz,2H),2.78(dt, J=12.3,7.1Hz,1H),2.72(dt,J=12.2,7.1Hz,1H),2.35–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 476.2[M+H] + .

[0179] Example A23: Synthesis of Compound A23

[0180] Compound A23 was obtained by replacing the morpholine chloride in Example A1 with compound 26-1 and following the synthesis method referred to compound A1. 1 H NMR(500MHz,DMSO-d6)δ9.02(d,J=1.4Hz,1H),8.38(d,J=1.4Hz,1H),7.26(d,J=7.6Hz,1H),7 .14(d,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H) ,6.59(d,J=1.0Hz,1H),4.92–4.85(m,1H),4.08(qd,J=8.0,4.6Hz,2H),3.83–3.77(m,8H),2. 91(tt,J=7.2,0.9Hz,2H),2.79–2.66(m,2H),2.34–2.17(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 476.2[M+H] + .

[0181] Example A24: Synthesis of Compound A24

[0182] Compound A24 was obtained by replacing the morpholine chloride in Example A1 with compound 27-1 and following the synthesis method referred to compound A1. 1 H NMR (500MHz, DMSO-d6) δ8.25(d,J=1.4Hz,1H),7.99(d,J=1.4Hz,1H),7.26(d,J=7.6Hz,1H),7.1 4(d,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.7Hz,1H),6.6 0(t,J=1.0Hz,1H),4.95(td,J=6.9,0.6Hz,1H),4.08(qd,J=8.0,4.6Hz,2H),3.87–3.77(m,8H), 2.91(tt,J=7.1,0.9Hz,2H),2.83–2.67(m,2H),2.35–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 476.2[M+H] + .

[0183] Example A25: Synthesis of Compound A25

[0184] Compound A25 was obtained by replacing the morpholine chloride in Example A1 with compound 28-1 and following the synthesis method referred to compound A1. 1 H NMR(500MHz,DMSO-d6)δ8.47(dd,J=7.5,1.6Hz,1H),7.72(dd,J=7.5,1.5Hz,1H),7.26(d,J=7.6Hz,1H) ,7.14(d,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.77–6.71(m,2H),6.60(t,J =1.0Hz,1H),4.98–4.92(m,1H),4.15–4.00(m,2H),3.88–3.77(m,8H),2.96(dt,J=12.3,7.1Hz,1H),2.9 1(tt,J=7.1,0.9Hz,2H),2.70(dt,J=12.4,7.1Hz,1H),2.35–2.18(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 475.2[M+H] + .

[0185] Example A26: Synthesis of Compound A26

[0186] Compound A26 was obtained by replacing the morpholine chloride in Example A1 with compound 29-1 and following the synthesis method referred to compound A1. 1 H NMR(500MHz,DMSO-d6)δ8.27(s,1H),7.28–7.23(m,2H),7.22(d,J=7.5Hz,1H),7.14(d,J=1.4Hz,1H) ,7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4. 93–4.87(m,1H),4.08(qd,J=8.0,4.6Hz,2H),3.88–3.75(m,8H),2.96(dt,J=12.3,7.1Hz,1H),2.91( tt,J=7.1,1.1Hz,2H),2.70(dt,J=12.3,7.1Hz,1H),2.33–2.17(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 475.2[M+H] + .

[0187] Example A27: Synthesis of Compound A27

[0188] Compound A27 was obtained by replacing the morpholine chloride in Example A1 with compound 30-1 and following the synthesis method referred to compound A1. 1 H NMR (500MHz, DMSO-d6) δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5 ,1.5Hz,1H),6.75(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.87(td,J=7.0,0.6Hz,1H),4.07(qd,J=7.9,4.4H z,2H),3.80(d,J=13.5Hz,7H),3.56(dddt,J=7.5,6.1,2.9,1.5Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),2.91(t t,J=7.1,0.9Hz,2H),2.78–2.64(m,2H),2.37–2.19(m,2H),1.98–1.86(m,4H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 478.3[M+H] + .

[0189] Example A28: Synthesis of Compound A28

[0190] Compound A28 was obtained by replacing the morpholine chloride in Example A1 with compound 31-1 and following the synthesis method referred to compound A1. 1 H NMR (500MHz, DMSO-d6) δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1 .5Hz,1H),6.75(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.90–4.84(m,1H),4.08(qd,J=8.0,2.9Hz,2H),3.80( d,J=12.1Hz,7H),3.57(t,J=7.1Hz,2H),3.52–3.43(m,3H),2.96(dt,J=12.3,7.1Hz,1H),2.91(tt,J=7.1,0.9 Hz,2H),2.70(dt,J=12.4,7.1Hz,1H),2.37–2.19(m,2H),1.93(p,J=7.1Hz,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 464.2[M+H] + .

[0191] Example A29: Synthesis of Compound A29

[0192] Compound A29 was obtained by replacing the morpholine chloride in Example A1 with compound 32-1 and following the synthesis method referred to compound A1. 1 H NMR (500MHz, DMSO-d6) δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6. 82(dd,J=7.4,1.5Hz,1H),6.74(s,1H),6.60(t,J=0.9Hz,1H),4.87(td,J=6.9,0.6Hz,1H),4.06 (qd,J=8.1,2.1Hz,2H),3.83–3.74(m,7H),3.52–3.42(m,5H),2.91(tt,J=7.1,0.9Hz,2H),2.77 –2.64(m,2H),2.45(t,J=7.1Hz,4H),2.28(s,3H),2.36–2.18(m,2H),1.44–1.37(m,3H).ESI-MS m / z 507.3[M+H] + .

[0193] Example A30: Synthesis of Compound A30

[0194] Compound 1-5 in Example A1 was replaced with compound 1-6, and the synthesis method was referred to compound A1 to obtain compound A30. 1 H NMR(500MHz, DMSO-d6)δ7.42(ddt,J=7.8,1.9,1.0Hz,2H),7.36(ddt,J=7.5,6.5,1.0Hz,2H),7.36–7.28(m,1H),7.26(d,J=7.6Hz,1H),7 .14(d,J=1.4Hz,1H),7.10(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.6Hz,1H),6.76(d,J=0.6Hz,1H),6.60(d,J=1.0Hz,1H),5.16(dt,J=12.5,1 .0Hz,1H),5.08(dt,J=12.4,1.1Hz,1H),4.87(td,J=7.0,0.6Hz,1H),3.83–3.74(m,7H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1 H),3.13(dt,J=12.5,7.0Hz,2H),2.96(dt,J=12.5,7.2Hz,2H),2.91(tt,J=7.1,1.1Hz,2H),2.77–2.65(m,2H),2.36–2.18(m,2H).ESI-MS m / z 556.3[M+H] + .

[0195] Example A31: Synthesis of Compound A31

[0196] Compound 1-5 in Example A1 was replaced with compound 1-7, and the synthesis method was referred to compound A1 to obtain compound A31. 1H NMR (500MHz, DMSO-d6) δ7.26(d,J=7.6Hz,1H),7.15(d,J=1.8Hz,1H),7.10(d,J=8.4Hz,1H),6.85–6. 79(m,2H),6.59(t,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),4.84–4.75(m,1H),3.79(d,J=4.4Hz,8H),3.5 5–3.43(m,5H),3.13(dt,J=12.5,7.0Hz,2H),3.00–2.86(m,4H),2.77–2.65(m,2H),2.36–2.18(m,2H ),1.76–1.66(m,1H),1.70–1.63(m,2H),1.66–1.56(m,1H),1.57(ddt,J=4.2,3.2,1.6Hz,1H).ESI-MS m / z 534.3[M+H] + .

[0197] Example A32: Synthesis of Compound A32

[0198] Compound 1-5 in Example A1 was replaced with compound 1-8, and the synthesis method was referred to compound A1 to obtain compound A32. 1 H NMR (500MHz, DMSO-d6) δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.6Hz,1H),6.75(d,J=0. 6Hz,1H),6.61(t,J=1.0Hz,1H),4.87(td,J=7.0,0.6Hz,1H),3.94(dd,J=12.4,7.0Hz,1H),3.86(dd,J=12.4,7.1Hz,1H),3.82–3.74(m, 7H),3.53(s,1H),3.53–3.43(m,4H),3.07–3.01(m,1H),3.01(d,J=7.1Hz,1H),2.98(d,J=7.2Hz,1H),2.98–2.91(m,1H),2.91(tt,J=7 .2,0.9Hz,2H),2.71(td,J=7.1,0.9Hz,2H),2.36–2.18(m,2H),1.26(hept,J=7.0Hz,1H),0.72–0.59(m,2H),0.48–0.35(m,2H).ESI-MS m / z 520.3[M+H] + .

[0199] Example A33: Synthesis of Compound A33

[0200] Compound 1-5 in Example A1 was replaced with compound 1-9, and the synthesis method was referred to compound A1 to obtain compound A33. 1 H NMR (500MHz, DMSO-d6) δ7.26(d,J=7.6Hz,1H),7.15(d,J=1.8Hz,1H),7.10(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.6Hz,1 H),6.75(d,J=0.6Hz,1H),6.59(t,J=1.0Hz,1H),4.87(td,J=7.0,0.6Hz,1H),4.15(dt,J=12.5,7.1Hz,1H),4.09(dt,J =12.5,7.1Hz,1H),3.83–3.74(m,7H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.07–3.01(m,1H),3.03–2. 86(m,6H),2.80(dt,J=12.4,7.1Hz,1H),2.76–2.65(m,2H),2.35(s,5H),2.36–2.25(m,1H),2.27–2.18(m,1H).ESI-MS m / z 537.3[M+H] + .

[0201] Example A34: Synthesis of Compound A34

[0202] Compound 1-10 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A34. 1H NMR (500MHz, DMSO-d6) δ7.26(d,J=7.6Hz,1H),7.15(d,J=1.8Hz,1H),7.10(d,J=8.4Hz,1H),6.82(dd,J=7.5,1. 6Hz,1H),6.75(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.87(td,J=6.9,0.6Hz,1H),4.24(t,J=7.1Hz,2H),3.83– 3.74(m,7H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.07–3.01(m,1H),3.01(d,J=7.1Hz,1H),2.9 7(d,J=7.0Hz,1H),2.97–2.91(m,1H),2.91(tt,J=7.2,0.9Hz,2H),2.84–2.65(m,4H),2.36–2.18(m,2H).ESI-MS m / z 538.2[M+H] + .

[0203] Example A35: Synthesis of Compound A35

[0204] Compound 1-5 in Example A1 was replaced with compound 1-11, and the synthesis method was referred to compound A1 to obtain compound A35. 1 H NMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.86–6.79(m,2H ),6.70(t,J=1.0Hz,1H),4.87(td,J=7.0,0.6Hz,1H),4.06(qd,J=8.0,2.2Hz,2H),3.83–3.74(m,7H),3.52(t, J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.03(dt,J=12.5,7.0Hz,2H),2.98(d,J=7.2Hz,1H),2.98–2.91( m,1H),2.91(ddd,J=7.1,6.6,1.0Hz,2H),2.78–2.64(m,2H),2.36–2.18(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 494.3[M+H] + .

[0205] Example A36: Synthesis of Compound A36

[0206] Compound 1-12 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A36. 1 H NMR (500MHz, DMSO-d6) δ7.42(ddt,J=7.8,1.9,0.9Hz,2H),7.36(ddt,J=7.5,6.5,1.0Hz,2H),7.36–7.28(m,1H),7.26(d,J=7.6Hz,1H),7. 14(d,J=1.4Hz,1H),7.10(d,J=8.4Hz,1H),6.87(d,J=0.7Hz,1H),6.82(dd,J=7.5,1.6Hz,1H),6.70(t,J=1.1Hz,1H),5.14(dt,J=12.5,1.0 Hz,1H),5.09(dt,J=12.4,1.0Hz,1H),4.87(td,J=6.9,0.6Hz,1H),3.79(d,J=12.3Hz,7H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz, 1H),3.13(dt,J=12.5,7.0Hz,2H),2.96(dt,J=12.5,7.2Hz,2H),2.91(tt,J=7.1,1.1Hz,2H),2.77–2.65(m,2H),2.36–2.18(m,2H).ESI-MS m / z 556.3[M+H] + .

[0207] Example A37: Synthesis of Compound A37

[0208] Compound 1-13 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A37. 1H NMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.15(d,J=1.8Hz,1H),7.10(d,J=8.4Hz,1H),6.87(s,1H),6 .82(dd,J=7.5,1.6Hz,1H),6.75(t,J=1.1Hz,1H),4.87(td,J=7.0,0.6Hz,1H),4.84–4.75(m,1H),3.83–3.7 4(m,7H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.13(dt,J=12.5,7.0Hz,2H),2.96(dt,J=12. 5,7.2Hz,2H),2.91(tt,J=7.1,1.1Hz,2H),2.77–2.65(m,2H),2.36–2.18(m,2H),1.76–1.50(m,6H).ESI-MS m / z 534.3[M+H] + .

[0209] Example A38: Synthesis of Compound A38

[0210] Compound 1-14 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A38. 1 H NMR (500MHz, DMSO-d6) δ7.26(d,J=7.6Hz,1H),7.15(d,J=1.8Hz,1H),7.10(d,J=8.4Hz,1H),6.87(d,J=0.7H z,1H),6.82(dd,J=7.5,1.6Hz,1H),6.69(d,J=1.0Hz,1H),4.87(td,J=6.9,0.6Hz,1H),4.20–4.05(m,2H),3 .83–3.74(m,7H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.07–3.01(m,1H),3.03–2.86(m,6H) ,2.80(dt,J=12.4,7.1Hz,1H),2.76–2.65(m,2H),2.35(s,5H),2.36–2.25(m,1H),2.27–2.18(m,1H).ESI-MS m / z 537.3[M+H] + .

[0211] Example A39: Synthesis of Compound A39

[0212] Compound 1-15 was used to replace 1-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A39. 1 H NMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d ,J=8.4Hz,1H),6.85–6.79(m,2H),6.77(t,J=1.0Hz,1H),4.87(td,J=6.9,0. 6Hz,1H),4.68–4.58(m,2H),3.83–3.74(m,7H),3.52(d,J=7.2Hz,3H),3.52– 3.43(m,2H),3.02–2.87(m,6H),2.77–2.64(m,2H),2.36–2.18(m,2H).ESI-MS m / z 524.2[M+H] + .

[0213] Example A40: Synthesis of Compound A40

[0214] Compound 1-16 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A40. 1 H NMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H), 6.84–6.79(m,2H),6.59(t,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),4.59(hept,J=6.8Hz,1H),3 .83–3.74(m,7H),3.54–3.43(m,5H),3.02–2.94(m,2H),2.97–2.87(m,4H),2.77–2.69(m,1H ),2.71–2.64(m,1H),2.36–2.18(m,2H),1.35(d,J=6.9Hz,3H),1.30(d,J=6.8Hz,3H).ESI-MS m / z 508.3[M+H] + .

[0215] Example A41: Synthesis of Compound A41

[0216] Compound 1-17 was used to replace 1-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A41. 1H NMR (500MHz, DMSO-d6) δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.89(d,J =0.6Hz,1H),6.82(dd,J=7.4,1.5Hz,1H),6.76(t,J=1.0Hz,1H),4.87(td,J=6.9,0.6Hz,1H),4.59(he pt,J=6.8Hz,1H),3.83–3.74(m,7H),3.54–3.43(m,5H),3.02–2.94(m,2H),2.97–2.87(m,4H),2.77–2 .69(m,1H),2.71–2.64(m,1H),2.36–2.18(m,2H),1.32(d,J=6.8Hz,3H),1.27(d,J=6.8Hz,3H).ESI-MS m / z 508.3[M+H] + .

[0217] Example A42: Synthesis of Compound A42

[0218] Compound 1-18 was used to replace 1-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A42. 1 H NMR (500MHz, DMSO-d6) δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),7.03(d,J= 0.7Hz,1H),6.82(dd,J=7.4,1.5Hz,1H),6.66(t,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),3.85(s,2H),3.79 (dt,J=12.5,7.1Hz,1H),3.78(s,3H),3.51(t,J=7.0Hz,4H),3.47(dd,J=12.4,7.1Hz,1H),3.02–2.94( m,2H),2.97–2.86(m,4H),2.77–2.69(m,1H),2.71–2.64(m,1H),2.36–2.18(m,2H),2.25(s,3H).ESI-MS m / z 508.2[M+H] + .

[0219] Example A43: Synthesis of Compound A43

[0220] Compound 1-19 was used to replace 1-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A43. 1 H NMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6 .90–6.85(m,2H),6.82(dd,J=7.4,1.5Hz,1H),4.87(td,J=6.9,0.6Hz,1H),3.82(s,2H),3.78 (s,3H),3.76(dt,J=12.5,7.2Hz,1H),3.51(t,J=7.0Hz,4H),3.47(dd,J=12.5,7.1Hz,1H),3. 02–2.94(m,2H),2.97–2.87(m,4H),2.77–2.64(m,2H),2.36–2.18(m,2H),2.25(s,3H).ESI-MS m / z 508.2[M+H] + .

