Novel tetrahydroisoquinoline compounds, processes for their preparation, pharmaceutical compositions containing such compounds and uses thereof

Abstract

The present invention provides novel tetrahydroisoquinoline compounds, their preparation methods, pharmaceutical compositions containing such compounds and their uses, specifically, the present invention provides a nitrogen-containing heterocyclic compound represented by the general formula (I), or a pharma- ceutically acceptable salt, enantiomer, diastereomer or racemate thereof. The compound can be used in the preparation of a pharmaceutical composition for treating a disease or condition associated with the activity or expression level of relaxin family peptide receptor 4. [Formula 1] TIFF2025517458000256.tif4168

Description

[Technical field]

[0001] The present invention relates to novel nitrogen-containing heterocyclic compounds, their preparation methods, pharmaceutical compositions containing such compounds and their use, and is related to the field of medical technology.The present invention relates to novel nitrogen-containing heterocyclic compounds represented by general formula (I), their pharma- ceutically acceptable salts, isomers, solvates, metabolites, metabolic precursors, drug combinations containing them, and the use of such compounds in the prevention and / or treatment of diseases or conditions such as constipation, anorexia, diabetes, non-alcoholic steatohepatitis, etc., associated with RXFP4 agonist activity. [Background technology]

[0002] The human relaxin(R) / insulin (INS) superfamily consists of INS, insulin-like growth factor (IGF) 1, IGF2, and R 1 , R 2 , INSL3, INSL4, INSL5, INSL6 and INSL7(R 3 ). Relaxin and related hormone peptides have multiple functions and are involved in various physiological and pathological processes, including reproduction, nerve signaling, wound healing, collagen metabolism and tumor development. Insulin-like peptide 5 (INSL5) is a member of the relaxin / insulin superfamily, and its structural composition includes a signal peptide, an A chain, a B chain and a C chain that plays a connecting effect. The A chain and the B chain are connected by two disulfide bonds, while the A chain has an additional disulfide bond. After the C peptide chain is hydrolyzed and removed under the action of enzymes, INSL5 can be activated and exert its biological activity. Northern blot detection results show that INSL5 is 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) detection reveals that human INSL5 is present in various peripheral tissues, especially in the colon, rectum, and uterus, as well as in the human brain, mainly in the pituitary gland.

[0003] Relaxin family peptides induce further biological signaling by binding to G protein-coupled receptors. Four types of relaxin receptors have been discovered so far, which are named RXFP 1-4, respectively. In 2003, Liu first discovered RXFP4 in the human genome database, and initially named it GPR100, and initially described it as a bradykinin receptor. A 2005 study showed that GPR100 is a receptor for INSL5, also known as G protein-coupled receptor 142 (GPCR142), which was renamed RXFP4. INSL5 is a specific agonist of RXFP4. Human RXFP4 is composed of 374 amino acids encoded by independent exons and belongs to the class A neuropeptide-like G protein-coupled receptor (rhodopsin-like receptor), which consists of a short N-terminal extracellular region, seven α-helical transmembrane domains, and an intracellular C-terminus. After INSL5 is bound to RXFP4, the conformation of the Gi protein coupled to RXFP4 changes, the α subunit is activated, and the exchange of Giα-guanosine diphosphate (GDP) with guanosine triphosphate (GTP) is induced to generate Giα-GTP, which is then separated from the β subunit and γ subunit and transferred to the adjacent adenylyl cyclase (AC) to inhibit AC, thereby inhibiting the production of intracellular cyclic adenosine monophosphate (cAMP) and reducing the cAMP concentration in tissues expressing RXFP4. Northern blot detection showed that human RXFP4 was expressed in the heart, skeletal muscle, kidney, liver and placenta, but was most highly expressed in the pancreas; RT-PCR detection showed that human RXFP4 was expressed in the heart, skeletal muscle, kidney, liver and placenta, and was also expressed in the human colon, thyroid, salivary gland, prostate, thymus, testis and brain; Western blot detection showed that human RXFP4 was expressed in the hypothalamus, pituitary gland, testis, epididymis, ovary, uterus, pancreas and liver; and immunohistochemistry detection showed that human RXFP4 was expressed in pancreatic islet B cells, and was also expressed in the pituitary gland, testis and ovary.RXFP4 is expressed only in a few species, rat and dog RXFP4 are pseudogenes, mouse RXFP4 is less conserved than human RXFP4, and further studies of RXFP4 in monkeys, cows, and pigs confirm that RXFP4 in these species is highly homologous to human RXFP4 and operates similarly to the human receptor in vitro.

[0004] Regulation of appetite is one of the main issues of concern in the current medical field, and gastrointestinal hormones have various physiological functions outside the intestine and play an important role in food intake behavior, appetite change 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 colonic region, so compared with ghrelin, which is mainly distributed in the pituitary gland, INSL5 and its analogs can directly exert their physiological functions by affecting the enteric nervous system without the need to cross the blood-brain barrier, which also gives its receptor RXFP4 a potential advantage as a target point for drug treatment.

[0005] Constipation refers to a condition in which stool is difficult to excrete or difficult to defecate due to the stool being too hard or too dry. Constipation usually has many causes, and common causes include slow movement of the colon containing stool, irritable bowel syndrome, or bone cavity disease, etc., and related underlying diseases include hypothyroidism, diarrhea, Parkinson's disease, colon cancer, diverticulitis, inflammatory bowel disease, etc. Recent studies have shown that RXFP4 agonists can promote intestinal peristalsis and significantly shorten defecation time in a mouse constipation model, suggesting that the discovery of RXFP4 agonists is expected to provide a new type of safe and effective drug treatment for constipation.

[0006] In summary, RXFP4 target points are closely related to important physiological functions of the human body, such as appetite regulation, intestinal peristalsis, etc., and the design and discovery of related agonists can provide strong support for subsequent research on the INSL5-RXFP4 system, and are also expected to provide a new class of drugs for treating metabolism-related diseases. Summary of the Invention [Problem to be solved by the invention]

[0007] One of the objects of the present invention is to provide a nitrogen-containing heterocyclic compound represented by the general formula (I), a pharma- ceutically acceptable salt, an enantiomer, a diastereomer or a racemate thereof. Another object of the present invention is to provide a process for preparing the compound represented by the above general formula (I). 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 a pharma- ceutically acceptable salt thereof.