[0221] Example A44: Synthesis of Compound A44

[0222] Compound 1-20 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A44. 1 H NMR (500MHz, DMSO-d6) δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.82(dd,J=7.5,1 .6Hz,1H),6.75(d,J=0.7Hz,1H),6.61(t,J=1.0Hz,1H),4.87(td,J=7.0,0.6Hz,1H),4.36(dt,J=12.5,7.1Hz, 1H),4.24(dt,J=12.5,7.1Hz,1H),3.83–3.74(m,7H),3.58(td,J=7.2,4.0Hz,2H),3.52(d,J=7.2Hz,3H),3.52 –3.43(m,2H),3.37(s,2H),3.02–2.94(m,2H),2.97–2.86(m,4H),2.77–2.64(m,2H),2.36–2.18(m,2H).ESI-MS m / z 524.3[M+H] + .

[0223] Example A45: Synthesis of Compound A45

[0224] Compound 1-21 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A45. 1 H NMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.85–6.7 9(m,2H),6.70(t,J=1.0Hz,1H),4.87(td,J=6.9,0.6Hz,1H),4.36(dt,J=12.5,7.0Hz,1H),4.25(dt,J= 12.5,7.1Hz,1H),3.83–3.74(m,7H),3.58(td,J=7.2,4.0Hz,2H),3.52(d,J=7.1Hz,3H),3.52–3.43(m ,2H),3.37(s,2H),3.02–2.94(m,2H),2.97–2.86(m,4H),2.77–2.64(m,2H),2.36–2.18(m,2H).ESI-MS m / z524.3[M+H] + .

[0225] Example A46: Synthesis of Compound A46

[0226] Compound 1-22 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A46. 1 H NMR (500MHz, DMSO-d6) δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.10(d,J=8. 4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.61(d,J=1.0Hz,1H) ,4.87(td,J=7.0,0.6Hz,1H),4.32(td,J=7.1,2.8Hz,2H),3.86–3.77(m,7H),3.53 (d,J=7.1Hz,3H),3.50(s,1H),3.52–3.43(m,2H),3.45–3.38(m,1H),3.07–3.01(m, 1H),3.04–2.91(m,3H),2.96(s,3H),2.91(tt,J=7.2,0.9Hz,2H),2.77–2.65(m,2H),2.36–2.18(m,2H).ESI-MS m / z 572.2[M+H] + .

[0227] Example A47: Synthesis of Compound A47

[0228] Compound 1-23 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A47. 1 H NMR (500MHz, DMSO-d6) δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.10(d,J=8.4Hz,1H),6.86–6.79(m,2H ),6.73(t,J=1.0Hz,1H),4.87(td,J=7.0,0.6Hz,1H),4.38–4.26(m,2H),3.86–3.77(m,7H),3.53(d,J=7.1Hz ,3H),3.50(s,1H),3.52–3.43(m,2H),3.45–3.38(m,1H),3.07–3.01(m,1H),3.01(d,J=7.2Hz,1H),2.98(d,J =7.2Hz,1H),2.96(s,3H),2.98–2.91(m,1H),2.94–2.86(m,2H),2.77–2.65(m,2H),2.36–2.18(m,2H).ESI-MS m / z 572.2[M+H] + .

[0229] Example A48: Synthesis of Compound A48

[0230] Compound 1-24 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A48. 1 H NMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6 .86–6.79(m,2H),6.77(t,J=1.0Hz,1H),6.73(d,J=7.7Hz,1H),6.67(d,J=7.7Hz,1H),4.87(td ,J=6.9,0.6Hz,1H),4.61–4.52(m,2H),3.83–3.74(m,7H),3.53(s,1H),3.52(s,2H),3.52–3. 43(m,2H),3.02–2.87(m,6H),2.77–2.69(m,1H),2.71–2.64(m,1H),2.36–2.18(m,2H).ESI-MS m / z 523.2[M+H] + .

[0231] Example A49: Synthesis of Compound A49

[0232] Compound 1-25 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A49. 1 H NMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H) ,6.85–6.77(m,2H),6.73(d,J=7.7Hz,1H),6.67(d,J=7.7Hz,1H),6.62(t,J=1.0Hz,1H),4.8 7(t,J=6.9Hz,1H),4.64–4.53(m,2H),3.83–3.74(m,7H),3.52(d,J=7.2Hz,3H),3.52–3.43 (m,2H),3.02–2.86(m,6H),2.77–2.69(m,1H),2.71–2.64(m,1H),2.36–2.18(m,2H).ESI-MS m / z 523.2[M+H] + .

[0233] Example A50: Synthesis of Compound A50

[0234] Compound 1-26 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A50. 1 H NMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.10(d,J=8.4Hz ,1H),6.93(t,J=1.0Hz,1H),6.86(d,J=0.7Hz,1H),6.82(dd,J=7.5,1.6Hz,1H),4.87( td,J=7.0,0.6Hz,1H),3.84(s,2H),3.81–3.72(m,3H),3.52(t,J=7.1Hz,4H),3.47(dt ,J=12.5,7.1Hz,1H),3.07–2.87(m,6H),2.77–2.65(m,2H),2.36–2.18(m,2H).ESI-MS m / z 562.2[M+H] + .

[0235] Example A51: Synthesis of Compound A51

[0236] Compound 1-27 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A51. 1 H NMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.12–7.06(m,2H),6.82( dd,J=7.5,1.6Hz,1H),6.67(t,J=1.0Hz,1H),4.91–4.85(m,1H),3.84–3.74(m,6H),3.52(t,J= 7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.07–3.01(m,1H),3.01(d,J=7.2Hz,1H),2.98(d,J= 7.2Hz,1H),2.98–2.91(m,1H),2.94–2.86(m,2H),2.77–2.65(m,2H),2.37–2.19(m,2H).ESI-MS m / z 562.2[M+H] + .

[0237] Example A52: Synthesis of Compound A52

[0238] Compound 1-28 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A52. 1 H NMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.10(d,J=8.4Hz,1H),6.87–6.79(m,2H),6.70 (t,J=1.0Hz,1H),4.87(td,J=6.9,0.6Hz,1H),4.00(dd,J=12.3,7.0Hz,1H),3.87(dd,J=12.4,7.0Hz,1H),3.79(d,J= 9.0Hz,7H),3.73(dt,J=12.4,7.1Hz,2H),3.63(dt,J=12.4,7.1Hz,2H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1H z,1H),3.07–2.86(m,6H),2.77–2.65(m,2H),2.36–2.18(m,2H),2.11(hept,J=7.0Hz,1H),1.83–1.68(m,4H).ESI-MS m / z 564.3[M+H] + .

[0239] Example A53: Synthesis of Compound A53

[0240] Compound 1-29 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A53. 1 H NMR (500MHz, DMSO-d6) δ7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.10(d,J=8.4Hz,1H),6.82(dd,J=7.5,1.5Hz,1H),6. 75(d,J=0.6Hz,1H),6.61(t,J=1.0Hz,1H),4.87(td,J=6.9,0.6Hz,1H),3.99(dd,J=12.4,7.0Hz,1H),3.87(dd,J=12.4,7.0H z,1H),3.83–3.74(m,7H),3.73(dt,J=12.4,7.1Hz,2H),3.63(dt,J=12.4,7.1Hz,2H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12. 5,7.1Hz,1H),3.07–2.86(m,6H),2.77–2.65(m,2H),2.36–2.18(m,2H),2.11(hept,J=7.0Hz,1H),1.83–1.68(m,4H).ESI-MS m / z 564.3[M+H] + .

[0241] Example A54: Synthesis of Compound A54

[0242] Compound 2-5 in Example A1 was replaced with compound 2-6, and the synthesis method was referred to compound A1 to obtain compound A54. 1H NMR(500MHz,DMSO-d6)δ9.27(d,J=8.4Hz,1H),7.47–7.41(m,2H),7.28(d,J=7.3Hz,1H),6. 93(d,J=0.6Hz,1H),6.81(dd,J=7.5,1.5Hz,1H),6.63(t,J=0.9Hz,1H),6.18(s,1H),4.08(q d,J=7.9,2.5Hz,2H),3.90(dt,J=12.4,7.1Hz,1H),3.82(d,J=4.2Hz,6H),3.57(q,J=7.2Hz, 5H), 3.12 (td, J=7.1, 0.9Hz, 4H), 2.91 (tt, J=7.2, 0.8Hz, 2H), 1.40 (t, J=8.0Hz, 3H).ESI-MS m / z 466.2[M+H] + .

[0243] Example A55: Synthesis of Compound A55

[0244] Compound 2-5 in Example A1 was replaced with compound 2-7, and the synthesis method was referred to compound A1 to obtain compound A55. 1 H NMR (500MHz, DMSO-d6) δ7.26(d,J=7.5Hz,1H),7.18(d,J=8.4Hz,1H),7.12(d,J=1.4Hz,1H),6. 81(dd,J=7.5,1.5Hz,1H),6.76(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),5.07–5.01(m,1H),4.06 (qd,J=8.0,2.3Hz,2H),3.83–3.74(m,6H),3.61–3.49(m,4H),3.51–3.44(m,1H),3.13(dt,J=1 2.5,7.1Hz,2H),3.03–2.87(m,5H),2.83(dd,J=12.4,7.1Hz,1H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 480.2[M+H] + .

[0245] Example A56: Synthesis of Compound A56

[0246] Compound 2-5 in Example A1 was replaced with compound 2-8, and the synthesis method was referred to compound A1 to obtain compound A56. 1H NMR(500MHz,DMSO-d6)δ7.26(d,J=7.6Hz,1H),7.17–7.13(m,1H),7.10(d,J=8.4Hz,1H),6.8 2(dd,J=7.4,1.5Hz,1H),6.74(d,J=0.7Hz,1H),6.59(t,J=1.0Hz,1H),4.90–4.83(m,1H),4.0 6(qd,J=8.1,2.1Hz,2H),3.83–3.74(m,7H),3.54–3.43(m,5H),3.02–2.94(m,2H),2.97–2.8 6(m,4H),2.72–2.63(m,2H),2.06–1.88(m,3H),1.92–1.79(m,1H),1.44–1.37(m,3H).ESI-MS m / z 508.3[M+H] + .

[0247] Example A57: Synthesis of Compound A57

[0248] Compound A57 was obtained by replacing 2-5 in Example A1 with compound 2-9 and following the synthesis method of compound A1. 1 H NMR(500MHz,DMSO-d6)δ7.86(t,J=1.0Hz,1H),7.47–7.40(m,2H),7.17(d,J=8.4Hz,1H),6.74( d,J=0.6Hz,1H),6.59(t,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),4.06(qd,J=8.0,1.3Hz,2H),3.83 –3.74(m,3H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.07–2.86(m,6H),2.78(dt, J=12.3,7.1Hz,1H),2.70(dt,J=12.3,7.0Hz,1H),2.37–2.19(m,2H),1.44–1.37(m,3H).ESI-MS m / z 489.2[M+H] + .

[0249] Example A58: Synthesis of Compound A58

[0250] Compound 2-10 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A58. 1H NMR(500MHz,DMSO-d6)δ7.10–7.03(m,2H),6.81–6.77(m,1H),6.74(d,J=0.7Hz,1H),6.60 (t,J=0.9Hz,1H),4.87(td,J=6.9,0.6Hz,1H),4.06(qd,J=8.1,2.1Hz,2H),3.81(s,3H),3 .82–3.74(m,1H),3.58(s,2H),3.53(s,1H),3.53–3.43(m,4H),3.02–2.94(m,2H),2.97–2 .86(m,4H),2.77–2.64(m,2H),2.33(s,3H),2.36–2.18(m,2H),1.44–1.37(m,3H).ESI-MS m / z 508.3[M+H] + .

[0251] Example A59: Synthesis of Compound A59

[0252] Compound 2-11 was used to replace 2-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A59. 1 H NMR(500MHz,DMSO-d6)δ7.29(s,1H),7.07(d,J=8.4Hz,1H),6.81(s,1H),6.74(d,J=0.7 Hz,1H),6.60(t,J=0.9Hz,1H),6.03(d,J=3.7Hz,2H),4.87(td,J=6.9,0.6Hz,1H),4.06( qd,J=8.1,2.1Hz,2H),3.83–3.74(m,3H),3.53(s,1H),3.53–3.43(m,4H),3.02–2.94(m, 2H),2.97–2.86(m,4H),2.77–2.64(m,2H),2.36–2.18(m,2H),1.44–1.37(m,3H).ESI-MS m / z 508.2[M+H] + .

[0253] Example A60: Synthesis of Compound A60

[0254] Compound 2-12 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A60. 1H NMR (500MHz, DMSO-d6) δ7.48(dd,J=7.5,1.6Hz,1H),7.20(t,J=7.5Hz,1H),7.10(d,J=8.4Hz,1H),7.03(dd ,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.59(t,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),4.06(qd,J=8.0,1 .3Hz,2H),3.83–3.74(m,3H),3.52(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.07–2.86(m,6H),2.78 –2.64(m,2H),2.61(qd,J=8.0,1.5Hz,2H),2.37–2.19(m,2H),1.44–1.37(m,3H),1.23–1.17(m,3H).ESI-MS m / z 492.3[M+H] + .

[0255] Example A61: Synthesis of Compound A61

[0256] Compound 2-13 was used to replace 2-5 in Example A1, and the synthesis method was referred to that of compound A1 to obtain compound A61. 1 H NMR(500MHz,DMSO-d6)δ7.74–7.70(m,1H),7.36–7.28(m,2H),7.15(d,J=8.4Hz,1H),6.75(d, J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),4.06(qd,J=8.0,2.2Hz,2H),3.83– 3.74(m,3H),3.59–3.43(m,5H),3.13(dt,J=12.5,7.0Hz,2H),2.96(dt,J=12.5,7.2Hz,2H),2. 91(tt,J=7.1,0.9Hz,2H),2.77–2.64(m,2H),2.36–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 542.2[M+H] + .

[0257] Example A62: Synthesis of Compound A62

[0258] Compound 2-14 was used to replace 2-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A62.1 H NMR (500MHz, DMSO-d6) δ7.49–7.45(m,1H),7.39(d,J=7.5Hz,1H),7.13–7.07(m,2H),6.74(d,J=0.6 Hz,1H),6.60(t,J=1.1Hz,1H),4.87(t,J=6.9Hz,1H),4.07(qd,J=7.9,4.4Hz,2H),3.83–3.74(m,3H) ,3.61–3.53(m,2H),3.56–3.48(m,2H),3.47(dt,J=12.5,6.5Hz,1H),3.13(dt,J=12.5,7.0Hz,2H), 3.00–2.86(m,4H),2.78–2.64(m,2H),2.41(s,2H),2.37–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 478.3[M+H] + .

[0259] Example A63: Synthesis of Compound A63

[0260] Compound 2-15 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A63. 1 H NMR(500MHz,DMSO-d6)δ7.91(d,J=1.5Hz,1H),7.57(dd,J=7.5,1.6Hz,1H),7.32(d,J=7.5Hz ,1H),7.12(d,J=8.4Hz,1H),6.74(s,1H),6.60(d,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),4.14– 4.00(m,2H),3.81(s,2H),3.79(dt,J=12.5,7.1Hz,1H),3.52(d,J=7.2Hz,3H),3.52–3.43(m ,2H),3.02–2.86(m,6H),2.78–2.65(m,2H),2.37–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 532.2[M+H] + .

[0261] Example A64: Synthesis of Compound A64

[0262] Compound 2-16 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A64. 1H NMR (500MHz, DMSO-d6) δ7.37(d,J=7.5Hz,1H),7.08(d,J=1.7Hz,1H),6.94(s,1H),6.83(dd,J=7. 5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=0.9Hz,1H),4.87(t,J=6.9Hz,1H),4.06(qd,J=8. 1,2.1Hz,2H),3.82(d,J=3.1Hz,6H),3.82–3.75(m,1H),3.73(s,3H),3.54–3.43(m,5H),3.02–2. 94(m,2H),2.97–2.87(m,4H),2.79(t,J=7.0Hz,2H),2.26–2.08(m,2H),1.44–1.37(m,3H).ESI-MS m / z 508.3[M+H] + .

[0263] Example A65: Synthesis of Compound A65

[0264] Compound 2-17 was used to replace 2-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A65. 1 H NMR (500MHz, DMSO-d6) δ9.72(s,1H),7.78(d,J=1.4Hz,1H),7.49(dd,J=7.5,1.5Hz,1H),7.37(d,J=7.5Hz,1H ),7.15(d,J=8.4Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=0.9Hz,1H),4.87(t,J=6.9Hz,1H),4.14–4.00(m,2 H),3.81(s,2H),3.79(dt,J=12.5,7.1Hz,1H),3.52(t,J=7.1Hz,4H),3.47(dd,J=12.4,7.1Hz,1H),3.02–2.9 4(m,2H),2.97–2.86(m,4H),2.77–2.64(m,2H),2.37–2.19(m,2H),2.15(s,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 521.3[M+H] + .

[0265] Example A66: Synthesis of Compound A66

[0266] Compound 2-18 was used to replace 2-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A66. 1 H NMR(500MHz,DMSO-d6)δ7.69–7.63(m,2H),7.51(dd,J=7.5,1.6Hz,1H),7.31(td,J=7.5,1.5Hz,1H),7 .23(td,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.91–4.84(m,1H),4.08(qd,J =8.0,2.9Hz,2H),3.83–3.74(m,3H),3.57(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.17–3.08(m ,4H),2.91(tt,J=7.1,0.9Hz,2H),2.84–2.72(m,2H),2.21–2.03(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 465.2[M+H] + .

[0267] Example A67: Synthesis of Compound A67

[0268] Compound 2-19 was used to replace 2-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A67. 1 H NMR (500MHz, DMSO-d6) δ7.83–7.76(m,1H),7.76–7.69(m,1H),7.45–7.36(m,2H),7.31(s,1H),6.75(d,J=0.6 Hz,1H),6.60(t,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),4.06(qd,J=8.0,1.1Hz,2H),3.83–3.74(m,3H),3.56(t d,J=7.0,2.7Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.13(dt,J=12.5,7.0Hz,2H),2.96(dt,J=12.5,7.1Hz,2H ),2.91(tt,J=7.2,0.9Hz,2H),2.84(td,J=7.1,3.1Hz,2H),2.26–2.07(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 481.2[M+H] + .

[0269] Example A68: Synthesis of Compound A68

[0270] Compound 2-20 was used to replace 2-5 in Example A1, and the synthesis method was referred to that of compound A1 to obtain compound A68. 1 H NMR(500MHz,DMSO-d6)δ7.91(dd,J=7.5,1.6Hz,1H),7.56(dd,J=7.6,1.5Hz,1H),7.41(td,J=7.5,1.5Hz,1H ),7.26(td,J=7.5,1.5Hz,1H),6.75(s,1H),6.60(t,J=1.0Hz,1H),4.96–4.89(m,1H),4.15–4.00(m,2H),3.8 3–3.73(m,3H),3.57(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.22(dt,J=12.4,7.1Hz,1H),3.20–3.11 (m,4H),3.11(d,J=1.1Hz,1H),2.91(tt,J=7.1,1.1Hz,2H),2.48–2.31(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 465.2[M+H] + .

[0271] Example A69: Synthesis of Compound A69

[0272] Compound 2-21 was used to replace 2-5 in Example A1, and the synthesis method was referred to that of compound A1 to obtain compound A69. 1H NMR (500MHz, DMSO-d6) δ9.94(d,J=8.4Hz,1H),8.62(dd,J=7.5,1.6Hz,1H),8.38(dd,J=7.5,1.6Hz,1H),7.39(t,J=7.5 Hz,1H),6.94(d,J=8.6Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),4.08(qd,J=8.0,2. 9Hz,2H),3.83–3.74(m,3H),3.57(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.17–3.08(m,4H),2.99(dt,J=12.3, 7.1Hz,1H),2.91(tt,J=7.1,0.9Hz,2H),2.78(dt,J=12.4,7.1Hz,1H),2.36–2.19(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 465.2[M+H] + .

[0273] Example A70: Synthesis of Compound A70

[0274] Compound 2-22 was used to replace 2-5 in Example A1, and the synthesis method was referred to that of compound A1 to obtain compound A70. 1 H NMR(500MHz,DMSO-d6)δ8.43(dd,J=7.4,1.6Hz,1H),8.39(d,J=1.5Hz,1H),7.50(dt,J=7.5,1.5Hz,1H),7.26 (t,J=7.5Hz,1H),6.74(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.91–4.84(m,1H),4.17–4.02(m,2H),3.85(d t,J=12.3,7.1Hz,1H),3.83(s,3H),3.78(dt,J=12.5,7.0Hz,1H),3.58(t,J=7.1Hz,4H),3.13(t,J=7.1Hz,4H ),2.90(td,J=7.1,1.0Hz,2H),2.82(td,J=7.1,1.4Hz,2H),2.32–2.15(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 426.2[M+H] + .

[0275] Example A71: Synthesis of Compound A71

[0276] Compound 2-23 was used to replace 2-5 in Example A1, and the synthesis method was referred to that of compound A1 to obtain compound A71. 1 H NMR(500MHz,DMSO-d6)δ6.94(dd,J=7.3,1.6Hz,1H),6.81–6.72(m,3H),6.60(t,J=1 .0Hz,1H),4.91–4.84(m,1H),4.17–4.02(m,2H),3.84(dt,J=12.5,7.1Hz,1H),3.82 (s,3H),3.75(dt,J=12.5,7.1Hz,1H),3.58(t,J=7.1Hz,4H),3.22–3.08(m,4H),2.9 5–2.87(m,3H),2.89–2.82(m,1H),2.34–2.17(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 414.2[M+H] + .

[0277] Example A72: Synthesis of Compound A72

[0278] Compound 2-24 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A72. 1 H NMR(500MHz,DMSO-d6)δ8.51–8.46(m,2H),7.21–7.16(m,2H),6.74(d,J=0.6Hz,1H),6.59 (t,J=1.0Hz,1H),4.91–4.84(m,1H),4.17–4.02(m,2H),3.85(dt,J=12.3,7.1Hz,1H),3.83 (s,3H),3.78(dt,J=12.5,7.0Hz,1H),3.58(t,J=7.1Hz,4H),3.13(t,J=7.1Hz,4H),2.95–2 .86(m,3H),2.79(dt,J=12.5,7.1Hz,1H),2.24–2.07(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 426.2[M+H] + .

[0279] Example A73: Synthesis of Compound A73

[0280] Compound 2-25 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A73.1 H NMR(500MHz,DMSO-d6)δ7.37–7.31(m,2H),7.14–7.03(m,3H),6.74(d,J=0.6H z,1H),6.60(d,J=1.0Hz,1H),4.99–4.92(m,1H),4.15–4.00(m,2H),3.83–3.73 (m,3H),3.57(t,J=7.1Hz,4H),3.47(dt,J=12.5,7.1Hz,1H),3.12(td,J=7.1,1 .0Hz,4H),2.98–2.83(m,4H),2.30–2.13(m,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 464.2[M+H] + .

[0281] Example A74: Synthesis of Compound A74

[0282] Compound 2-26 was used to replace 2-5 in Example A1, and the synthesis method was referred to that of compound A1 to obtain compound A74. 1 H NMR(500MHz,DMSO-d6)δ7.76(d,J=7.9Hz,1H),7.45–7.41(m,1H),7.12(d,J=7.5Hz,1H),6.82(dd,J= 7.5,1.6Hz,1H),6.74(s,1H),6.59(t,J=1.0Hz,1H),6.11(t,J=6.8Hz,1H),5.09–5.02(m,1H),4.06( qd,J=8.0,1.3Hz,2H),3.96(dt,J=12.4,6.8Hz,1H),3.87–3.79(m,7H),3.82–3.76(m,1H),3.78–3.7 1(m,1H),3.52(t,J=7.1Hz,4H),2.95(d,J=7.0Hz,3H),2.95–2.87(m,3H),1.44–1.37(m,3H).ESI-MS m / z 495.3[M+H] + .

[0283] Example A75: Synthesis of Compound A75

[0284] Compound 2-27 was used to replace 2-5 in Example A1, and the synthesis method was referred to that of compound A1 to obtain compound A75. 1H NMR (500MHz, DMSO-d6) δ7.44–7.40(m,1H),7.24(d,J=9.2Hz,1H),7.16(d,J=7.5Hz,1H),6.84–6. 79(m,2H),6.59(t,J=1.1Hz,1H),5.30–5.23(m,1H),4.55(dd,J=12.3,7.0Hz,1H),4.46(dd,J=12. 4,7.1Hz,1H),4.06(qd,J=8.1,1.4Hz,2H),3.81(d,J=3.1Hz,6H),3.76(t,J=7.1Hz,2H),3.52(t, J=7.1Hz,4H),3.07–2.98(m,4H),2.91(ddd,J=7.2,6.6,1.0Hz,2H),1.40(t,J=8.0Hz,3H).ESI-MS m / z 496.2[M+H] + .

[0285] Example A76: Synthesis of Compound A76

[0286] Replace 1-2 in Example (S)-A1 with iodomethane, replace 2-5 in Example (S)-A1 with compound 2-28, replace morpholine chloride in Example (S)-A1 with compound 33-1, and follow the synthesis method with reference to compound (S)-A1 to obtain compound A76. 1H NMR(500MHz,Chloroform-d)δ9.91(d,J=8.6Hz,1H),7.55(d,J=7.5Hz,1H),7.17(dd,J=1.4,0.8Hz,1H),7.19–7.11(m,1H),6.98(dq,J=7.8,1. 3Hz,1H),6.83(d,J=0.6Hz,1H),6.58(t,J=1.0Hz,1H),4.67–4.60(m,1H),3.83(d,J=6.2Hz,6H),3.81–3.74(m,2H),3.74(d,J=7.0Hz,1H),3.6 9(dt,J=12.3,7.1Hz,1H),3.55(dt,J=12.4,7.1Hz,2H),3.18(dt,J=12.3,7.1Hz,1H),3.02(dt,J=12.5,7.1Hz,1H),2.91(td,J=7.0,0.9Hz,2H ),2.55(p,J=7.0Hz,1H),2.47(d,J=0.9Hz,2H),2.33(dq,J=12.5,7.1Hz,1H),2.25(dq,J=12.5,7.1Hz,1H),1.70(qd,J=7.1,4.3Hz,4H).ESI-MS m / z 462.3[M+H] +

[0287] Example A77: Synthesis of Compound A77

[0288] Compound A77 was obtained by replacing 1-2 in Example A1 with iodomethane, replacing 2-5 in Example A1 with compound 2-29, and replacing morpholine chloride in Example A1 with compound 10-1. The synthesis method was similar to that of compound A1. 1H NMR(500MHz,Chloroform-d)δ9.94(d,J=8.4Hz,1H),8.70–8.65(m,2H),7.78–7.73(m,2H),7.60(dd,J =7.3,1.6Hz,1H),7.36(dd,J=7.4,1.7Hz,1H),7.18–7.12(m,2H),7.09(td,J=7.4,1.5Hz,1H),6.82(s ,1H),6.58(t,J=1.0Hz,1H),4.93–4.86(m,1H),3.84(d,J=4.4Hz,6H),3.75–3.63(m,2H),3.18(dt,J= 12.2,7.1Hz,1H),3.02(dt,J=12.5,7.1Hz,1H),2.90(td,J=7.0,0.9Hz,2H),2.35–2.18(m,2H).ESI-MS m / z 442.2[M+H] + .

[0289] Example A80: Synthesis of Compound A80

[0290] Compound A80 was obtained by replacing the morpholine chloride in Example (S)-A1 with compound 34-1 and following the synthesis method referring to compound (S)-A1. 1 H NMR(500MHz,Chloroform-d)δ9.07(d,J=2.7Hz,1H),7.27–7.20(m,2H),7.09(d,J=8.4Hz,1H),7.05(d,J =1.5Hz,1H),6.81(dd,J=7.5,1.5Hz,1H),6.75(d,J=0.6Hz,1H),6.60(t,J=1.0Hz,1H),4.82–4.76(m,1H) ,4.07(qd,J=7.9,1.6Hz,2H),3.82(d,J=12.8Hz,5H),3.72(t,J=7.1Hz,2H),2.92(tt,J=7.2,1.0Hz,2H), 2.79(dt,J=12.2,7.0Hz,1H),2.66(dt,J=12.4,7.1Hz,1H),2.36–2.19(m,2H),1.45–1.38(m,3H).ESI-MS m / z 492.2[M+H] + .

[0291] Example A83: Synthesis of Compound A83

[0292] Replace 1-2 in Example A1 with iodomethane and 2-5 in Example A1 with compound 2-32. Refer to the synthesis method of intermediate 3-8 to obtain intermediate 3-9. Dissolve 3-9 in acetonitrile, add potassium carbonate and 35-1, and reflux under argon for 5 hours. Cool, evaporate the solvent, dilute with dichloromethane, and wash twice with saturated ammonium chloride and sodium chloride. Combine the organic phases, dry over anhydrous sodium sulfate, and spin dry the solvent. Column chromatography (petroleum ether: ethyl acetate 1:1) gives an off-white solid in a yield of 90%. Compound A83 is obtained. 1 H NMR(500MHz,Chloroform-d)δ7.62(dd,J=7.1,1.8Hz,1H),7.38–7.33(m,1H),7.18(d,J=8.4Hz,1H),7.12–7.02(m,2H),6.78 (d,J=0.6Hz,1H),6.57(t,J=1.0Hz,1H),3.90–3.82(m,7H),3.74(td,J=7.1,2.4Hz,4H),3.52(dd,J=12.4,7.1Hz,1H),3.06(d t,J=12.5,7.2Hz,1H),2.95(dt,J=12.3,6.9Hz,1H),2.87(dd,J=12.4,7.0Hz,1H),2.85–2.76(m,1H),2.74(dtd,J=12.3,7.2 ,0.9Hz,1H),2.61(dd,J=12.3,7.0Hz,1H),2.55(dd,J=12.4,6.9Hz,1H),1.95(hept,J=7.0Hz,1H),1.87–1.68(m,4H).ESI-MS m / z 421.2[M+H] + .

[0293] Example A84: Synthesis of Compound A84

[0294] Compound A84 was obtained by replacing the morpholine chloride in Example A1 with compound 36-1 and synthesizing it according to the method of compound A83. 1H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7 .3,2.0Hz,1H),6.69(s,1H),6.61(d,J=0.9Hz,1H),4.11(q,J=6.2Hz,2H),3.83( d,J=4.0Hz,7H),3.63–3.56(m,5H),3.54(s,0H),2.93–2.82(m,4H),2.75–2.60 (m,1H),2.55(dt,J=6.1,3.7Hz,4H),2.11(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 480.3[M+H] + .

[0295] Example A85: Synthesis of Compound A85

[0296] Compound A85 was obtained by replacing the morpholine chloride in Example A1 with compound 37-1 and following the synthesis method referred to compound A1. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3,2.0H z,1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2Hz,2H),3.9 2–3.84(m,1H),3.84–3.80(m,8H),3.79–3.71(m,1H),3.72(d,J=6.2Hz,2H),2.92(td,J= 5.5,1.0Hz,2H),2.69(td,J=7.8,2.5Hz,2H),2.14(m,2H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 506.3[M+H] + .

[0297] Example A86: Synthesis of Compound A86

[0298] Compound A86 was obtained by replacing the morpholine chloride in Example A1 with compound 38-1 and following the synthesis method referred to compound A1. 1H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3,2.0Hz,1H),6.74(s,1H),6 .61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.24(m,2H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1H),3.82(s,3H), 3.79–3.71(m,1H),3.70(dd,J=12.4,2.7Hz,2H),3.56(dd,J=12.5,2.8Hz,2H),2.92(td,J=5.6,1.0Hz,2H),2 .69(td,J=7.8,2.5Hz,2H),2.14(m,2H),1.95–1.83(m,2H),1.82–1.70(m,2H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 520.3[M+H] + .

[0299] Example A87: Synthesis of Compound A87

[0300] Compound A87 was obtained by replacing the morpholine chloride in Example A1 with compound 39-1 and following the synthesis method referred to compound A1. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3,2.0Hz, 1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.96–4.90(m,1H),4.16–4.07(m,4H),3.89–3.81 (m,7H),3.76(s,2H),3.77–3.68(m,3H),2.92(td,J=5.5,1.0Hz,2H),2.69(td,J=7.8,2.5 Hz,2H),2.14(m,2H),2.02–1.90(m,2H),1.88–1.76(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 520.3[M+H] + .

[0301] Example A88: Synthesis of Compound A88

[0302] Compound A88 was obtained by replacing the morpholine chloride in Example A1 with compound 40-1 and following the synthesis method referred to compound A1. 1H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3,2.0Hz,1H),6.74(s,1H ),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.62(t,J=4.2Hz,1H),4.11(q,J=6.2Hz,2H),3.98–3.89(m,2H ),3.92–3.84(m,1H),3.83(s,3H),3.84–3.72(m,2H),3.69(s,3H),3.75–3.64(m,1H),3.59(m,1H),3.49(m ,1H),2.92(td,J=5.5,1.0Hz,2H),2.69(td,J=7.8,2.5Hz,2H),2.14(m,2H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 552.3[M+H] + .