[0008] Another object of the present invention is to provide a use of the compound represented by the above general formula (I) in the preparation of a medicament for treating glucose and lipid metabolism disorders such as constipation, anorexia, diabetes, non-alcoholic steatohepatitis, etc. The compounds of the present invention can be used to stimulate relaxin family peptide receptor 4 (RXFP4). [Means for solving the problem]

[0009] A first aspect of the present invention provides a nitrogen-containing heterocyclic compound represented by general formula (I) or a pharma- ceutically acceptable salt, enantiomer, diastereomer or racemate thereof, [ka] Where: the chiral carbon atom C* is independently S, R, racemic, or a combination thereof; n=0, 1 or 2; X 1 and X 2 are each independently selected from the group consisting of O or NH; X 3 is a chemical bond, CHR 6 or (CHR 6 ) 2 and R 1 and R 2 are each independently hydrogen, deuterium, tritium, a halogen, a hydroxyl group, a carboxyl group, a substituted or unsubstituted C 1 ~C 6 Alkyl groups, substituted or unsubstituted C 1 ~C 6 Alkoxy groups, substituted or unsubstituted C 2 ~C 6 Alkenyl group, substituted or unsubstituted C 2 ~C 6 Alkynyl group, substituted or unsubstituted C 6 ~C 10 Aryl group, substituted or unsubstituted 5- to 7-membered heterocycle, substituted or unsubstituted C 1 ~C 6 Alkylphenyl groups, substituted or unsubstituted C 1 ~C 6 Alkyl 5-7 membered heteroaryl group, substituted or unsubstituted C 3 ~C 12 Cycloalkyl groups, substituted or unsubstituted C 2 ~C 10 Acyl groups, substituted or unsubstituted C 2 ~C 10 Ester group, amino group, substituted or unsubstituted C 1 ~C 6 Alkylamino group, substituted or unsubstituted C 1 ~C 6 Amide, -SOR 5 , -OSOR 5 , -OCOR 5 , C(=NH)NH 2 , Fmoc, and allyloxycarbonyl group (Alloc); When n=0, R 1 and R 2is not a methyl group, and n=1, R 1 and R 2 is not hydrogen at the same time, Or the above R 1 and R 2 is the adjacent (CH 2 ) n together with O and C=C, a substituted or unsubstituted 5- to 7-membered heterocycle, wherein the heterocycle is a fully saturated heterocycle, a partially unsaturated heterocycle, or an aromatic heterocycle; X is O, S, or CHR 6 , C 2 H 4 (i.e., forming a cyclopropyl group at the substitution position of X) or NR 6 wherein R 6 H, CN, C 1 ~C 6 Alkyl group, C 1 ~C 6 alkoxy groups; Y is a chemical bond, C 1 ~C 6 Straight or branched chain alkyl group, -CH 2 NH-, C 2 ~C 6 Linear or branched alkenyl groups, -CH 2 O-, -CH 2 S-, -CONH-, -NHCO-, -COO-, -OOC-, [ka] is a linking group selected from the group consisting of Ring A is a 5-12 membered nitrogen-containing heterocyclic group (including monocyclic, fused polycyclic, bridged or spirocyclic, where the linking site is preferably on the nitrogen atom), C 6 ~C 12 Aryl groups (preferably C 6 ~C 10 A substituted or unsubstituted group selected from the group consisting of a heterocyclic group, a 5- to 12-membered heteroaryl group (preferably a 5- to 7-membered heteroaryl group), wherein the heterocyclic group or heteroaryl group is selected from the group consisting of N, NH, S, O, S(O) 2The ring skeleton contains a heteroatom selected from the group consisting of R 4 is unsubstituted or substituted by 1 to 3 substituents, C 3 ~C 7 Cycloalkyl groups, 5-12 membered heterocyclic groups, C 6 ~C 12 aryl group, 5-12 membered heteroaryl group (preferably 5-7 membered heteroaryl group, or benzo 5-7 membered heteroaryl group), wherein each of said heterocyclic or heteroaryl groups contains 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, and each of said substituents is independently selected from halogen, C 1 ~C 6 Linear or branched alkyl group, C 2 ~C 6 Linear or branched alkenyl group, C 2 ~C 6 Straight or branched chain alkynyl group, C 1 ~C 6 Linear or branched alkoxy group, C 1 ~C 6 Linear or branched alkylcarbonyloxy group, cyano group, nitro group, hydroxy group, amino group, hydroxymethyl group, trifluoromethyl group, trifluoromethoxy group, carboxy group, thiol group, C 1 ~C 4 Acyl group, amide, sulfonyl group, aminosulfonyl group, C 1 ~C 4 or two substituents located on adjacent ring atoms, together with the carbon atoms connected thereto, form a 5- to 7-membered ring; R 3 and R 5 are each independently hydrogen, deuterium, tritium, halogen, or C unsubstituted or substituted with 1 to 3 halogens. 1 ~C 6 Alkyl group or unsubstituted or substituted with 1 to 3 halogens 3 ~C 6 Cycloalkyl groups, unsubstituted or substituted with 1 to 3 halogens 6 ~C 10Aryl group, unsubstituted or substituted with 1 to 3 halogens 1 -C 3 Alkyl-C 6 ~C 10 an aryl group, a 5-7 membered heteroaryl group unsubstituted or substituted by 1 to 3 halogens; Unless otherwise specified, the term "substituted" refers to one or more hydrogen atoms on a group being replaced with a C 1 ~C 10 Alkyl group, C 1 ~C 10 Alkoxy group, C 3 ~C 10 Cycloalkyl groups, C 1 ~C 10 Alkoxy group, 5-12 membered heterocyclic group, halogen, hydroxy group, carboxy group (-COOH), C 1 ~C 10 Aldehyde group, C 2 ~C 10 Acyl group, C 2 ~C 10 The phenyl group includes an unsubstituted phenyl group or a substituted phenyl group having 1 to 3 substituents, and the substituents are selected from the group consisting of halogen, C 1 -C 10 Alkyl group, cyano group, hydroxy group, nitro group, C 3 ~C 10 Cycloalkyl groups, C 1 ~C 10 is selected from an alkoxy group, an amino group, And the compound is [ka] is not a structure selected from the group consisting of:

[0010] In another preferred embodiment, the compound has a structure as shown in the following formula: [ka] Where: the chiral carbon atom C* is independently S, R, racemic, or a combination thereof; n=0, 1 or 2; R 1 and R 2 are each independently hydrogen, deuterium, tritium, a halogen, a hydroxyl group, a carboxyl group, a substituted or unsubstituted C 1 ~C 6 Alkyl groups, substituted or unsubstituted C 1 ~C 6 Alkoxy groups, substituted or unsubstituted C 6 ~C 10 Aryl group, substituted or unsubstituted 5- to 7-membered heterocycle, substituted or unsubstituted C 1 ~C 6 Alkylphenyl groups, substituted or unsubstituted C 1 ~C 6 Alkyl 5-7 membered heteroaryl group, substituted or unsubstituted C 3 ~C 12 Cycloalkyl groups, substituted or unsubstituted C 2 ~C 10 Acyl groups, substituted or unsubstituted C 2 ~C 10 Ester group, amino group, substituted or unsubstituted C 1 ~C 6 Alkylamino group, substituted or unsubstituted C 1 ~C 6 Amide, -SOR 5 , -OSOR 5 , -OCOR 5 is selected from the group consisting of When n=0, R 1 and R 2 is not a methyl group, and n=1, R 1 and R 2 is not hydrogen at the same time, Or the above R 1 and R 2 is the adjacent (CH 2 ) n together with O and C=C, a substituted or unsubstituted 5- to 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 chemical bond, C 1 ~C 6 Straight or branched chain alkyl group, -CH 2 NH-, C 2 ~C 6 Linear or branched alkenyl groups, -CH 2 O-, -CH 2 S-, -CONH-, -NHCO-, -COO-, -OOC-, [ka] is a linking group selected from the group consisting of Ring A is a 5- to 12-membered azaheterocyclyl group (wherein the linking site is preferably on the nitrogen atom), C 6 ~C 12 Aryl groups (preferably C 6 ~C 10 A substituted or unsubstituted group selected from the group consisting of a heterocyclic group, a 5- to 12-membered heteroaryl group (preferably a 5- to 7-membered heteroaryl group), wherein the heterocyclic group or heteroaryl group is selected from the group consisting of N, NH, S, O, S(O) 2 The ring skeleton contains a heteroatom selected from the group consisting of R 4 is unsubstituted or substituted by 1 to 3 substituents, C 3 ~C7 cycloalkyl group, 5-12 membered heterocyclic group, C 6 ~C 12 aryl group, 5-12 membered heteroaryl group (preferably 5-7 membered heteroaryl group, or benzo 5-7 membered heteroaryl group), wherein each of said heterocyclic or heteroaryl groups contains 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, and each of said substituents is independently selected from halogen, C 1 ~C 6 Linear or branched alkyl group, C 2 ~C 6 Linear or branched alkenyl group, C 2 ~C 6 Straight or branched chain alkynyl group, C 1 ~C 6 Linear or branched alkoxy group, C 1 ~C6 Linear or branched alkylcarbonyloxy group, cyano group, nitro group, hydroxy group, amino group, hydroxymethyl group, trifluoromethyl group, trifluoromethoxy group, carboxy group, thiol group, C 1 ~C 4 Acyl group, amide, sulfonyl group, aminosulfonyl group, C 1 ~C 4 or two substituents located on adjacent ring atoms, together with the carbon atoms connected thereto, form a 5- to 7-membered ring; R 3 and R 5 are each independently hydrogen, deuterium, tritium, halogen, or C unsubstituted or substituted with 1 to 3 halogens. 1 ~C 6 Alkyl group or unsubstituted or substituted with 1 to 3 halogens 3 ~C 6 Cycloalkyl groups, unsubstituted or substituted with 1 to 3 halogens 6 ~C 10 Aryl group, unsubstituted or substituted with 1 to 3 halogens 1 -C 3 Alkyl-C 6 ~C 10 and 5-7 membered heteroaryl groups unsubstituted or substituted with 1 to 3 halogens.

[0011] In another preferred example, the A ring is an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, an azepanyl group, a morpholinyl group, a piperazinyl group, a homopiperazinyl group, a thiomorpholinyl group, a thiomorpholinyl group in which the ring sulfur is substituted with a sulfoxide or a sulfone, an imidazolidinyl group, a pyrazinyl group, a hexahydropyrimidinyl group, or [ka] and the A ring is optionally selected from the group consisting of hydrogen, C 1 -C 3 Linear or branched alkyl groups, halogens, hydroxyl groups and C1 -C 4 It is substituted with 1 to 2 groups selected from alkoxycarbonyl groups.

[0012] In another preferred embodiment, the A ring is [ka] and the A ring is optionally selected from the group consisting of hydrogen, C 1 -C 3 Linear or branched alkyl groups, halogens, hydroxyl groups and C 1 -C 4 It is substituted with 1 to 2 groups selected from alkoxycarbonyl groups.

[0013] In another preferred embodiment, R 1 and R 2 are each independently hydrogen, deuterium, tritium, a halogen, a hydroxyl group, a carboxyl group, a phenyl group, a substituted or unsubstituted C 1 ~C 6 Alkyl groups, substituted or unsubstituted C 1 ~C 6 Alkoxy group, substituted or unsubstituted 5- to 7-membered heterocycle, substituted or unsubstituted C 1 ~C 6 Alkyl 5-7 membered heteroaryl group, substituted or unsubstituted C 3 ~C8 cycloalkyl group, substituted or unsubstituted C 2 ~C 10 Acyl groups, substituted or unsubstituted C 2 ~C 10 Ester group, amino group, substituted or unsubstituted C 1 ~C 6 Alkylamino group, substituted or unsubstituted C 1 ~C 6 Amide, -SOR 5 , -OSOR 5 , -OCOR 5 is selected from the group consisting of:

[0014] In another preferred embodiment, X is O. Y is -CH 2 -, -CH2 -CH 2 -, -CH 2 -CH 2 -CH 2 -, -CH 2 NH-, -CH 2 O- or -CH 2 S-.