[0303] Example A89: Synthesis of Compound A89

[0304] Compound A88 was dissolved in methanol and 1M sodium hydroxide solution was added. The reaction was allowed to react at room temperature for 2 hours. Most of the methanol was removed by rotary evaporation, and most impurities were washed away with dichloromethane. The aqueous phase was adjusted to pH 1-2 with 1M hydrochloric acid, and extracted with ethyl acetate. The ethyl acetate layers were combined, dried over anhydrous sodium sulfate, and the solvent was evaporated to afford A89 as a white solid in a 95% yield. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3,2.0Hz,1H),6.74(s,1H ),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.44(t,J=4.3Hz,1H),4.11(q,J=6.2Hz,2H),3.97–3.88(m,2 H),3.91–3.84(m,1H),3.83(s,3H),3.82–3.71(m,2H),3.67(dd,J=12.3,4.2Hz,1H),3.59(m,1H),3.49(m ,1H),2.92(td,J=5.6,1.0Hz,2H),2.69(td,J=7.8,2.5Hz,2H),2.14(m,2H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 538.2[M+H] + .

[0305] Example A90: Synthesis of Compound A90

[0306] Compound A90 was obtained by replacing the morpholine chloride in Example A1 with compound 41-1 and synthesizing it according to the method of compound A83. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3,2.0Hz ,1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.66–4.59(m,1H),4.56(d,J=1.0Hz,2H),4.11( q,J=6.2Hz,2H),3.83(d,J=4.0Hz,6H),3.73–3.67(m,2H),3.69–3.62(m,4H),3.41–3.31 (m,4H),2.87(m,2H),2.73–2.62(m,2H),2.23–2.05(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 492.3[M+H] + .

[0307] Example A96: Synthesis of Compound A96

[0308] Compound A96 was obtained by replacing the morpholine chloride in Example A1 with compound 47-1 and following the synthesis method referring to compound A1. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3,2.0Hz,1H ),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.92(t,J=6.4Hz,1H),4.11(q,J=6.2Hz,2H),3.82(s, 3H),3.78–3.67(m,2H),3.66–3.55(m,4H),2.95–2.81(m,2H),2.69(td,J=7.8,2.5Hz,2H),2 .68–2.60(m,1H),2.16(m,1H),2.04(m,1H),1.84–1.69(m,4H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 493.3[M+H] + .

[0309] Example A97: Synthesis of Compound A97

[0310] Compound A97 was obtained by replacing the morpholine chloride in Example A1 with compound 48-1 and following the synthesis method referred to compound A1. 1 H NMR(500MHz,DMSO-d6)δ7.60(s,1H),7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3,2.0Hz, 1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.82–4.76(m,1H),4.11(q,J=6.2Hz,2H),3.83(d,J=4.0Hz,6H ),3.81–3.75(m,1H),3.71(dt,J=12.3,5.0Hz,1H),3.70–3.64(m,4H),3.67–3.57(m,2H),3.44–3.36(m ,2H),2.86(td,J=5.1,1.0Hz,2H),2.73–2.63(m,2H),2.22–2.07(m,2H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 493.3[M+H] + .

[0311] Example A98: Synthesis of Compound A98

[0312] Compound A98 was obtained by replacing the morpholine chloride in Example A1 with compound 49-1 and following the synthesis method referred to compound A1. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3,2.0Hz,1H) ,6.74(s,1H),6.61(t,J=1.0Hz,1H),4.83(t,J=6.1Hz,1H),4.11(q,J=6.2Hz,2H),3.91(m,1H) ,3.83(d,J=4.0Hz,6H),3.76–3.66(m,5H),3.60(dt,J=12.3,4.6Hz,2H),3.51–3.43(m,2H),2. 94–2.83(m,2H),2.69(td,J=7.8,2.5Hz,2H),2.21–2.04(m,2H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 518.3[M+H] + .

[0313] Example A99: Synthesis of Compound A99

[0314] Compound A99 was obtained by replacing the morpholine chloride in Example A1 with compound 50-1 and following the synthesis method referred to compound A1. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3,2.0Hz,1H),6. 74(s,1H),6.61(t,J=1.0Hz,1H),5.92(d,J=4.0Hz,1H),5.28(dt,J=4.2,3.4Hz,1H),4.92–4.86( m,1H),4.11(q,J=6.2Hz,2H),3.83(s,3H),3.92–3.70(m,5H),3.67–3.54(m,2H),3.47(m,1H),2. 92(td,J=5.5,1.0Hz,2H),2.69(td,J=7.8,2.5Hz,2H),2.14(m,2H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 510.3[M+H] + .

[0315] Example A100: Synthesis of Compound A100

[0316] Compound A100 was obtained by replacing the morpholine chloride in Example A1 with compound 51-1 and following the synthesis method referred to compound A1. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3,2.0Hz,1H),6.74(s,1H),6.61(t,J=1 .0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2Hz,2H),3.92–3.85(m,1H),3.83(d,J=4.0Hz,6H),3.79–3.71(m,1H),3.61–3 .49(m,4H),3.51–3.43(m,2H),3.42–3.32(m,2H),2.92(td,J=5.5,1.0Hz,2H),2.69(td,J=7.8,2.5Hz,2H),2.14(m,2H) ,1.79(dd,J=5.0,3.3Hz,1H),1.71–1.65(m,1H),1.66(td,J=3.8,2.1Hz,2H),1.57(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 548.3[M+H] + .

[0317] Example A101: Synthesis of Compound A101

[0318] Compound A101 was obtained by replacing the morpholine chloride in Example A1 with compound 52-1 and synthesizing it according to the method of compound A83. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3,2.0Hz,1H),6.74(s,1H ),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.24(d,J=5.0Hz,1H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1 H),3.82(s,3H),3.79–3.71(m,1H),3.70(p,J=4.9Hz,1H),3.53(m,2H),3.35(m,2H),2.92(td,J=5.6,1.0 Hz,2H),2.69(td,J=7.8,2.5Hz,2H),2.14(m,2H),1.87(m,2H),1.69(m,2H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 508.3[M+H] + .

[0319] Example A102: Synthesis of Compound A102

[0320] Compound 1-30 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A102. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.85–6.77(m ,2H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.69(s,2H),3.92–3.85(m,1H) ,3.82(d,J=3.0Hz,6H),3.79–3.71(m,1H),3.64–3.57(m,4H),3.27–3.13(m,4H ),2.92(td,J=5.6,1.0Hz,2H),2.69(td,J=7.8,2.5Hz,2H),2.14(m,2H).ESI-MS m / z 524.2[M+H] + .

[0321] Example A103: Synthesis of Compound A103

[0322] Compound 1-31 was used to replace 1-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A103. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.85–6.74(m,3H),4.8 5–4.79(m,1H),4.75(d,J=6.9Hz,1H),4.69(d,J=6.9Hz,1H),3.88(dt,J=12.5,5.5Hz,1H) ,3.85(s,3H),3.82(s,2H),3.75(dt,J=12.5,5.5Hz,1H),3.65–3.57(m,4H),3.27–3.13(m ,4H),2.90(td,J=5.4,1.0Hz,2H),2.69(td,J=7.8,2.4Hz,2H),2.25–2.08(m,2H).ESI-MS m / z 465.2[M+H] + .

[0323] Example A104: Synthesis of Compound A104

[0324] Compound 1-32 was used to replace 1-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A104. 1 H NMR(500MHz,DMSO-d6)δ7.84(s,1H),7.65(d,J=0.7Hz,1H),7.25(d,J=7.4Hz,1H),7.13–7.08(m ,2H),6.85–6.80(m,2H),5.97(tt,J=17.0,5.8Hz,1H),5.29(m,2H),4.91(s,0H),4.66(m,2H),3. 89(s,3H),3.92–3.84(m,1H),3.82(s,2H),3.75(dt,J=12.5,5.5Hz,1H),3.65–3.57(m,4H),3.2 7–3.13(m,4H),2.90(td,J=5.4,1.0Hz,2H),2.75–2.62(m,2H),2.20(m,1H),2.10(m,1H).ESI-MS m / z 549.3[M+H] + .

[0325] Example A105: Synthesis of Compound A105

[0326] Compound 1-33 was used to replace 1-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A105. 1 H NMR(500MHz,DMSO-d6)δ7.81(dd,J=7.4,1.6Hz,1H),7.70–7.64(m,1H),7.43(m,2H),7.25(d ,J=7.3Hz,0H),7.13–7.08(m,1H),6.85–6.80(m,1H),4.52(d,J=4.8Hz,1H),4.42(t,J=4.8H z,0H),3.89(s,1H),3.82(s,1H),3.75(dt,J=12.5,5.5Hz,0H),3.64–3.57(m,2H),3.27–3.1 3(m,2H),2.90(td,J=5.4,1.0Hz,1H),2.69(td,J=7.8,2.4Hz,1H),2.24–2.06(m,1H).ESI-MS m / z 687.3[M+H] + .

[0327] Example A106: Synthesis of Compound A106

[0328] Compound 1-34 was used to replace 1-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A106. 1 H NMR (500MHz, DMSO-d6) δ7.28–7.22(m,1H),7.13–7.08(m,1H),6.85–6.78(m,1H),6.00(s,1H),3.88(s,2H),3.82(s,1H),3.75(dt,J=12. 5,5.5Hz,1H),3.65–3.57(m,2H),3.27–3.13(m,2H),2.90(td,J=5.4,1.0Hz,1H),2.69(td,J=7.8,2.4Hz,1H),2.24–2.06(m,1H).ESI-MS m / z 507.3[M+H] + .

[0329] Example A107: Synthesis of Compound A107

[0330] Compound 1-35 was used to replace 1-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A107. 1H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.22(q,J=0.9Hz,1H),7.13–7.08(m,2H),6 .82(dd,J=7.3,2.0Hz,1H),6.72(t,J=1.1Hz,1H),5.04(q,J=6.6Hz,1H),4.92–4.86(m,1H) ,4.68(q,J=6.6Hz,1H),4.01–3.84(m,3H),3.82(s,2H),3.80–3.71(m,3H),3.65–3.57(m,4 H),3.27–3.13(m,4H),2.91(m,2H),2.69(td,J=7.8,2.5Hz,2H),2.23–2.04(m,2H).ESI-MS m / z 479.3[M+H] + .

[0331] Example A108: Synthesis of Compound A108

[0332] Compound 1-36 was used to replace 1-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A108. 1 H NMR(500MHz,DMSO-d6)δ7.52(s,1H),7.25(d,J=7.4Hz,1H),7.23–7.18(m,2H),7.13–7.08(m,2H),6.82( dd,J=7.3,2.0Hz,1H),6.70(t,J=1.0Hz,1H),6.05(d,J=6.5Hz,1H),5.99(d,J=6.5Hz,1H),4.92–4.86(m, 1H),4.49(dd,J=4.2,1.0Hz,2H),3.92–3.84(m,1H),3.82(s,2H),3.76(s,3H),3.79–3.71(m,1H),3.65–3 .55(m,4H),3.27–3.13(m,4H),2.96–2.87(m,2H),2.69(td,J=7.8,2.5Hz,2H),2.24–2.06(m,2H).ESI-MS m / z 521.3[M+H] + .

[0333] Example A109: Synthesis of Compound A109

[0334] Compound 1-37 was used to replace 1-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A109. 1H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.3Hz,1H),7.13–7.08(m,3H),6.82(dd,J=7.3,2.0Hz,1H ),6.73(t,J=1.0Hz,1H),4.92–4.86(m,1H),3.92–3.84(m,1H),3.82(d,J=2.0Hz,6H),3.79– 3.71(m,1H),3.65–3.57(m,4H),3.27–3.13(m,4H),3.09(m,2H),2.96–2.81(m,4H),2.69(td ,J=7.8,2.5Hz,2H),2.23–2.04(m,2H),1.62(q,J=6.6Hz,1H),1.49(q,J=6.6Hz,1H).ESI-MS m / z 493.3[M+H] + .

[0335] Example A110: Synthesis of Compound A110

[0336] Compound 1-38 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A110. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.4,2.0 Hz,1H),6.80(s,1H),6.68(t,J=1.1Hz,1H),4.93–4.87(m,1H),4.62(s,1H),4.09(q,J= 6.1Hz,2H),3.88(m,1H),3.82(s,2H),3.75(m,1H),3.65–3.57(m,4H),3.27–3.13(m,4H ),2.93(m,2H),2.69(td,J=7.8,2.5Hz,2H),2.14(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 479.3[M+H] + .

[0337] Example A111: Synthesis of Compound A111

[0338] Compound 1-39 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A111. 1H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.07(m,2H),7.03(p,J=1.0Hz,1H),6.83(s,1H),6. 85–6.80(m,1H),5.00(q,J=6.5Hz,1H),4.90(s,0H),4.65(q,J=6.5Hz,1H),4.09(q,J=6.3Hz,2H),4.04– 3.92(m,2H),3.92–3.84(m,1H),3.82(s,2H),3.79–3.71(m,1H),3.65–3.57(m,4H),3.27–3.13(m,4H),2 .92(td,J=5.4,1.0Hz,2H),2.69(td,J=7.8,2.5Hz,2H),2.24–2.05(m,2H),1.42(t,J=6.2Hz,3H).ESI-MS m / z 493.3[M+H] + .

[0339] Example A112: Synthesis of Compound A112

[0340] Compound 1-5 in Example A1 was replaced with compound 1-40, and the synthesis method was referred to compound A1 to obtain compound A112. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.92(p,J=1.0Hz,1H),6.82(dd,J =7.3,2.0Hz,1H),6.79(d,J=0.6Hz,1H),4.90(s,0H),4.09(q,J=6.3Hz,2H),3.88(m,1H),3.82(s,2H ),3.75(m,1H),3.65–3.57(m,4H),3.27–3.13(m,4H),3.09(m,2H),2.96–2.81(m,4H),2.73–2.65(m ,1H),2.24–2.05(m,2H),1.62(q,J=6.6Hz,1H),1.49(t,J=6.6Hz,1H),1.42(t,J=6.2Hz,3H).ESI-MS m / z 507.3[M+H] + .

[0341] Example A113: Synthesis of Compound A113

[0342] Compound 1-41 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A113. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3,2.0 Hz,1H),6.76–6.70(m,2H),4.92–4.86(m,1H),4.11(q,J=6.2Hz,4H),3.92–3.84(m,1H ),3.82(s,2H),3.79–3.71(m,1H),3.64–3.57(m,4H),3.27–3.13(m,4H),2.92(td,J=5 .6,1.0Hz,2H),2.69(td,J=7.8,2.5Hz,2H),2.14(m,2H),1.41(t,J=6.3Hz,6H).ESI-MS m / z 508.3[M+H] + .

[0343] Example A114: Synthesis of Compound A114

[0344] Compound 1-42 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A114. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.06(m,3H),6.82(dd,J=7.3,2.0Hz,1H),6.65(t,J=1.0Hz,1H),4.90(t,J=6.6Hz,1H),3.92–3 .81(m,5H),3.79–3.71(m,1H),3.65–3.55(m,4H),3.27–3.13(m,4H),2.9 2(td,J=5.5,1.0Hz,2H),2.69(td,J=7.8,2.5Hz,2H),2.14(m,2H).ESI-MS m / z 537.3[M+H] + .

[0345] Example A115: Synthesis of Compound A115

[0346] Compound 1-43 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A115. 1H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3,2.0Hz,1H),6.7 6(d,J=0.7Hz,1H),6.59(t,J=1.0Hz,1H),6.05(m,1H),5.36(m,2H),4.92–4.86(m,1H),4.60(dt,J= 5.5,1.0Hz,2H),3.92–3.85(m,1H),3.82(d,J=2.6Hz,6H),3.79–3.71(m,1H),3.65–3.57(m,4H),3 .27–3.13(m,4H),2.92(td,J=5.5,1.0Hz,2H),2.76–2.62(m,2H),2.20(m,1H),2.09(m,1H).ESI-MS m / z 506.3[M+H] + .

[0347] Example A116: Synthesis of Compound A116

[0348] Compound 1-44 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A116. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.85–6.78(m,2H),6 .60(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.86–4.78(m,2H),3.92–3.84(m,1H),3.82(d ,J=2.0Hz,6H),3.79–3.71(m,1H),3.65–3.55(m,4H),3.36(d,J=6.2Hz,0H),3.27–3.1 3(m,4H),2.92(td,J=5.6,1.0Hz,2H),2.69(td,J=7.8,2.5Hz,2H),2.14(m,2H).ESI-MS m / z 504.2[M+H] + .

[0349] Example A117: Synthesis of Compound A117

[0350] Compound 1-45 was used to replace 1-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A117. 1H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3,2. 0Hz,1H),6.75(s,1H),6.64(t,J=1.1Hz,1H),4.92–4.86(m,1H),4.26(d,J=0.7Hz,4H ),3.92–3.84(m,1H),3.82(s,2H),3.79–3.71(m,1H),3.65–3.57(m,4H),3.27–3.13( m,4H),2.92(td,J=5.4,1.0Hz,2H),2.69(td,J=7.8,2.5Hz,2H),2.14(m,2H).ESI-MS m / z 478.2[M+H] + .