[0015] In another preferred embodiment, R 4 is unsubstituted or substituted by 1 to 3 substituents, C 6 -C 10 The heterocyclic and heteroaromatic ring moieties are preferably selected from the group consisting of indole, benzodioxole, isoxazole, pyridine, pyrazole, dihydroimidazopyridine, imidazopyridine, benzothiophene, dihydrobenzodioxane, quinoxaline, pyrrole, benzofuran, indazole, benzimidazole, quinoline, and 1,3-dioxoisoindoline.

[0016] In another preferred embodiment, hydrogen, deuterium, tritium, halogen, unsubstituted or substituted with 1 to 3 halogens, 1 ~C 6 Alkyl group or unsubstituted or substituted with 1 to 3 halogens 3 ~C 6 Cycloalkyl groups. In another preferred embodiment, the chiral carbon atom C* is in the S configuration.

[0017] A second aspect of the present invention provides a process for the preparation of a compound of formula (I) according to the first aspect of the present invention, said process comprising the steps of: (1) reacting a compound of formula II with a compound of formula I in the presence of a condensing agent in an inert solvent; c with a compound of formula I d Preferably, the condensing agent is EDCI (1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride), [ka] (2) In an inert solvent, d to carry out a Bischler-Napieralski ring closure reaction to obtain a compound of formula I e Preferably, the ring closure reaction is carried out using phosphorus oxychloride as Lewis acid, [ka] (3) In an inert solvent, e to carry out a reduction reaction using a compound of formula I f Preferably, the reduction reaction uses borohydride as a reducing agent or Noyori's catalyst as an asymmetric reduction catalyst; [ka] (4) In an inert solvent, f Compounds of and [ka] to carry out a condensation reaction to obtain a compound of formula (I), [ka] In the above formulae, the definitions of each group are as described in the first aspect of the present invention.

[0018] A third aspect of the present invention provides a pharmaceutical composition, said pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to the first aspect of the present invention, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

[0019] A fourth aspect of the present invention provides the use of a compound of formula (I) as described in the first aspect of the present invention for the preparation of a pharmaceutical composition for treating a disease or condition associated with relaxin family peptide receptor 4 activity or expression level, preferably the compound is used for the preparation of a pharmaceutical composition for treating a disease or condition selected from the group consisting of constipation, anorexia, or glucose and lipid metabolism related disorders.

[0020] In another preferred embodiment, the compound is used for the preparation of a pharmaceutical composition for treating a disease or condition caused by underactivity or underexpression of relaxin family peptide receptor 4. In another preferred embodiment, the glucose and lipid metabolism-related disease is selected from the group consisting of diabetes mellitus and non-alcoholic steatohepatitis. Effect of the Invention

[0021] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (e.g., in the Examples) can be combined with each other to form new or preferred technical solutions, which will not be repeated here due to space limitations. [Brief description of the drawings]

[0022] [Figure 1] The promotion of intestinal peristalsis effect of various doses of compounds in constipated model mice. A: Fecal water content, B: Fecal weight, C: Fecal particle number, D: Bead expulsion time. [Diagram 2] Compounds that improve colon histopathological changes in constipation model mice. A: Thickness of colonic muscle layer, B: Thickness of colonic mucosal layer, C: Number of Libekos stripes, D: Number of goblet cells. [Diagram 3] Modulatory effects of compounds on colonic AQP3, TRPV1 and CGRP expression levels in mice. [Figure 4] Effect of compounds on serum levels of 5-HT, NO and VIP in mice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0023] After extensive research, the present inventors have prepared a class of compounds of formula I, which can stimulate relaxin family peptide receptor 4 (RXFP4).Compared with the relaxin family peptide receptor 4 (RXFP4) of the prior art, said compounds have higher inhibitory activity and selectivity.Based on the above findings, the present inventors have completed the present invention.

[0024] term In this specification, unless otherwise stated, the term "substituted" means that one or more hydrogen atoms on a group have been replaced with a C 1 ~C 10 Alkyl group, C 3 ~C 10 Cycloalkyl groups, C 1 ~C 10 Alkoxy group, halogen, hydroxy group, carboxy group (-COOH), C 1 ~C 10 Aldehyde group, C 2 ~C 10 Acyl group, C 2 ~C 10 The phenyl group includes an unsubstituted phenyl group or a substituted phenyl group having 1 to 3 substituents, and the substituents are selected from the group consisting of halogen, C 1 -C 10 Alkyl group, cyano group, hydroxy group, nitro group, C 3 ~C 10 Cycloalkyl groups, C 1 ~C 10 It is selected from an alkoxy group and an amino group.

[0025] Unless otherwise specified, in all compounds of the present invention, each chiral carbon atom may optionally be of the R or S configuration, or a mixture of R and S configurations. "C 1 ~C 6The term "alkyl group" refers to a straight or branched chain alkyl group having from 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s-butyl, t-butyl, or the like.

[0026] The term "3- to 8-membered heterocyclic group" refers to a group formed by losing one hydrogen atom from a 3- to 8-membered saturated ring having 1 to 3 heteroatoms selected from the group consisting of N, S, and O, such as a pyrrolidinyl group, a piperidinyl group, a piperazinyl group, a morpholinyl group, or similar groups. The term "6- to 10-membered aryl group" refers to a group formed by the loss of a hydrogen atom from a 6- to 10-membered aryl group, such as a phenyl group, naphthyl group, or the like.

[0027] The term "5- to 10-membered heteroaryl group" refers to a group formed by the loss of one hydrogen atom from a 5- to 8-membered aryl group having 1-3 heteroatoms selected from the group consisting of N, S, and O, where the ring system of each heteroaryl group can be monocyclic or polycyclic, such as pyrrolyl, pyridyl, thienyl, furyl, imidazolyl, pyrimidinyl, benzothienyl, indolyl, imidazopyridyl, quinoline, or the like.

[0028] "C 1 ~C 6 The term "alkoxy" refers to straight or branched chain alkoxy groups having from 1 to 6 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-butoxy, t-butoxy, or the like. "C 2 -C 6 The term "ester group" means -COOCH 3 , -COOC 2 H 5 , -COOC 3 H 7 , -COOC 4 H 9 or a similar group having 2 to 6 carbon atoms.