[0351] Example A118: Synthesis of Compound A118

[0352] Compound 1-46 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A118. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3,2. 0Hz,1H),6.67(s,1H),6.57(t,J=1.0Hz,1H),5.98(d,J=0.8Hz,2H),4.92–4.86(m,1H ),3.92–3.84(m,1H),3.82(s,2H),3.79–3.71(m,1H),3.65–3.57(m,4H),3.27–3.13( m,4H),2.92(td,J=5.4,1.0Hz,2H),2.69(td,J=7.8,2.5Hz,2H),2.14(m,2H).ESI-MS m / z 464.2[M+H] + .

[0353] Example A119: Synthesis of Compound A119

[0354] Compound 2-33 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A119. 1H NMR (500MHz, DMSO-d6) δ7.49(d,J=7.9Hz,1H),7.23(d,J=2.1Hz,1H),6.85(dd,J=7.7,2.0Hz,1H ),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.97–4.90(m,1H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1 H),3.83(d,J=3.6Hz,6H),3.79–3.71(m,1H),3.65–3.55(m,4H),3.27–3.13(m,5H),2.98–2.88( m,3H),2.29(dq,J=14.5,7.8Hz,1H),2.11(dq,J=14.5,7.7Hz,1H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 495.3[M+H] + .

[0355] Example A120: Synthesis of Compound A120

[0356] Compound 2-34 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A120. 1 H NMR(500MHz,DMSO-d6)δ7.84(t,J=1.2Hz,1H),7.53(d,J=1.3Hz,2H),6.74(s,1H),6.6 1(t,J=1.0Hz,1H),4.97–4.90(m,1H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1H),3.83( s,2H),3.79–3.71(m,1H),3.65–3.55(m,4H),3.27–3.13(m,5H),2.98–2.88(m,2H),2. 28(dq,J=14.5,7.6Hz,1H),2.13(dq,J=14.5,7.8Hz,1H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 543.2[M+H] + .

[0357] Example A121: Synthesis of Compound A121

[0358] Compound 2-35 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A121. 1H NMR (500MHz, DMSO-d6) δ7.54(d,J=2.1Hz,1H),7.47(d,J=7.7Hz,1H),7.35(dd,J=7.7,2.0Hz, 1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.97–4.90(m,1H),4.11(q,J=6.2Hz,2H),3.92–3.84 (m,1H),3.83(s,2H),3.79–3.71(m,1H),3.65–3.55(m,4H),3.27–3.13(m,5H),2.98–2.88(m, 2H), 2.28 (dq, J=14.5, 7.6Hz, 1H), 2.13 (dq, J=14.5, 7.8Hz, 1H), 1.41 (t, J=6.3Hz, 3H).ESI-MS m / z 499.2[M+H] + .

[0359] Example A122: Synthesis of Compound A122

[0360] Compound 2-36 was used to replace 2-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A122. 1 H NMR(500MHz,DMSO-d6)δ8.07(d,J=2.2Hz,1H),7.68–7.60(m,2H),6.74(s,1H),6.61( t,J=1.0Hz,1H),4.97–4.90(m,1H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1H),3.83(s, 2H),3.79–3.71(m,1H),3.65–3.55(m,4H),3.27–3.13(m,5H),2.98–2.88(m,2H),2.2 8(dq,J=14.5,7.6Hz,1H),2.13(dq,J=14.5,7.8Hz,1H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 490.2[M+H] + .

[0361] Example A123: Synthesis of Compound A123

[0362] Compound 2-37 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A123. 1H NMR (500MHz, DMSO-d6) δ7.57(d,J=7.7Hz,1H),7.45(s,1H),7.26(d,J=1.6Hz,1H),7.05(dd,J=7.9 ,2.0Hz,1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.93–4.86(m,1H),4.11(q,J=6.2Hz,2H),3.92–3. 85(m,1H),3.83(d,J=4.2Hz,6H),3.79–3.71(m,1H),3.65–3.57(m,4H),3.27–3.13(m,4H),2.92(t d,J=5.5,1.0Hz,2H),2.78(td,J=7.3,5.0Hz,2H),2.20–2.02(m,2H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 511.2[M+H] + .

[0363] Example A124: Synthesis of Compound A124

[0364] Compound 2-38 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A124. 1 H NMR(500MHz,DMSO-d6)δ7.77–7.73(m,1H),7.66(d,J=7.9Hz,1H),7.49(dd,J=7.9,2.0Hz,1H),7 .43(s,1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.93–4.86(m,1H),4.11(q,J=6.2Hz,2H),3.92– 3.84(m,1H),3.83(s,2H),3.79–3.71(m,1H),3.65–3.57(m,4H),3.27–3.13(m,4H),2.92(td,J= 5.6,1.0Hz,2H),2.75(dd,J=14.3,7.1Hz,2H),2.19–2.02(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 559.1[M+H] + .

[0365] Example A125: Synthesis of Compound A125

[0366] Compound 2-39 was used to replace 2-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A125. 1H NMR (500MHz, DMSO-d6) δ7.91(d,J=2.0Hz,1H),7.75(dd,J=6.4,1.8Hz,1H),7.71(d,J=6.3Hz,1H ),7.43(s,1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.93–4.86(m,1H),4.11(q,J=6.2Hz,2H),3.9 2–3.84(m,1H),3.83(s,2H),3.79–3.71(m,1H),3.65–3.57(m,4H),3.27–3.13(m,4H),2.92(td, J=5.6,1.0Hz,2H),2.77(td,J=7.3,4.5Hz,2H),2.19–2.02(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 506.2[M+H] + .

[0367] Example A126: Synthesis of Compound A126

[0368] Compound 2-40 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A126. 1 H NMR (500MHz, DMSO-d6) δ7.76(s,1H),7.33(d,J=8.4Hz,1H),7.20(d,J=2.1Hz,1H),6.96(dd,J=8 .4,1.9Hz,1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.89(s,0H),4.11(q,J=6.2Hz,2H),3.92–3.8 5(m,1H),3.83(d,J=5.4Hz,6H),3.79–3.71(m,1H),3.65–3.57(m,4H),3.27–3.13(m,4H),2.92(t d,J=5.6,1.0Hz,2H),2.85–2.71(m,2H),2.08(m,1H),1.99(m,1H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 495.2[M+H] + .

[0369] Example A127: Synthesis of Compound A127

[0370] Compound 2-41 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A127. 1H NMR(500MHz,DMSO-d6)δ7.85(d,J=1.8Hz,1H),7.76(s,1H),7.57–7.48(m,2H),6.74 (s,1H),6.61(t,J=1.0Hz,1H),4.89(s,0H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1H ),3.83(s,2H),3.79–3.71(m,1H),3.65–3.55(m,4H),3.27–3.13(m,4H),2.95–2.89 (m,2H),2.85–2.71(m,1H),2.08(m,1H),1.99(m,1H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 543.1[M+H] + .

[0371] Example A128: Synthesis of Compound A128

[0372] Compound 2-42 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A128. 1 H NMR (500MHz, DMSO-d6) δ7.94(d,J=2.0Hz,1H),7.76(s,1H),7.70(dd,J=7.0,1.9Hz,1H),7.53(d,J=7.0Hz,1H),6.74(s,1H ),6.61(t,J=1.0Hz,1H),4.89(s,0H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1H),3.83(s,2H),3.79–3.71(m,1H),3.65–3.55 (m,4H),3.27–3.13(m,4H),2.97–2.89(m,2H),2.85–2.71(m,1H),2.08(m,1H),1.99(m,1H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 490.2[M+H] + .

[0373] Example A129: Synthesis of Compound A129

[0374] Compound 2-43 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A129. 1H NMR(500MHz,DMSO-d6)δ7.33–7.26(m,2H),7.14–7.08(m,2H),6.74(s,1H),6.61(t ,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1H),3.83( s,2H),3.79–3.71(m,1H),3.65–3.57(m,4H),3.27–3.13(m,4H),2.92(td,J=5.6,1 .0Hz,2H),2.69(td,J=7.8,2.5Hz,2H),2.14(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 548.2[M+H] + .

[0375] Example A130: Synthesis of Compound A130

[0376] Compound 2-44 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A130. 1 H NMR (500MHz, DMSO-d6) δ9.91 (s, 1H), 7.38–7.32 (m, 1H), 7.13 (d, J = 2.0Hz, 1H), 6.84 ( dd,J=8.8,1.9Hz,1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.90–4.84(m,1H),4.11(q, J=6.2Hz,2H),3.92–3.71(m,6H),3.67(t,J=6.0Hz,1H),3.64–3.57(m,4H),3.27–3.13 (m,4H),2.92(td,J=5.6,1.0Hz,2H),2.08–1.92(m,4H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 510.3[M+H] + .

[0377] Example A131: Synthesis of Compound A131

[0378] Compound 2-45 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A131. 1H NMR(500MHz,DMSO-d6)δ7.31–7.24(m,2H),7.14–7.06(m,2H),6.74(s,1H),6.61 (t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1H),3 .83(s,2H),3.79–3.71(m,1H),3.65–3.55(m,4H),3.27–3.13(m,4H),2.95–2.89 (m,2H),2.69(td,J=7.8,2.5Hz,2H),2.14(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 530.2[M+H] + .

[0379] Example A132: Synthesis of Compound A132

[0380] Compound 2-46 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A132. 1 H NMR (500MHz, DMSO-d6) δ7.30(d,J=7.3Hz,1H),7.16(d,J=1.5Hz,1H),7.11(d,J=6.9Hz,1H),6.94(dd,J=7.3 ,2.0Hz,1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),5.89(d,J=0.8Hz,1H),5.80(d,J=1.0Hz,1H),4.92–4.86(m, 1H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1H),3.83(s,2H),3.79–3.71(m,1H),3.65–3.57(m,4H),3.27–3.13 (m,4H),2.92(td,J=5.6,1.0Hz,2H),2.69(td,J=7.8,2.5Hz,2H),2.14(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 512.2[M+H] + .

[0381] Example A133: Synthesis of Compound A133

[0382] Compound 2-47 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A133. 1H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.1Hz,1H),7.08(d,J=7.1Hz,1H),6.95(d,J=2.0Hz,1H), 6.74(s,1H),6.63–6.55(m,2H),4.92–4.86(m,1H),4.89(s,2H),4.11(q,J=6.2Hz,2H),3.92 –3.84(m,1H),3.83(s,2H),3.79–3.71(m,1H),3.65–3.57(m,4H),3.27–3.13(m,4H),2.92(t d,J=5.5,1.0Hz,2H),2.69(td,J=7.8,2.4Hz,2H),2.14(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 479.3[M+H] + .

[0383] Example A134: Synthesis of Compound A134

[0384] Compound 2-48 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A134. 1 H NMR (500MHz, DMSO-d6) δ8.63(d,J=2.0Hz,1H),8.16(dd,J=8.1,2.0Hz,1H),7.46(d,J=8.0Hz,1 H),7.15(d,J=7.0Hz,1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6. 2Hz,2H),3.92–3.84(m,1H),3.83(s,2H),3.79–3.71(m,1H),3.65–3.57(m,4H),3.27–3.13(m, 4H),2.92(td,J=5.6,1.0Hz,2H),2.76–2.68(m,2H),2.14(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 509.2[M+H] + .

[0385] Example A135: Synthesis of Compound A135

[0386] Compound 2-49 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A135. 1H NMR(500MHz,DMSO-d6)δ7.26(d,J=7.4Hz,1H),7.14(d,J=7.0Hz,1H),7.09(q,J=4.8Hz,1H), 6.85(d,J=2.1Hz,1H),6.74(s,1H),6.65–6.59(m,2H),4.92–4.86(m,1H),4.11(q,J=6.2Hz, 2H),3.92–3.84(m,1H),3.83(s,2H),3.79–3.71(m,1H),3.65–3.55(m,4H),3.27–3.13(m,4H ),2.97–2.89(m,5H),2.69(td,J=7.8,2.4Hz,2H),2.14(m,2H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 493.3[M+H] + .

[0387] Example A136: Synthesis of Compound A136

[0388] Compound 2-50 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A136. 1 H NMR (500MHz, DMSO-d6) δ8.38(d,J=2.0Hz,1H),7.91(dd,J=7.2,1.9Hz,1H),7.37(d,J=7.2Hz,1H),7. 13(d,J=7.0Hz,1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2Hz,2H),3. 89(s,3H),3.92–3.84(m,1H),3.83(s,2H),3.79–3.71(m,1H),3.65–3.57(m,4H),3.27–3.13(m,4H), 2.92(td,J=5.6,1.0Hz,2H),2.69(td,J=7.8,2.6Hz,2H),2.14(m,2H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 522.3[M+H] + .

[0389] Example A137: Synthesis of Compound A137

[0390] Compound 2-51 was used to replace 2-5 in Example A1, and the synthesis method was referred to that of compound A1 to obtain compound A137. 1H NMR(500MHz,DMSO-d6)δ8.41(d,J=1.7Hz,1H),7.88(dd,J=7.3,2.0Hz,1H),7.42(d,J=7.4Hz,1H) ,7.14(d,J=7.1Hz,1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2Hz, 2H),3.92–3.84(m,1H),3.83(s,2H),3.79–3.71(m,1H),3.65–3.57(m,4H),3.27–3.13(m,4H),2. 92(td,J=5.6,1.0Hz,2H),2.69(td,J=7.8,2.6Hz,2H),2.14(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 508.2[M+H] + .

[0391] Example A138: Synthesis of Compound A138

[0392] Compound 2-52 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A138. 1 H NMR(500MHz,DMSO-d6)δ9.45(d,J=7.1Hz,1H),7.09(d,J=6.9Hz,1H),7.03(d,J=2.3Hz,1H),6.76– 6.69(m,2H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1H),3 .83(s,2H),3.79–3.71(m,1H),3.72(s,2H),3.64–3.57(m,4H),3.27–3.13(m,4H),2.92(td,J=5.6 ,1.0Hz,2H),2.72–2.60(m,4H),2.14(m,2H),1.41(t,J=6.2Hz,3H),1.26(t,J=7.2Hz,3H).ESI-MS m / z 522.3[M+H] + .

[0393] Example A139: Synthesis of Compound A139

[0394] Compound 2-53 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A139. 1H NMR(500MHz,DMSO-d6)δ9.72(d,J=7.1Hz,1H),7.09(d,J=6.9Hz,1H),7.03(d,J=2.3Hz,1H),6.74(s,1H), 6.63–6.56(m,2H),4.92–4.86(m,1H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1H),3.83(s,2H),3.79–3.71( m,1H),3.72(s,2H),3.64–3.57(m,4H),3.27–3.13(m,4H),2.92(td,J=5.6,1.0Hz,2H),2.80(t,J=6.3Hz, 2H),2.64(d,J=7.8Hz,1H),2.14(m,2H),1.73(m,2H),1.41(t,J=6.2Hz,3H),0.96(t,J=7.5Hz,3H).ESI-MS m / z 536.3[M+H] + .

[0395] Example A140: Synthesis of Compound A140

[0396] Compound 2-54 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A140. 1 H NMR (500MHz, DMSO-d6) δ9.48(d,J=7.5Hz,1H),7.09(d,J=7.4Hz,1H),7.03(d,J=2.3Hz,1H),6.74(d,J=2. 6Hz,2H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1H),3.83(s,2H) ,3.79–3.72(m,1H),3.71(s,2H),3.64–3.56(m,4H),3.56–3.45(m,1H),3.27–3.13(m,4H),2.92(td,J=5. 6,1.0Hz,2H),2.64(t,J=7.8Hz,2H),2.24–2.05(m,2H),1.44(d,J=6.6Hz,3H),1.44–1.37(m,6H).ESI-MS m / z 536.3[M+H] + .

[0397] Example A141: Synthesis of Compound A141

[0398] Compound 2-55 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A141. 1 H NMR(500MHz,DMSO-d6)δ9.98(d,J=7.5Hz,1H),7.09(d,J=7.4Hz,1H),7.03(d,J=2.3Hz,1H),6.79–6.72 (m,2H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1H),3.83(s,2H ),3.79–3.72(m,1H),3.71(s,2H),3.65–3.57(m,4H),3.49–3.41(m,1H),3.27–3.13(m,4H),2.92(td,J =5.6,1.0Hz,2H),2.64(t,J=7.8Hz,2H),2.14(m,2H),1.41(t,J=6.2Hz,3H),1.11–0.97(m,4H).ESI-MS m / z 534.3[M+H] + .

[0399] Example A142: Synthesis of Compound A142

[0400] Compound 2-56 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A142. 1 H NMR (500MHz, DMSO-d6) δ7.54–7.46(m,1H),7.43–7.33(m,2H),7.11(dd,J=4.6,2. 4Hz,1H),6.74(s,0H),6.61(t,J=1.0Hz,0H),4.92–4.86(m,0H),4.11(q,J=6.2Hz ,1H),3.92–3.71(m,3H),3.65–3.57(m,2H),3.27–3.13(m,2H),2.92(td,J=5.6,1 .0Hz,1H),2.63(t,J=7.9Hz,1H),2.24–2.05(m,1H),1.41(t,J=6.2Hz,1H).ESI-MS m / z 570.3[M+H] + .