[0029] "C 2 -C 6 The term "alkenyl group" refers to a group formed by the loss of one or two hydrogen atoms from an alkene having 2 to 6 carbon atoms, the alkene being -CH=CH 2 , -C 2 H 4 =CH 2 , -CH=C 2 H 4 or similar groups. The term "halogen" refers to F, Cl, Br and I.

[0030] Unless otherwise indicated, the structural formulae depicted in the present invention are intended to include all isomers (e.g., enantiomers, diastereomers, and geometric (or conformational) isomers), such as the R and S configurations including asymmetric centers, the (Z) and (E) isomers of double bonds, and the (Z) and (E) conformational isomers. Thus, all individual stereochemical isomers of the compounds of the present invention or mixtures of their enantiomers, diastereomers, or geometric (or conformational) isomers are within the scope of the present invention.

[0031] The term "tautomer" refers to structural isomers that have different energies and can be interconverted across a low energy barrier. For example, proton tautomers (i.e., proton transfer) include interconversions via proton transfer between 1H-indazole and 2H-indazole, 1H-benzo[d]imidazole and 3H-benzo[d]imidazole, etc., and valence tautomers include interconversions via recombination of some of the bonding electrons. In this specification, "C 1 ~C 6 " indicates that the group can have 1 to 6 carbon atoms, such as 1, 2, 3, 4 or 5.

[0032] Tetrahydroisoquinoline compounds represented by formula (I) The present invention provides a tetrahydroisoquinoline compound represented by the general formula (I), its enantiomer, diastereomer, racemate, mixture thereof, or a pharma- ceutically acceptable salt thereof, [ka] Here, each group is as defined above.

[0033] In another preferred embodiment, n, X, Y, R 1 , R 2 , R 3 , R 4 are each independently the corresponding group corresponding to each specific compound in the Examples. In particular, the tetrahydroisoquinoline compound according to the present invention is preferably selected from the compounds shown in Table A below. [Table A-1] [Table A-2] [Table A-3] [Table A-4] [Table A-5] [Table A-6] [Table A-7] [Table A-8] [Table A-9] [Table A-10] [Table A-11]

Table A-12

Table A-13

Table A-14

Table A-15

Table A-16

Table A-17

Table A-18

Table A-19

Table A-20

Table A-21

Table A-22

Table A-23

Table A-24

Table A-25

Table A-26

Table A-27

Table A-28

[0034] Preparation of Compounds of Formula (I) The present invention further provides a method for the synthesis of a compound of general formula I, specifically, the compound of formula I is prepared by the following process: [ka] Stage a:I c is dissolved in a solvent and subjected to a condensation reaction with II under the assistance of a condensing agent to obtain compound I d wherein the solvent is dichloromethane; Stage b:I d is dissolved in a solvent, excess phosphorus oxychloride is added, and the mixture is stirred at reflux to obtain compound I. e wherein the solvent is anhydrous acetonitrile; Stage c:I e was dissolved in a solvent, excess sodium borohydride was added, the mixture was stirred until the reaction was complete, and the solvent was spun dry to give compound I. f and the solvent is methanol; or Noyori's catalyst is added and stirred until the reaction is completed, and the solvent is a mixed solvent of water and methanol. Stage d:I f is dissolved in a solvent and reacted with a corresponding raw material to obtain compound Ig, the solvent being dichloromethane; X, Y, R 1 , R 2 , R 3 , R 4 is the same as the definition of the requirement above.

[0035] Pharmaceutical compositions containing compounds of formula (I) The present invention also relates to a pharmaceutical composition, which comprises a therapeutically effective amount of one or more selected from the nitrogen-containing heterocyclic compound represented by formula (I), its pharma- ceutically acceptable salt, its prodrug, and its hydrate and solvate, and optionally a pharma- ceutically acceptable carrier, which can be used for the treatment of autoimmune-related diseases such as psoriasis. The pharmaceutical composition can be prepared in various forms according to different administration routes.

[0036] The pharmaceutical composition of one or more selected from the aldehyde-based compound represented by formula (I) according to the present invention, its pharma- ceutically acceptable salt, its prodrug, and its hydrate and solvate, or the above-mentioned therapeutically effective amount of the tetrahydroisoquinoline compound represented by formula (I), its pharma- ceutically acceptable salt, its prodrug, and its hydrate and solvate, can be used as a phosphodiesterase 4 (PDE4) inhibitor for treating glucose and lipid metabolism disorders such as constipation, anorexia, diabetes, and non-alcoholic steatohepatitis.

[0037] Pharmaceutically acceptable salts of the compounds of the present invention can be prepared by directly reacting the free base of the compound with an inorganic or organic acid to form a salt, which 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, p-toluenesulfonic acid, and the like.

[0038] The compound of the present invention has excellent inhibitory activity against relaxin family peptide receptor 4 (RXFP4), so the compound of the present invention and its various crystal forms, pharma- ceutically acceptable inorganic or organic salts, hydrates or solvates, as well as pharmaceutical compositions containing the compound of the present invention as the main active ingredient, can be used to treat and alleviate diseases related to relaxin family peptide receptor 4 (RXFP4). Based on the prior art, the compound of the present invention can be used to treat diseases such as constipation, anorexia, diabetes, glucose and lipid metabolism disorders such as non-alcoholic steatohepatitis.

[0039] The pharmaceutical composition of the present invention contains the compound of the present invention or its pharmacologically acceptable salt and a pharmacologically acceptable excipient or vector within a safe and effective amount. Here, "safe and effective amount" refers to an amount of the compound sufficient to significantly improve the condition without causing serious side effects. Usually, the pharmaceutical composition contains 1-2000 mg of the compound / agent of the present invention, more preferably 5-200 mg of the compound / agent of the present invention. Preferably, the "one agent" is one capsule or tablet.