[0401] Example A143: Synthesis of Compound A143

[0402] Compound 2-57 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A143.1 H NMR (500MHz, DMSO-d6) δ9.98(d,J=7.5Hz,1H),7.09(d,J=7.4Hz,1H),7.03(d,J=2.3Hz,1H),6.74(s,1H),6.70(d,J= 2.4Hz,1H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1H),3.83(s,2H),3.79–3. 72(m,1H),3.71(s,2H),3.65–3.57(m,4H),3.27–3.13(m,4H),2.92(td,J=5.5,1.0Hz,2H),2.92–2.84(m,1H),2.64( t,J=7.8Hz,2H),2.24–2.05(m,2H),1.85(m,2H),1.83–1.73(m,2H),1.76–1.59(m,4H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 562.3[M+H] + .

[0403] Example A144: Synthesis of Compound A144

[0404] Compound 2-58 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A144. 1 H NMR (500MHz, DMSO-d6) δ9.98(d,J=7.5Hz,1H),7.09(d,J=7.4Hz,1H),7.03(d,J=2.3Hz,1H),6.74(s,1H),6.70(d, J=2.4Hz,1H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1H),3.83(s,2H),3.7 9–3.72(m,1H),3.71(s,2H),3.65–3.55(m,4H),3.38–3.31(m,1H),3.27–3.13(m,4H),2.92(td,J=5.5,1.0Hz,2H), 2.64(d,J=15.7Hz,1H),2.14(m,2H),1.82–1.69(m,4H),1.69–1.56(m,2H),1.56–1.39(m,6H),1.40(s,1H).ESI-MS m / z 576.3[M+H] + .

[0405] Example A145: Synthesis of Compound A145

[0406] Compound 2-59 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A145. 1 H NMR (500MHz, DMSO-d6) δ7.15(d,J=2.2Hz,1H),7.08(d,J=7.5Hz,1H),6.74(s,1H),6.61(t,J=1. 0Hz,1H),6.29(d,J=2.2Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1H),3. 84–3.71(m,10H),3.64–3.55(m,4H),3.31(td,J=5.8,3.3Hz,4H),3.27–3.13(m,4H),2.92(td,J =5.5,1.0Hz,2H),2.67(td,J=7.9,1.0Hz,2H),2.24–2.05(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 579.3[M+H] + .

[0407] Example A146: Synthesis of Compound A146

[0408] Compound 2-60 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A146. 1 H NMR(500MHz,DMSO-d6)δ9.15(s,1H),7.01(d,J=7.3Hz,1H),6.95(d,J=2.3Hz,1H),6.74(s,1H), 6.61(t,J=1.0Hz,1H),6.31(d,J=2.2Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2Hz,2H),3.92–3. 85(m,1H),3.83(d,J=5.0Hz,6H),3.79–3.71(m,1H),3.64–3.57(m,4H),3.27–3.13(m,4H),2.92 (td,J=5.6,1.0Hz,2H),2.67(t,J=7.8Hz,2H),2.24–2.05(m,2H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 510.3[M+H] + .

[0409] Example A147: Synthesis of Compound A147

[0410] Compound 2-61 was used to replace 2-5 in Example A1, and the synthesis method was referred to that of compound A1 to obtain compound A147. 1 H NMR(500MHz,DMSO-d6)δ8.65(s,1H),7.21(d,J=7.6Hz,1H),7.11(d,J=7.0Hz,1H),7.07–7. 03(m,1H),6.76–6.71(m,2H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2Hz,2H ),3.92–3.84(m,1H),3.83(s,2H),3.79–3.71(m,1H),3.65–3.55(m,4H),3.27–3.13(m,4H) ,2.95–2.89(m,2H),2.69(td,J=7.8,2.5Hz,2H),2.14(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 480.2[M+H] + .

[0411] Example A148: Synthesis of Compound A148

[0412] Compound 2-62 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A148. 1 H NMR(500MHz,DMSO-d6)δ7.08(dd,J=4.4,0.8Hz,2H),7.05(d,J=6.9Hz,1H),6.80–6.7 2(m,2H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2Hz,2H),3.92–3.81( m,5H),3.79–3.71(m,1H),3.64–3.55(m,4H),3.26–3.13(m,4H),2.92(td,J=5.6,1.0H z,2H),2.64(t,J=7.8Hz,2H),2.18(m,1H),2.05(m,1H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 494.3[M+H] + .

[0413] Example A149: Synthesis of Compound A149

[0414] Compound 2-63 was used to replace 2-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A149. 1 H NMR(500MHz,DMSO-d6)δ7.50(dd,J=8.6,0.9Hz,1H),7.11(d,J=7.0Hz,1H),6.90(d,J=2.2Hz,1H), 6.81(dd,J=8.5,2.4Hz,1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2H z,2H),3.92–3.85(m,1H),3.83(d,J=6.1Hz,6H),3.79–3.71(m,1H),3.65–3.55(m,4H),3.26–3.13 (m,4H),2.92(td,J=5.5,1.0Hz,2H),2.76–2.64(m,2H),2.14(m,2H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 494.3[M+H] + .

[0415] Example A150: Synthesis of Compound A150

[0416] Compound 2-64 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A150. 1 H NMR(500MHz,DMSO-d6)δ9.73(d,J=7.1Hz,1H),7.51–7.45(m,1H),7.21(t,J=7.7Hz,1H),7.04(d,J=7.1Hz ,1H),6.82(dd,J=7.8,1.1Hz,1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2H z,2H),3.94(s,2H),3.92–3.84(m,1H),3.83(s,2H),3.79–3.71(m,1H),3.65–3.55(m,4H),3.26–3.13(m, 4H),2.92(td,J=5.6,1.0Hz,2H),2.68(td,J=7.8,2.2Hz,2H),2.14(m,2H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 494.3[M+H] + .

[0417] Example A151: Synthesis of Compound A151

[0418] Compound 2-65 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A151. 1 H NMR(500MHz,DMSO-d6)δ7.47–7.43(m,1H),7.30(d,J=7.2Hz,1H),7.25(dd,J=7.3,1.8Hz,1H) ,7.11(d,J=7.0Hz,1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2H z,2H),3.92–3.84(m,1H),3.83(s,2H),3.79–3.71(m,1H),3.65–3.55(m,4H),3.27–3.13(m,4 H),2.97–2.89(m,2H),2.69(td,J=7.8,2.4Hz,2H),2.14(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 498.2[M+H] + .

[0419] Example A152: Synthesis of Compound A152

[0420] Compound 2-66 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A152. 1 H NMR(500MHz,DMSO-d6)δ7.30(m,2H),7.28–7.22(m,1H),7.13(d,J=6.9Hz,1H),6.74(s,1 H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1H),3 .83(s,2H),3.79–3.71(m,1H),3.65–3.57(m,4H),3.27–3.13(m,4H),2.92(td,J=5.6,1. 0Hz,2H),2.76(t,J=7.7Hz,2H),2.18(m,1H),2.08(m,1H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 498.2[M+H] + .

[0421] Example A153: Synthesis of Compound A153

[0422] Compound 2-67 was used to replace 2-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A153. 1 H NMR (500MHz, DMSO-d6) δ7.63(d,J=8.2Hz,1H),7.29(d,J=1.9Hz,1H),7.26(dd,J=8.4,2.3Hz ,1H),7.11(d,J=7.0Hz,1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q, J=6.2Hz,2H),3.92–3.84(m,1H),3.83(s,2H),3.79–3.71(m,1H),3.65–3.55(m,4H),3.27–3 .13(m,4H),2.97–2.88(m,2H),2.76–2.64(m,2H),2.14(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 498.2[M+H] + .

[0423] Example A154: Synthesis of Compound A154

[0424] Compound 2-68 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A154. 1 H NMR(500MHz,DMSO-d6)δ9.95(d,J=6.9Hz,1H),7.62(dd,J=7.7,1.2Hz,1H),7.33(dd,J=7.7,1.2Hz,1H), 7.22(t,J=7.7Hz,1H),7.11(d,J=7.1Hz,1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.1 1(q,J=6.2Hz,2H),3.92–3.84(m,1H),3.83(s,2H),3.79–3.71(m,1H),3.65–3.57(m,4H),3.27–3.13(m, 4H),2.92(td,J=5.5,1.0Hz,2H),2.69(td,J=7.8,2.4Hz,2H),2.14(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 498.2[M+H] + .

[0425] Example A155: Synthesis of Compound A155

[0426] Compound 2-69 was used to replace 2-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A155. 1 H NMR(500MHz,DMSO-d6)δ7.37(m,2H),7.12(d,J=7.0Hz,1H),7.07(m,1H),6.74(s,1H) ,6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1H), 3.83(s,2H),3.79–3.71(m,1H),3.65–3.57(m,4H),3.27–3.13(m,4H),2.92(td,J=5. 6,1.0Hz,2H),2.69(td,J=7.8,2.4Hz,2H),2.14(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 482.2[M+H] + .

[0427] Example A156: Synthesis of Compound A156

[0428] Compound 2-70 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A156. 1 H NMR (500MHz, DMSO-d6) δ7.17(d,J=7.4Hz,1H),7.02(dd,J=7.2,1.9Hz,1H),6.78(d,J=2.2Hz,1H),6.74(s,1H ),6.61(t,J=1.0Hz,1H),4.89(s,0H),4.89(d,J=13.3Hz,0H),4.11(q,J=6.2Hz,2H),3.92–3.84(m,1H),3.83( d,J=4.0Hz,6H),3.79–3.71(m,1H),3.65–3.57(m,4H),3.27–3.13(m,4H),2.92(td,J=5.5,1.0Hz,2H),2.65( dt,J=15.3,7.6Hz,1H),2.57(dt,J=15.4,7.7Hz,1H),2.24(m,1H),2.06(m,1H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 508.3[M+H] + .

[0429] Example A157: Synthesis of Compound A157

[0430] Compound 2-71 was used to replace 2-5 in Example A1, and the synthesis method was referred to that of compound A1 to obtain compound A157. 1 H NMR (500MHz, DMSO-d6) δ7.30(d,J=7.4Hz,1H),7.11(d,J=7.0Hz,1H),7.05(d,J=2.0Hz,1H),6.85(dd,J= 7.3,1.8Hz,1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q,J=6.2Hz,2H),4.03(q,J= 6.6Hz,2H),3.92–3.84(m,1H),3.83(s,2H),3.79–3.71(m,1H),3.65–3.57(m,4H),3.27–3.13(m,4H),2. 92(td,J=5.5,1.0Hz,2H),2.69(td,J=7.8,2.5Hz,2H),2.14(m,2H),1.40(dt,J=10.3,6.4Hz,6H).ESI-MS m / z 508.3[M+H] + .

[0431] Example A158: Synthesis of Compound A158

[0432] Compound 2-72 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A158. 1 H NMR (500MHz, DMSO-d6) δ7.29(d,J=6.6Hz,1H),7.09(d,J=7.0Hz,1H),6.98(d,J=1.7Hz,1H) ,6.84(dd,J=6.7,2.0Hz,1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),4.92–4.86(m,1H),4.11(q ,J=6.2Hz,2H),3.92–3.84(m,1H),3.83(s,2H),3.79–3.71(m,5H),3.64–3.57(m,4H),3.33 (m,4H),3.27–3.13(m,4H),2.92(td,J=5.5,1.0Hz,2H),2.69(td,J=7.8,2.4Hz,2H),2.14(m 2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 549.3[M+H] + .

[0433] Example A159: Synthesis of Compound A159

[0434] Compound 2-73 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A159. 1 H NMR (500MHz, DMSO-d6) δ8.82(d,J=6.9Hz,1H),7.25(dd,J=17.7,7.2Hz,2H),7.18(d,J=2.1Hz,1H),6.82(dd,J=7.3,2 .0Hz,1H),6.74(d,J=0.6Hz,1H),6.61(t,J=1.0Hz,1H),4.94(s,0H),4.11(q,J=6.2Hz,2H),3.92–3.85(m,1H),3.83(d ,J=4.0Hz,6H),3.79–3.71(m,1H),3.64–3.55(m,4H),3.27–3.13(m,4H),2.92(td,J=5.6,1.0Hz,2H),2.87(p,J=7.1Hz ,1H),2.16(dt,J=13.1,7.5Hz,1H),1.96(dt,J=12.9,7.3Hz,1H),1.41(t,J=6.2Hz,3H),1.33(d,J=7.1Hz,3H).ESI-MS m / z 508.3[M+H] + .

[0435] Example A160: Synthesis of Compound A160

[0436] Compound 2-74 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A160. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.3Hz,1H),7.15–7.10(m,2H),6.82(dd,J=7.3,2.0H z,1H),6.69(d,J=0.7Hz,1H),6.59(t,J=1.0Hz,1H),4.91–4.85(m,1H),4.11(q,J=6.2H z,2H),3.89–3.81(m,7H),3.72(m,1H),3.65–3.57(m,4H),3.27–3.13(m,4H),2.99–2.8 4(m,2H),2.73–2.54(m,3H),1.41(t,J=6.3Hz,3H),1.01(dd,J=7.4,1.5Hz,3H).ESI-MS m / z 508.3[M+H] + .

[0437] Example A161: Synthesis of Compound A161

[0438] Compound 2-75 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A161. 1 H NMR(500MHz,DMSO-d6)δ9.18(d,J=6.7Hz,1H),7.27(dd,J=13.6,6.9Hz,2H), 7.09(d,J=1.7Hz,1H),6.83(dd,J=7.3,2.0Hz,1H),6.75(s,1H),6.61(t,J=1.0Hz,1H),4. 96(t,J=6.8Hz,1H),4.11(q,J=6.2Hz,2H),3.94–3.86(m,1H),3.83(d,J=4.0Hz,6H),3.80 –3.72(m,1H),3.64–3.57(m,4H),3.27–3.13(m,4H),2.92(td,J=5.5,1.0Hz,2H),2.28(dd ,J=12.9,6.7Hz,1H),2.17(dd,J=12.9,6.7Hz,1H),1.46–1.38(m,5H),1.39(s,3H).ESI-MS m / z 522.3[M+H] + .

[0439] Example A162: Synthesis of Compound A162

[0440] Compound 2-76 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A162. 1H NMR (500MHz, DMSO-d6) δ9.16(d,J=7.3Hz,1H),7.29(dd,J=7.4,1.8Hz,2H),7.03(d,J=1.6Hz,1H),6.83(dd,J=7.3,2.0Hz ,1H),6.75(s,1H),6.61(t,J=1.0Hz,1H),4.97(t,J=6.1Hz,1H),4.11(q,J=6.2Hz,2H),3.94–3.86(m,1H),3.83(d,J=4.0 Hz,6H),3.80–3.72(m,1H),3.64–3.57(m,4H),3.27–3.13(m,4H),2.92(td,J=5.6,1.0Hz,2H),2.30(dd,J=12.7,6.1Hz,1 H),2.07(dd,J=12.9,6.1Hz,1H),1.69–1.58(m,2H),1.41(t,J=6.2Hz,3H),1.24–1.17(m,1H),1.19–1.12(m,1H).ESI-MS m / z 520.3[M+H] + .

[0441] Example A163: Synthesis of Compound A163

[0442] Compound 2-77 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A163. 1 H NMR(500MHz,DMSO-d6)δ9.28(d,J=6.9Hz,1H),7.46(d,J=6.9Hz,1H),7.29–7.24(m,2H),6.83(dd ,J=7.3,2.0Hz,1H),6.74(s,1H),6.61(t,J=1.0Hz,1H),5.95(t,J=6.7Hz,0H),5.86(t,J=6.6Hz, 0H),5.04(s,0H),4.11(q,J=6.2Hz,2H),3.90–3.81(m,7H),3.78–3.70(m,1H),3.65–3.57(m,4H) ,3.27–3.13(m,4H),2.92(td,J=5.5,1.0Hz,2H),2.58–2.38(m,2H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 512.2[M+H] + .

[0443] Example A164: Synthesis of Compound A164

[0444] Compound 2-78 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A164. 1 H NMR(500MHz,DMSO-d6)δ9.44(d,J=6.3Hz,1H),7.58(d,J=6.5Hz,1H),7.31–7.26(m,2H) ,6.83(dd,J=7.3,2.0Hz,1H),6.75(s,1H),6.61(t,J=1.0Hz,1H),5.01(dd,J=7.4,6.6Hz ,1H),4.11(q,J=6.2Hz,2H),3.91–3.83(m,1H),3.83(d,J=4.0Hz,6H),3.78–3.70(m,1H) ,3.65–3.55(m,4H),3.27–3.04(m,5H),2.95–2.77(m,3H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 530.2[M+H] + .

[0445] Example A165: Synthesis of Compound A165

[0446] Compound 2-79 was used to replace 2-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A165. 1 H NMR (500MHz, DMSO-d6) δ9.01(d,J=6.7Hz,1H),7.37(d,J=6.7Hz,1H),7.27(d,J=7.3Hz,1H),7.14(d,J=2.1H z,1H),6.83(dd,J=7.3,2.0Hz,1H),6.74(d,J=0.7Hz,1H),6.61(t,J=1.0Hz,1H),5.00(s,0H),4.52–4.41(m, 1H),4.11(q,J=6.2Hz,2H),3.92–3.85(m,1H),3.83(d,J=4.0Hz,6H),3.79–3.71(m,1H),3.65–3.57(m,4H),3 .27–3.13(m,4H),2.92(td,J=5.6,1.0Hz,2H),2.35(m,1H),2.22–2.12(m,1H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 562.2[M+H] + .

[0447] Example A166: Synthesis of Compound A166

[0448] Compound 1-47 was used to replace 1-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A166. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3,2.0Hz,1H) ,6.75(s,1H),6.71(s,1H),4.94(t,J=6.4Hz,1H),4.11(q,J=6.2Hz,2H),3.83(d,J=4.0Hz,6H) ,3.76(d,J=5.1Hz,2H),3.64–3.55(m,4H),3.45–3.35(m,1H),3.27–3.13(m,4H),2.69(td,J=7 .8,2.4Hz,2H),2.20(m,1H),2.10(m,1H),1.41(t,J=6.2Hz,3H),1.31(d,J=6.7Hz,3H).ESI-MS m / z 508.3[M+H] + .

[0449] Example A167: Synthesis of Compound A167

[0450] Compound 1-48 was used to replace 1-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A167. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3,2.0Hz,1H),6.74 (d,J=0.8Hz,1H),6.69(t,J=1.0Hz,1H),5.04(t,J=6.5Hz,1H),4.28(h,J=7.0Hz,1H),4.11(q,J=6.2 Hz,2H),3.83(d,J=4.0Hz,6H),3.64–3.57(m,4H),3.27–3.20(m,1H),3.23–3.15(m,3H),3.12(m,1H ),2.79–2.65(m,3H),2.22(m,1H),2.06(m,1H),1.41(t,J=6.2Hz,3H),1.20(d,J=6.9Hz,3H).ESI-MS m / z 508.3[M+H] + .

[0451] Example A168: Synthesis of Compound A168

[0452] Compound 1-49 was used to replace 1-5 in Example A1. The synthesis method was similar to that of compound A1 to obtain compound A168. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.85–6.80(m,2H),6.72 (d,J=0.7Hz,1H),5.19(dt,J=5.2,4.6Hz,1H),4.94(dd,J=7.5,5.7Hz,2H),4.10(q,J=6.1 Hz,2H),3.85–3.78(m,7H),3.77(dd,J=12.3,4.8Hz,1H),3.64–3.57(m,4H),3.27–3.13(m ,4H),2.69(td,J=7.8,2.5Hz,2H),2.19(m,1H),2.08(m,1H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 510.3[M+H] + .

[0453] Example A169: Synthesis of Compound A169

[0454] Compound 1-50 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A169. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3 ,2.0Hz,1H),6.74(s,1H),6.66(t,J=1.0Hz,1H),6.02(d,J=5.4Hz,1H),5.86(td, J=6.6,5.4Hz,1H),5.04(t,J=6.6Hz,1H),4.11(q,J=6.2Hz,2H),3.83(d,J=4.0Hz ,6H),3.60(m,4H),3.27–3.20(m,2H),3.22–3.15(m,2H),3.07–2.99(m,2H),2.85– 2.72(m,2H),2.23(m,1H),2.13(m,1H),1.41(t,J=6.2Hz,3H).ESI-MS m / z 510.3[M+H] + .

[0455] Example A170: Synthesis of Compound A170

[0456] Compound 1-51 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A170. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.94(t,J=1.1Hz,1H) ,6.82(dd,J=7.3,2.0Hz,1H),6.62(s,1H),4.94(t,J=5.9Hz,1H),4.69–4.59(m,2H),4.1 1(q,J=6.2Hz,2H),3.83(d,J=2.8Hz,6H),3.64–3.57(m,4H),3.27–3.13(m,4H),2.69(td ,J=7.8,2.5Hz,2H),2.24–2.14(m,1H),2.14–2.04(m,1H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 480.2[M+H] + .

[0457] Example A171: Synthesis of Compound A171

[0458] Compound 1-52 was used to replace 1-5 in Example A1, and the synthesis method was similar to that of compound A1 to obtain compound A171. 1 H NMR(500MHz,DMSO-d6)δ7.25(d,J=7.4Hz,1H),7.13–7.08(m,2H),6.82(dd,J=7.3,2.0Hz,1H),6.74( s,1H),6.61(t,J=1.1Hz,1H),4.86–4.80(m,1H),4.11(q,J=6.2Hz,2H),3.83(d,J=4.0Hz,6H),3.65– 3.58(m,2H),3.62–3.55(m,3H),3.27–3.13(m,6H),2.82(m,2H),2.69(td,J=7.8,2.5Hz,2H),2.19(d q,J=12.9,7.6Hz,1H),2.08(dq,J=12.9,7.6Hz,1H),1.95–1.78(m,2H),1.41(t,J=6.3Hz,3H).ESI-MS m / z 508.3[M+H] + .

[0459] Biological activity test

[0460] 1. Detection method: determination of intracellular cAMP concentration

[0461] 1.1 Test materials and instruments

[0462] cAMP detection kit (PerkinElmer), cell culture incubator (Thermo Fisher Scientific), EnVision multi-function microplate reader (PerkinElmer), Forskolin (Sigma-Aldrich), IBMX (Sigma-Aldrich), DSMO (Sigma-Aldrich), hINSL5 (Genova, human insulin-like peptide 5), hRXFP4-CHO stable cell line stably expressing human RXFP4, and the test compound.

[0463] 1.2 Test methods

[0464] Stably transfected hRXFP4-CHO cells were cultured at 2.5×10 5 The cells were inoculated at a density of 70%-80% on the next day. On the day of the experiment, cells were digested using either trypsin-free digestion buffer or 0.02% EDTA-containing PBS. After centrifugation, the supernatant was discarded and cAMP assay buffer (0.5mM IBMX + 5mM HEPES + 0.1% BSA) was prepared using 1× HBSS (calcium- and magnesium-free). The cells were resuspended and plated at 4000 cells / well in a 384-well plate. Compounds were diluted to various concentrations in DMSO and added to the plate. 500nM Forskolin was also added and incubated at room temperature for 40 minutes. Eu-cAMP and ULight-anti-cAMP working solutions were then added according to the cAMP assay kit instructions. After incubation at room temperature for 40 minutes, the samples were read using an EnVision multi-function microplate reader (excitation wavelength: 320 or 340nm, emission wavelength: 665nm).

[0465] 1.3 Test results

[0466] The results of the in vitro RXFP4 agonist activity test of the compounds are shown in Table 1.

[0467] Table 1. In vitro RXFP4 agonist activity test results of compounds

[0468] a ND=Not determined

[0469] 2. Detection method: ligand receptor affinity detection

[0470] 2.1 Test materials and instruments

[0471] hRXFP4-CHO stable cells and Eu-R3 / I5 (lanthanide europium-labeled chimeric peptide R3 / I5), BMG POLARstar plate reader (BMG Labtech) and test compounds.

[0472] 2.2 Test methods

[0473] hRXFP4-CHO cells were seeded into 96-well plates at 80,000 cells / well and cultured in a cell culture incubator for 24 hours. The supernatant was discarded and the cells were washed once with PBS. Binding buffer containing 1% BSA was added and incubated at room temperature for 1 hour. The cell plate was washed again with PBS, and then different concentrations of positive controls and test compounds and 5 nM Eu-R3 / I5 were added and incubated at room temperature for 1 hour. After washing the cell plate with PBS, enhancement solution was added, and fluorescence values ​​were measured 45 minutes later on a BMG POLARstar plate reader (excitation wavelength: 340 nm, detection emission wavelength: 614 nm).

[0474] 2.3 Test results

[0475] The results of the in vitro ligand receptor affinity test of the compounds are shown in Table 2

[0476] Table 2 In vitro ligand receptor affinity test results of the compounds

[0477] a ND=Not determined

[0478] In vivo pharmacodynamic evaluation of compounds

[0479] Effects of compounds on promoting intestinal motility in constipation model mice

[0480] 1. Experimental reagents, instruments and animals

[0481] 1.1 Experimental Materials

[0482] Mosapride citrate tablets (Chengdu Kanghong Pharmaceutical); HE staining kit (KeyGEN Biotech); loperamide hydrochloride capsules (Xi'an Janssen Pharmaceutical Co.LTD); nitric oxide test kit / microplate method (mlbio); anti-TRPV1 antibody, anti-CGRP antibody (Thermo Fisher Scientific); anti-AQP3 antibody, Goat Anti-Rabbit IgG H&L (Alexa 488), Goat Anti-mouse IgG H&L (Alexa 488) (Abcam), Mouse VIP ELISA Kit (LSBio); Mouse 5-HT ELISA Kit (mlbio).

[0483] 1.2 Experimental instruments

[0484] The following equipment was used: FORMA 700 ultra-low temperature freezer (Thermo Fisher Scientific); YC-300L medicine storage cabinet (Zhongke Meiling Cryogenic Technology Co., Ltd.); Direct-Q ultrapure water meter with pump (Millipore); SW-CJ-2FD ultra-clean workbench (Suzhou Purification Equipment Co., Ltd.); 3K1 low-temperature high-speed centrifuge (Sigma-Aldrich); BS224 electronic balance (Beijing Sartorius Instrument System Co., Ltd.); ZS-MV-IV small animal anesthesia machine (Beijing Zhongshi Di Chuang Technology Development Co., Ltd.); Y-3102 mouse metabolic cage (Shanghai Yuyan Scientific Instrument Co., Ltd.); paraffin embedding machine and microtome (Leica); Olympus inverted phase contrast microscope (Olympus); Zeiss LSM laser confocal microscope (Zeiss, Germany); Berthold LB941 microplate multifunctional microplate reader (Berthold).

[0485] 1.3 Experimental animals

[0486] SPF-grade ICR mice, male, 6-8 weeks old, weighing 20 ± 2 g, were provided by Changzhou Cavens Laboratory Animal Co., Ltd., with animal qualification certificate number: SCXK (Su) 2022-0010. They were housed in an SPF-grade environment with the indoor temperature controlled at 22 ± 2°C and free access to food and water.

[0487] 2. Animal Model and Dosage Regimen

[0488] 2.1 Mouse model construction

[0489] ICR mice were housed in an SPF animal room with environmental conditions controlled at 20°C–26°C, relative humidity 40%–70%, and a 12-h light-dark cycle. They were allowed to eat freely. After one week of adaptive feeding, mice in the model group were orally gavaged with 3 mg / kg loperamide (0.1 mL / 10 g) once daily for 5 consecutive days. Mice in the normal control group were orally gavaged with an equal volume of normal saline daily.

[0490] 2.2 Experimental Grouping

[0491] Control group: mice were gavaged with an equal volume of normal saline once a day for 7 consecutive days (n=8);

[0492] Model group: After the constipation model was established, mice were gavaged with an equal volume of normal saline once a day for 7 consecutive days (n=8);

[0493] Positive control group: After the constipation model was established, mice were gavaged with 10 mg / kg Mosapride Citrate (0.1 mL / 10 g) once daily for 7 consecutive days (n=8);

[0494] Experimental group: After the constipation model was established in mice, the mice in the experimental group were divided into three groups and gavage-administered compound (S)-A1 at 1 mg / kg, 5 mg / kg, and 25 mg / kg, respectively, with a gavage volume of 0.1 ml / 10 g, once daily for 7 consecutive days (n = 8 per group);

[0495] 3. Detection indicators and detection methods

[0496] After the modeling and the last administration, the mice in each group were placed in metabolic cages and allowed to move freely for 2 hours. The feces of the mice were collected, and the weight, number, hardness, and water content were calculated. The effects of the compounds on the colon function of the mice were evaluated by a bead excretion experiment. After the bead excretion experiment, the mice were euthanized by CO2 method, and the colon tissue (colon tissue about 2 cm long near the anus) was obtained. HE staining was used to observe the morphological changes of the mouse colon, and the thickness of the colon muscle layer, mucosal thickness, goblet cells and Liberkunst glands were counted. Blood was collected, and the levels of nitric oxide (NO), serotonin (5-HT), and vasoactive intestinal peptide (VIP) in the serum of the mice were detected by kits. Immunohistochemistry experiments were used to detect the changes in the expression levels of aquaporin 3 (AQP3), transient receptor potential channel V1 (TRPV1), and calcitonin gene-related peptide (CGRP) in the colon tissue of the mice.

[0497] 3.1 Fecal moisture content detection

[0498] Each group of mice was placed in a metabolic cage and allowed to move freely for 2 hours. Feces were collected and placed in dry EP tubes and weighed. The wet weight of the feces was then recorded. The feces were then placed in a drying oven at 50°C for 4 hours, removed and weighed, and then placed back in the drying oven and weighed every 2 hours. The dry weight of the feces was calculated when the feces weight remained stable. The formula for calculating fecal moisture content was: fecal moisture content (%) = [(fecal wet weight - fecal dry weight) / fecal wet weight] × 100%.

[0499] 3.2 Bead expulsion experiment

[0500] After anesthetizing the mice using a small animal anesthesia machine, glass beads with a diameter of 1.5 mm were inserted into the terminal colon about 3 cm away from the anus. After the glass beads were inserted into the terminal colon of the mice, the mice were placed in separate cages, and the time between the mice waking up and the excretion of the glass beads was recorded as the bead excretion time.

[0501] 3.3 HE staining

[0502] 1) Baking: Place the prepared tissue paraffin sections in an electric constant temperature drying oven and bake at 60°C for 3 hours;

[0503] 2) Dewax the dried paraffin sections with conventional xylene, hydrate with descending gradient ethanol, and wash with distilled water;

[0504] 3) Stain the nucleus with hematoxylin for 2 minutes, differentiate with hydrochloric acid and alcohol for a few seconds, and wash with water to return to blue;

[0505] 4) Stain the slides with eosin solution for 1 minute and then rinse with water to remove any residual stain.

[0506] 5) The sections were dehydrated and dried using gradient alcohol, transparentized with xylene, and mounted with neutral gum;

[0507] 6) Use a phase contrast microscope to randomly select a field of view and take a picture at 400× magnification.

[0508] 3.4 Immunohistofluorescence

[0509] 1) Wash the paraffin sections of mouse colon tissue with PBS for 5 min × 3 times;

[0510] 2) Wipe away the liquid around the sliced ​​tissue and use an immunohistochemistry pen to draw a circle 2 mm away from the tissue to prevent dilution of the various liquid components added later;

[0511] 3) Incubate in 0.4% Triton X-100 at room temperature for 10 min; wash with PBS for 5 min × 3 times;

[0512] 4) Antigen retrieval (1.5 minutes after the pressure relief valve of the autoclave begins to release steam, then reduce the pressure with cold water). After cooling naturally, wash with PBS for 5 minutes x 3 times;

[0513] 5) Block with 5% goat serum at 37°C for 10 min;

[0514] 6) Discard the serum and add the primary antibody (see Table 1 for specific primary antibodies and their dilution ratios). Place in a humidified chamber and react overnight at 4°C.

[0515] 7) Aspirate the antibody reaction solution and wash with PBS for 5 min x 3 times;

[0516] 8) Add fluorescently labeled secondary antibody (dilution ratio see Table 1) and incubate in a 37°C humidified chamber in the dark for 1-2 hours;

[0517] 9) Aspirate the antibody reaction solution and wash with PBS for 5 minutes x 3 times;

[0518] 10) Seal the slides with 90% glycerol and place them in a light-proof box;

[0519] 11) Observe and take photos under a laser confocal microscope at 630× magnification.

[0520] Table 3: Antibodies and their dilution ratios

[0521] 3.4 NO content detection

[0522] Serum: Take 100 μL of serum stock solution and add 200 μL of reagent 1, mix well, add 100 μL of reagent 2, vortex thoroughly to mix, let it stand for 10 minutes, centrifuge at 3500-4000 rpm / min for 15 minutes, and take 160 μL of supernatant.

[0523] Action Sheet

[0524] Preparation of standard curve

[0525] Dilute the 2 mmol / L sodium nitrite standard solution with double-distilled water at 1:39, 1:79, 1:99, 1:159, 1:319, and 1:39. The concentrations of the sodium nitrite standard solutions are: 0.05 mM, 0.025 mM, 0.02 mM, 0.0125 mM, 0.00625 mM, and 0.003125 mM, respectively.