[0040] "Pharmaceutically acceptable vector" refers to one or more compatible solid or liquid fillers or gel substances that must be suitable for human use, have sufficient purity and sufficiently low toxicity. "Compatibility" refers to the ability of each component of the composition to be blended with the compounds of the present invention and with each other without significantly reducing the efficacy of the compounds. Some examples of pharmaceutically acceptable vectors include cellulose and its derivatives (e.g., sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (e.g., stearic acid, magnesium stearate), calcium sulfate, vegetable oils (e.g., soybean oil, sesame oil, peanut oil, olive oil, etc.), polyols (e.g., propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifiers (e.g., Tween R), wetting agents (e.g., sodium dodecyl sulfate), colorants, flavorings, stabilizers, antioxidants, preservatives, pyrogen-free water, etc.

[0041] The mode of administration of the compounds or pharmaceutical compositions of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular, or subcutaneous), and topical administration.

[0042] 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 vector), such as, for example, sodium citrate or dicalcium phosphate, or with (a) fillers or compatibilizers, such as starch, lactose, sucrose, glucose, mannitol, and silicic acid, (b) binders, such as hydroxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and gum arabic, (c) humectants, such as glycerin, (d) agar, calcium carbonate, potato tempura, (e) glyceryl stearate, and (f) glyceryl stearate. The pharmaceutical composition is mixed with ingredients such as potato starch or tapioca starch, alginic acid, certain complex silicates, and disintegrating agents such as sodium carbonate, (e) retarders such as paraffin, (f) absorption promoters such as quaternary amine compounds, (g) wetting agents such as cetyl alcohol and glyceryl monostearate, (h) adsorbents such as kaolin, and (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium dodecyl sulfate, or mixtures thereof. In capsules, tablets, and pills, the dosage form may also include buffering agents.

[0043] Solid dosage forms such as tablets, sugar pills, capsules, pills and granules can be prepared with coating and shell materials, such as enteric coatings and other materials known in the art. They can contain opacifying agents, and the release of the active compound or compounds of such compositions can be delayed in a certain part of the digestive tract. Examples of embedding components that can be used are polymeric substances and waxes. If necessary, the active compound can be formed into microcapsules with one or more of the above-mentioned excipients.

[0044] Liquid dosage forms for oral administration include pharma- ceutically acceptable emulsions, solutions, suspensions, syrups, or tinctures. In addition to the active compound, the liquid dosage forms can contain inert diluents conventionally used in the art, such as water or other solvents, and solubilizers and emulsifiers, such as, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-butanediol, dimethylformamide, and oils, particularly cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, and sesame oil, or mixtures of these substances.

[0045] Besides these inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents. In addition to the active compound, suspensions may contain suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and dehydrated sorbitan esters, microcrystalline cellulose, aluminum methoxide, and agar-agar, or mixtures of these substances.

[0046] Compositions for parenteral injection can include 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 vehicles, diluents, solvents or excipients include water, ethanol, polyols and suitable mixtures thereof. The dosage forms of the compounds of the present invention used for topical administration include ointments, powders, patches, sprays and inhalants. The active ingredient is mixed under sterile conditions with a physiologically acceptable vector and any preservatives, buffers or propellants that may be required.

[0047] The compounds of the present invention can be administered alone or in combination with other pharma- ceutically acceptable compounds. The compounds according to the present invention can be clinically used in mammals, including humans and animals, through routes of administration such as the mouth, nose, skin, lungs, and gastrointestinal tract, more preferably through oral administration. The daily dosage is preferably 0.01-200 mg / kg body weight administered orally once, or 0.01-100 mg / kg body weight administered orally in batches. Regardless of the oral administration method, the optimal dose for an individual will vary depending on the specific treatment. Usually, starting with a small amount, the dosage is gradually increased until the optimal dose is found. Of course, the specific dosage should also take into account factors such as the route of administration, the health condition of the patient, and the like, all of which are within the skill of a skilled physician.

[0048] The present invention will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present invention and do not limit the scope of the present invention. In the following examples, the experimental methods without specific conditions are usually in accordance with conventional conditions or conditions suggested by manufacturers. Unless otherwise specified, percentages and parts are calculated by weight.

[0049] The present invention will be further described in the following examples. These examples are only used to illustrate the present invention, but do not limit the present invention in any way. All parameters and other descriptions in the examples are based on quality unless otherwise specified.

[0050] The analytical data of the samples are measured by the following instruments: nuclear magnetic resonance is measured by GEMINI-300, Bruker AMX-400 and INVOA-600 nuclear magnetic resonance instruments, TMS (tetramethylsilane) is the internal standard, the chemical shift unit is ppm, the coupling constant unit is Hz, and the mass spectrum is measured by Finnigan MAT-711, MAT-95 and LCQ-DECA mass spectrometers and IonSpec 4.7 Tesla mass spectrometer.

[0051] Column chromatography uses silica gel 200-300 mesh (manufactured by Qingdao Ocean Chemical Plant), TLC silica gel plate is HSGF-254 type prefabricated plate for thin layer chromatography manufactured by Yantai Chemical Plant, the boiling point range of petroleum ether is 60-90 ° C, and color is developed using ultraviolet lamp and element cylinder. Unless otherwise specified, conventional reagents and drugs used in the following examples are purchased from Sinopharm Group. All reagents and solvents used in the experiments are treated according to the specific conditions of the reaction.

[0052] Example A1: Synthesis of Compound A1 [ka] Synthesis Route: [ka]

[0053] Synthesis of compounds 1-3: Dissolve 1-1 in acetone, add potassium carbonate, add 1-2 dropwise, and stir overnight under reflux under argon gas protection. Filter the reaction mixture, evaporate to dryness, dilute with dichloromethane, add water and stir for 10 minutes, let stand to separate, and evaporate the organic layer to dryness to obtain a yellow solid 1-3, which is used directly in the next step without purification.

[0054] Synthesis of compounds 1-4: 1-3 was dissolved in nitromethane, added with ammonium acetate, refluxed for 2 hours, evaporated to dryness, added to ice water and stirred for 2 hours, allowed to stand, filtered, and the filter cake was washed with ethyl acetate to give a yellow solid, yield 90%. 1 H NMR (500 MHz, CDCl 3 )δ 7.95(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]+ .