[0526] Action Sheet

[0527] 3.5 ELISA detection of serum VIP content

[0528] 1) All reagents and samples are equilibrated at room temperature, mixed thoroughly (avoid foaming), and all reagents, diluted standards, controls, and samples are prepared;

[0529] 2) Add 50 μL of standard, blank, or sample to each well. The concentrations of the standard are as follows: 6.173, 18.52, 55.57, 166.7, and 500 pg / mL;

[0530] 3) Immediately add 50 μL of Detection Reagent A working solution to each well, cover the plate, gently stir to ensure thorough mixing, and incubate at 37°C for 1 hour;

[0531] 4) Aspirate the liquid from each well and wash three times. Use a spray bottle, multichannel pipette, or automated washer to add approximately 350 μL of wash buffer. Let the plate sit for 1-2 minutes after each wash. After the final wash, aspirate any remaining wash buffer, invert the plate, and pat dry with absorbent paper.

[0532] 5) Add 100 μL of Detection Reagent B working solution to each well, stir gently to ensure thorough mixing, cover with new plate sealant, and incubate at 37°C for 30 min;

[0533] 6) Aspirate the liquid from each well and wash 5 times as described in step 4;

[0534] 7) Add 90 μL of TMB substrate solution to each well, gently stir to ensure thorough mixing, cover with new plate sealant, and incubate at 37°C for 10-20 minutes. Protect from light and monitor regularly until optimal color development is achieved.

[0535] 8) Add 50 μL of stop solution to each well in the same order and at the same time as for the TMB substrate solution. Mix thoroughly until the solution turns from blue to yellow.

[0536] 9) Measure the optical density (OD value) of each well in sequence at a wavelength of 450 nm using a microplate reader.

[0537] 3.7 ELISA detection of serum 5-HT content

[0538] 1) Before use, mix all reagents thoroughly and equilibrate at room temperature;

[0539] 2) Standard sample addition: Set up standard wells and sample wells, and add 50 μL of standard sample of different concentrations to each well. The concentrations of the standard samples are as follows: 240, 120, 60, 30, and 15 ng / mL;

[0540] 3) Sample Addition: Set up blank wells (blank control wells do not contain sample or enzyme-labeled reagent, and all other steps are the same) and test sample wells. First, add 40 μL of sample diluent to the test sample wells on the enzyme-labeled plate, then add 10 μL of the test sample (the final sample dilution is 5 times). Add the sample to the bottom of the plate well, avoiding touching the well walls as much as possible, and gently shake to mix.

[0541] 4) Incubation: Seal the plate with sealing film and incubate at 37°C for 30 min;

[0542] 5) Liquid preparation: dilute the 30-fold concentrated washing solution with distilled water for later use;

[0543] 6) Washing: Carefully remove the sealing film, discard the liquid, spin dry, fill each well with washing solution, let it stand for 30 seconds, then discard, repeat 5 times, and pat dry;

[0544] 7) Add enzyme: Add 50 μL of enzyme-labeled reagent to each well, except for the blank well;

[0545] 8) Incubation: Same as step 4;

[0546] 9) Washing: Same operation as 6;

[0547] 10) Color development: Add 50 μL of color developer A to each well, then add 50 μL of color developer B, gently shake to mix, and incubate at 37°C in the dark for 15 min.

[0548] 11) Stop: Add 50 μL of stop solution to each well, and the solution will turn from blue to yellow;

[0549] 12) Measurement: Use the blank well as the zero setting, and measure the absorbance (OD value) of each well in sequence at a wavelength of 450 nm.

[0550] 4. Experimental results

[0551] Compared with the Control group, the fecal volume, fecal water content, and number of fecal particles in the Model group were reduced, the hardness was increased, and the bead excretion time was increased. The intestinal villi in the colon tissue of the mice were disordered, with a large amount of inflammatory infiltration, thinning of the colonic muscle layer and mucosa, and a decrease in the number of goblet cells and Liebbekunst glands. The expression levels of AQP3 protein, TRPV1 protein, and CGRP in the colon tissue were significantly increased, the serum 5-HT level was significantly decreased, and the VIP level and NO level were significantly increased. Compared with the Model group, after oral administration of the compound, the fecal volume, fecal water content, and number of fecal particles were increased, the hardness was reduced, the bead excretion time was shortened, and intestinal peristalsis was enhanced (Figure 1). The thinning of the colonic muscle layer and mucosa was significantly improved, and the number of goblet cells and Liebbekunst glands increased to varying degrees (Figure 2). The expression levels of AQP3 protein, TRPV1 protein, and CGRP in the colon tissue were significantly decreased (Figure 3). The serum 5-HT level was increased, and the VIP and NO levels were decreased (Figure 4).

[0552] All documents mentioned in this application are incorporated herein by reference, just as if each document were incorporated herein by reference individually. It should also be understood that after reading the above teachings of the present invention, those skilled in the art may make various changes or modifications to the present invention, and that such equivalents also fall within the scope of the claims appended hereto.

Claims

1. A nitrogen-containing heterocyclic compound represented by general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof: in, The chiral carbon atom C* is independently S-type, R-type, racemic, or a combination thereof; n = 0, 1, or 2; X1 and X2 are each independently selected from the group consisting of O or NH; X3 is a chemical bond, CHR6 or (CHR6)2; R1 and R2 are each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, hydroxyl, carboxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C2-C6 alkenyl, substituted or unsubstituted C2-C6 alkynyl, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C1-C6 alkylphenyl, substituted or unsubstituted C1-C6 alkyl 5-7 membered heteroaryl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, amino, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 amide, -SOR5, -OSOR5, -OCOR5, C(=NH)NH2, Fmoc, allyloxycarbonyl (Alloc); When n=0, R1 and R2 are not methyl at the same time; when n=1, R1 and R2 are not hydrogen at the same time; or said R1 and R2 and adjacent (CH2) n O and C=C together constitute a substituted or unsubstituted 5-7 membered heterocycle, wherein the heterocycle is a fully saturated heterocycle, a partially unsaturated heterocycle or an aromatic heterocycle; X is selected from the group consisting of O, S, CHR6, C2H4 (i.e., forming a cyclopropyl group at the X substitution position) or NR6; wherein R6 is selected from the group consisting of H, CN, C1-C6 alkyl, C1-C6 alkoxy; Y is a linking group selected from the group consisting of: a chemical bond, a C1-C6 straight or branched alkyl group, -CH2NH-, a C2-C6 straight or branched alkenyl group, -CH2O-, -CH2S-, -CONH-, -NHCO-, -COO-, -OOC-, Ring A is a substituted or unsubstituted group selected from the following group: a 5-12 membered nitrogen-containing heterocyclic group (including a monocyclic, fused polycyclic, bridged or spirocyclic ring, wherein the connection point is preferably located on the nitrogen atom), a C6-C12 aryl group (preferably a C6-C10 aryl group), a 5-12 membered heteroaryl group (preferably a 5-7 membered heteroaryl group); wherein the heterocyclic group or heteroaryl group includes a heteroatom selected from the following group as the ring skeleton: N, NH, S, O, S(O)2; R4 is selected from the following groups which are unsubstituted or substituted with 1-3 substituents: C3-C7 cycloalkyl, 5-12 membered heterocyclic group, C6-C12 aryl, 5-12 membered heteroaryl (preferably 5-7 membered heteroaryl, or benzo 5-7 membered heteroaryl); wherein each of the heterocyclic group or heteroaryl contains 1-3 heteroatoms selected from oxygen, sulfur and nitrogen; and the substituents are each independently selected from halogen, C1-C6 straight or branched alkyl, C2-C6 straight or branched alkyl, C3-C7 cycloalkyl, C1-C7 straight or branched alkyl, C2-C6 straight or branched alkyl, C3-C7 cycloalkyl, C1-C7 straight or branched alkyl, C3 ... a C2-C6 straight-chain or branched alkenyl group, a C2-C6 straight-chain or branched alkynyl group, a C1-C6 straight-chain or branched alkoxy group, a C1-C6 straight-chain or branched alkylcarbonyloxy group, a cyano group, a nitro group, a hydroxyl group, an amino group, a hydroxymethyl group, a trifluoromethyl group, a trifluoromethoxy group, a carboxyl group, a mercapto group, a C1-C4 acyl group, an amide group, a sulfonyl group, an aminosulfonyl group, a C1-C4 alkyl-substituted sulfonyl group, or two substituents on adjacent ring atoms together with the carbon atom to which they are attached form a 5-7 membered ring; R3 and R5 are each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, C1-C6 alkyl unsubstituted or substituted by 1-3 halogens, or C3-C6 cycloalkyl unsubstituted or substituted by 1-3 halogens, C6-C10 aryl unsubstituted or substituted by 1-3 halogens, C1-C3 alkyl-C6-C10 aryl unsubstituted or substituted by 1-3 halogens, 5-7 membered heteroaryl unsubstituted or substituted by 1-3 halogens; Unless otherwise specified, the term "substituted" refers to the replacement of one or more hydrogen atoms on a group by a substituent selected from the group consisting of: C1 to C 10 Alkyl, C1~C 10 Alkoxy, C3~C 10 Cycloalkyl, C1~C 10 Alkoxy, 5-12 membered heterocyclic group, halogen, hydroxyl, carboxyl (-COOH), C1~C 10 Aldehyde, C2~C 10 Acyl, C2~C 10 Ester group, cyano group, amino group, phenyl group; the phenyl group includes unsubstituted phenyl group or substituted phenyl group having 1-3 substituents, the substituents are selected from: halogen, C1-C 10 Alkyl, cyano, hydroxyl, nitro, C3~C 10 Cycloalkyl, C1~C 10 Alkoxy, amino; And the compound is not a structure selected from the following group:

2. A nitrogen-containing heterocyclic compound represented by general formula (I), or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof: in, The chiral carbon atom C* is independently S-type, R-type, racemic, or a combination thereof; n = 0, 1, or 2; R1 and R2 are each independently selected from the group consisting of hydrogen, deuterium, tritium, halogen, hydroxyl, carboxyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted C6-C10 aryl, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C1-C6 alkylphenyl, substituted or unsubstituted C1-C6 alkyl 5-7 membered heteroaryl, substituted or unsubstituted C3-C12 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, amino, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 amide, -SOR5, -OSOR5, -OCOR5; When n=0, R1 and R2 are not methyl at the same time; when n=1, R1 and R2 are not hydrogen at the same time; or said R1 and R2 and adjacent (CH2) n O and C=C together constitute a substituted or unsubstituted 5-7 membered heterocycle, wherein the heterocycle is a fully saturated heterocycle, a partially unsaturated heterocycle or an aromatic heterocycle; X is O or S; Y is a linking group selected from the group consisting of: a chemical bond, a C1-C6 straight or branched alkyl group, -CH2NH-, a C2-C6 straight or branched alkenyl group, -CH2O-, -CH2S-, -CONH-, -NHCO-, -COO-, -OOC-, Ring A is a substituted or unsubstituted group selected from the group consisting of a 5- to 12-membered nitrogen heterocyclic group (wherein the attachment site is preferably located on the nitrogen atom), a C6-C12 aryl group (preferably a C6-C10 aryl group), or a 5- to 12-membered heteroaryl group (preferably a 5- to 7-membered heteroaryl group); wherein the heterocyclic group or heteroaryl group includes a heteroatom selected from the group consisting of N, NH, S, O, and S(O)2 as the ring backbone; R4 is selected from the following groups which are unsubstituted or substituted with 1-3 substituents: C3-C7 cycloalkyl, 5-12 membered heterocyclic group, C6-C12 aryl, 5-12 membered heteroaryl (preferably 5-7 membered heteroaryl, or benzo 5-7 membered heteroaryl); wherein each of the heterocyclic group or heteroaryl contains 1-3 heteroatoms selected from oxygen, sulfur and nitrogen; and the substituents are each independently selected from halogen, C1-C6 straight or branched alkyl, C2-C6 straight or branched alkyl, C3-C7 cycloalkyl, C1-C7 straight or branched alkyl, C2-C6 straight or branched alkyl, C3-C7 cycloalkyl, C1-C7 straight or branched alkyl, C3 ... a C2-C6 straight-chain or branched alkenyl group, a C2-C6 straight-chain or branched alkynyl group, a C1-C6 straight-chain or branched alkoxy group, a C1-C6 straight-chain or branched alkylcarbonyloxy group, a cyano group, a nitro group, a hydroxyl group, an amino group, a hydroxymethyl group, a trifluoromethyl group, a trifluoromethoxy group, a carboxyl group, a mercapto group, a C1-C4 acyl group, an amide group, a sulfonyl group, an aminosulfonyl group, a C1-C4 alkyl-substituted sulfonyl group, or two substituents on adjacent ring atoms together with the carbon atom to which they are attached form a 5-7 membered ring; R3 and R5 are each independently selected from the following groups: hydrogen, deuterium, tritium, halogen, C1-C6 alkyl which is unsubstituted or substituted by 1-3 halogens, or C3-C6 cycloalkyl which is unsubstituted or substituted by 1-3 halogens, C6~C10 aryl which is unsubstituted or substituted by 1-3 halogens, C1-C3 alkyl-C6~C10 aryl which is unsubstituted or substituted by 1-3 halogens, 5-7 membered heteroaryl which is unsubstituted or substituted by 1-3 halogens.

3. The nitrogen-containing heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof, wherein: The A ring is selected from the following groups: aziridine, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl, morpholinyl, piperazinyl, homopiperazinyl, thiomorpholinyl, thiomorpholinyl with ring sulfur replaced by sulfoxide or sulfone, imidazolidinyl, pyrazinyl, hexahydropyrimidinyl or The A ring is optionally substituted by 1-2 groups selected from hydrogen, C1-C3 straight or branched alkyl, halogen, hydroxyl and C1-C4 alkoxycarbonyl.

4. The nitrogen-containing heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof, wherein: R1 and R2 are each independently selected from the following group: hydrogen, deuterium, tritium, halogen, hydroxyl, carboxyl, phenyl, substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 alkoxy, substituted or unsubstituted 5-7 membered heterocycle, substituted or unsubstituted C1-C6 alkyl 5-7 membered heteroaryl, substituted or unsubstituted C3-C8 cycloalkyl, substituted or unsubstituted C2-C10 acyl, substituted or unsubstituted C2-C10 ester, amino, substituted or unsubstituted C1-C6 alkylamino, substituted or unsubstituted C1-C6 amide, -SOR5, -OSOR5, -OCOR5.

5. The nitrogen-containing heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof, wherein: X is O; Y is selected from the group consisting of -CH2-, -CH2-CH2-, -CH2-CH2-CH2-, -CH2NH-, -CH2O-, or -CH2S-.

6. The nitrogen-containing heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof, wherein: R4 is selected from the following groups which are unsubstituted or substituted with 1-3 substituents: C6-C10 aryl, 5-7 membered heteroaryl, or benzo 5-7 membered heteroaryl; preferably, the heterocyclic ring and heteroaromatic ring moieties in the group are selected from the group formed by indole, benzodioxole, isoxazole, pyridine, pyrazole, dihydroimidazopyridine, imidazopyridine, benzothiophene, dihydrobenzodioxane, quinoxaline, pyrrole, benzofuran, indazole, benzimidazole, quinoline, and 1,3-dioxoisoindoline.

7. The nitrogen-containing heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof, wherein: Hydrogen, deuterium, tritium, halogen, C1-C6 alkyl which is unsubstituted or substituted by 1-3 halogens, or C3-C6 cycloalkyl which is unsubstituted or substituted by 1-3 halogens.

8. The nitrogen-containing heterocyclic compound according to claim 1, or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof, wherein: The tetrahydroisoquinoline compound is selected from the following compounds:

9. The method for preparing the compound of formula (I) according to claim 1, wherein The method comprises the steps of: (1) In an inert solvent, in the presence of a condensing agent, a compound of formula II and a compound of formula I c Compound reaction to obtain formula I d Compound; preferably, the condensing agent is EDCI (1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride); (2) In an inert solvent, use formula I d The compound is subjected to Bischler-Napieralski ring closure reaction to obtain formula I e Compound; preferably, the ring-closure reaction uses phosphorus oxychloride as a Lewis acid; (3) In an inert solvent, use formula I e The compound is subjected to reduction reaction to obtain formula I f Compound; preferably, the reduction reaction uses borohydride as a reducing agent or Noyori catalyst as an asymmetric reduction catalyst; (4) In an inert solvent, f Compounds and Carrying out a condensation reaction to obtain a compound of formula (I); In the above formulae, the definitions of the groups are as described in any one of claims 1 to 8.

10. A pharmaceutical composition, characterized in that The pharmaceutical composition comprises: a therapeutically effective amount of the compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

11. The use of the compound of formula (I) according to claim 1, characterized in that Used for preparing a pharmaceutical composition for treating diseases or conditions related to the activity or expression of type 4 relaxin family receptors.

12. The use according to claim 11, characterized in that The compound is used for preparing a pharmaceutical composition for treating diseases or conditions selected from the following groups: constipation, anorexia, or diseases related to glycolipid metabolism.

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