[0055] Synthesis of compounds 1-5: Add lithium aluminum tetrahydride in batches to tetrahydrofuran under argon gas protection in an ice bath, add 1-4 in tetrahydrofuran solution dropwise while stirring, stir at room temperature for 2 hours after the dropwise addition is complete, add water slowly in an ice bath to quench the reaction, filter, wash the filter cake with ethyl acetate, methanol, evaporate to dryness to obtain a slightly yellow transparent oil, which is used directly in the next step without purification.

[0056] Synthesis of compound 2-3: Compounds 2-1 and 2-2 are dissolved in toluene and refluxed for 18 hours. After cooling, the solvent is evaporated to dryness and subjected to column chromatography (dichloromethane:methanol 100:1) to obtain a white solid, the yield is 85%. 1 H NMR (500 MHz, CDCl 3 )δ 9.49(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] + .

[0057] Synthesis of Compound 2-4: Compound 2-3 is dissolved in methanol, palladium hydroxide on carbon is added, and the mixture is reacted at 60° C. for 6 hours. The palladium on carbon is removed by suction filtration, and the solvent is spin-dried to obtain a white solid. The solid is used directly in the next reaction step without purification.

[0058] Synthesis of Compounds 2-5: Compound 2-4 is dissolved in methanol, 1M aqueous sodium hydroxide solution is added, and the mixture is reacted at 50°C for 2 hours. Most of the methanol is removed using a rotary evaporator, most of the impurities are washed away with dichloromethane, and the aqueous phase is adjusted to pH 1-2 with 1M hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layers are combined, dried over anhydrous sodium sulfate, and the solvent is spin-dried to obtain a white solid. It is used directly in the next step reaction.

[0059] Synthesis of compounds 3-6: Dissolve 2-5 in dichloromethane, add EDCI, HOBT, and TEA, stir for 30 minutes, slowly add the dichloromethane solution of 1-5, stir overnight, dilute with dichloromethane, wash successively with saturated sodium bicarbonate, saturated ammonium chloride, and saturated sodium chloride, dry with anhydrous sodium sulfate, evaporate to dryness, and purify by column chromatography with petroleum ether / ethyl acetate=1:1 to obtain 1.2g of a yellowish white solid, with a yield of 92%. 1 H NMR (500 MHz, CDCl 3 )δ 9.48(t,J=2.3Hz,1H),7.22(dd,J=8.4,2.0Hz,1H),7.04(dd,J=12.4,2.6Hz,2H ),6.87-6.81(m,1H),6.80-6.70(m,2H),6.66(dt,J=9.1,0.9Hz,2H),4.08(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] + .

[0060] Synthesis of compounds 3-7: 1g of compound 3-6 is dissolved in 100mL of anhydrous acetonitrile, phosphorus oxychloride is added, and the mixture is stirred at reflux under argon gas protection. After monitoring the completion of the reaction by TLC, the mixture is evaporated to dryness under reduced pressure, and ice-cold saturated sodium bicarbonate is added to make it weakly alkaline, extracted with dichloromethane, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain an orange oil, which is used directly in the next step reaction without purification.

[0061] Synthesis of compounds 3-8: Compound 3-7 was dissolved in methanol, sodium borohydride was added in batches under ice bath, and the mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated ammonium chloride solution, and the mixture was extracted with dichloromethane, washed with saturated sodium bicarbonate and saturated sodium chloride, and the organic layer was dried with anhydrous sodium sulfate, concentrated, and subjected to column chromatography (dichloromethane:methanol 20:1) to obtain a yellow solid, with a two-step yield of 70%. 1 H NMR (500 MHz, CDCl 3 )δ 9.74(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,5H),3.7 8(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] + .

[0062] Synthesis of compound A1: 3-8 100mg is dissolved in dichloromethane, morpholinoyl chloride and triethylamine are added, and the mixture is stirred at room temperature for 2 hours. After monitoring the completion of the reaction by TLC, saturated ammonium chloride is added, and the mixture is extracted with dichloromethane three times, and the organic phases are combined and washed with saturated sodium chloride. The mixture is dried with anhydrous sodium sulfate, and the solvent is evaporated to dryness, and then subjected to column chromatography (petroleum ether:ethyl acetate 1:1) to obtain a white solid A1, with a yield of 90%. 1 H NMR (500 MHz, CDCl 3 )δ 9.63(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=1.1H) z,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,1 H),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] + .

[0063] Example (S)-A1: Synthesis of compound (S)-A1 [ka] Dissolve 3-7 in a small amount of methanol, add deionized water, add (R,R)-Noyori catalyst, silver hexafluoroantimonate, lanthanum trifluoromethanesulfonate, and sodium formate dihydrate, stir overnight at room temperature under argon gas protection, extract with dichloromethane, wash with water, filter the organic layer through diatomaceous earth, concentrate, and subject to column chromatography with dichloromethane / methanol = 40:1 to obtain 4-8. Refer to the synthesis method of compound A1 to obtain compound (S)-A1. 1 H NMR (500 MHz, CDCl 3 )δ 9.63(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=1.1H) z,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,1 H),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] + .

[0064] Example (R)-A1: Synthesis of compound (R)-A1 [ka] The compound (R)-A1 is obtained by using the (S,S)-Noyori catalyst instead of the (R,R)-Noyori catalyst in the examples and referring to the synthesis method of the compound (S)-A1. 1 H NMR (500 MHz, CDCl 3)δ 9.63(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=1.1H) z,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,1 H),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] + .

[0065] Example A2: Synthesis of Compound A2 [ka] Compound 5-1 is used instead of morpholinoyl chloride in Example A1, and the synthesis method is similar to that of Compound A1 to obtain Compound A2. 1 H NMR (500 MHz, CDCl 3)δ 9.63(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] + .

[0066] Example A3: Synthesis of Compound A3 [ka] Compound 4-8 is dissolved in dichloromethane and saturated sodium bicarbonate is added. A solution of triphosgene in dichloromethane is added to the two-phase system. After reacting at room temperature for 1 hour, the dichloromethane phase is separated. The aqueous phase is extracted twice with dichloromethane. The solution is dried over anhydrous sodium sulfate. The solution is transferred to a one-mouth bottle, and 6-3 and diisopropylethylamine are added and reacted at room temperature overnight. After monitoring the completion of the reaction by TLC, saturated ammonium chloride is added, and the organic phase is combined and washed with saturated sodium chloride. The mixture is dried over anhydrous sodium sulfate, the solvent is evaporated to dryness, and subjected to column chromatography (petroleum ether:ethyl acetate 1:1) to obtain a white solid A3, with a yield of 90%. 1 H NMR (500 MHz, CDCl 3)δ 9.63(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,1H),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] + .

[0067] Example A4: Synthesis of Compound A4

change

[0068] Example A5: Synthesis of Compound A5

change

[0069] Example A6: Synthesis of Compound A6

change

[0070] Example A7: Synthesis of Compound A7

Chemical Structure

[0071] Example A8: Synthesis of Compound A8

Chem.

[0072] Example A9: Synthesis of Compound A9

Chem.

[0073] Example A10: Synthesis of Compound A10 [ka] Using compound 13-1 instead of morpholinoyl chloride in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A10. 1 H NMR (500MHz, DMSO-d 6)δ 9.43 (d, J = 1.5 Hz, 1H), 8.84 (d, J = 7.5 Hz, 1H), 7.72 (dd, J = 7.5, 1.6 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 1.8 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.82 (dd, J = 7.5, 1.5 Hz, 1H), 6.74 (d, J = 0.7 Hz, 1H), 6.60 (t, J = 1.0 Hz, 1H), 4.98 - 4.92 (m, 1H), 4.06 (qd, J = 8.0, 1.3 Hz, 2H), 3.84 - 3.75 (m, 8H), 2.91 (tt, J = 7.1, 0.8 Hz, 2H), 2.78 (dt, J = 12.3, 7.1 Hz, 1H), 2.70 (dt, J = 12.3, 7.0 Hz, 1H), 2.36 - 2.19 (m, 2H), 1.44 - 1.37 (m, 3H). ESI-MS m / z 487.2 [M+H] + 。

[0074] Example A11: Synthesis of Compound A11

Chemical Structure

[0075] Example A12: Synthesis of Compound A12 [ka] Compound 15-1 is used instead of morpholinoyl chloride in Example A1, and the synthesis method is similar to that of Compound A1 to obtain Compound A12. 1 H NMR (500MHz, DMSO-d 6 )δ 9.22(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),4.95(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] + .

[0076] Example A13: Synthesis of Compound A13 [ka] Use compound 16-1 instead of morpholinoyl chloride in Example A1, and refer to the synthesis method of compound A1 to obtain compound A13. 1 H NMR (500MHz, DMSO-d 6)δ 8.82 (dd, J = 7.5, 1.5 Hz, 1H), 8.13 (dd, J = 7.5, 1.5 Hz, 1H), 7.95 (t, J = 7.4 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 1.8 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.82 (dd, J = 7.5, 1.5 Hz, 1H), 6.74 (d, J = 0.6 Hz, 1H), 6.60 (d, J = 1.0 Hz, 1H), 4.95 (td, J = 6.9, 0.7 Hz, 1H), 4.06 (qd, J = 8.0, 1.3 Hz, 2H), 3.89 - 3.77 (m, 8H), 2.91 (tt, J = 7.1, 0.9 Hz, 2H), 2.78 (dt, J = 12.3, 7.1 Hz, 1H), 2.70 (dt, J = 12.2, 7.1 Hz, 1H), 2.36 - 2.19 (m, 2H), 1.44 - 1.37 (m, 3H). ESI-MS m / z 487.2 [M + H] + 。

[0077] Example A14: Synthesis of Compound A14

Chemical Structure

[0078] Example A15: Synthesis of Compound A15 [ka] Use compound 18-1 instead of morpholinoyl chloride in Example A1, and refer to the synthesis method of compound A1 to obtain compound A15. 1 H NMR (500MHz, DMSO-d 6 )δ 8.19(s,1H),8.15(d,J=8.2Hz,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=0.7Hz,1H),6.60(t,J=1.0Hz,1H),5.01-4.9 5(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] + .

[0079] Example A16: Synthesis of Compound A16 [ka] Using compound 19-1 instead of morpholinoyl chloride in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A16. 1 H NMR (500 MHz, CDCl 3) δ 9.52 (t, J = 2.4 Hz, 1H), 7.56 - 7.51 (m, 2H), 7.23 (dd, J = 8.4, 2.1 Hz, 1H), 7.09 (d, J = 2.6 Hz, 1H), 7.02 (d, J = 1.8 Hz, 1H), 6.95 (d, J = 0.9 Hz, 1H), 6.75 (dd, J = 8.4, 1.8 Hz, 1H), 6.64 (t, J = 1.0 Hz, 1H), 5.06 (td, J = 5.5, 1.1 Hz, 1H), 4.19 - 3.96 (m, 3H), 3.88 - 3.80 (m, 7H), 3.12 - 3.01 (m, 2H), 2.98 - 2.86 (m, 2H), 2.42 (dtd, J = 12.6, 7.3, 5.3 Hz, 1H), 2.29 (dtd, J = 12.6, 7.3, 5.4 Hz, 1H), 1.42 (t, J = 7.0 Hz, 3H). ESI-MS m / z 475.2 [M + H] + 。

[0080] Example A17: Synthesis of Compound A17

Chemical Structure

[0081] Example A18: Synthesis of Compound A18 [ka] Using compound 21-1 instead of morpholinoyl chloride in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A18. 1 H NMR (500MHz, DMSO-d 6 )δ 8.18(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=1.0Hz,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] + .

[0082] Example A19: Synthesis of Compound A19 [ka] Use compound 22-1 instead of morpholinoyl chloride in Example A1, and refer to the synthesis method of compound A1 to obtain compound A19. 1 H NMR (500MHz, DMSO-d 6)δ 8.34 (d, J = 7.5 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 1.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.82 (dd, J = 7.5, 1.5 Hz, 1H), 6.74 (s, 1H), 6.59 (t, J = 0.9 Hz, 1H), 4.89 - 4.83 (m, 1H), 4.08 (qd, J = 8.0, 4.6 Hz, 2H), 3.80 (d, J = 13.7 Hz, 5H), 3.72 (td, J = 7.0, 1.2 Hz, 2H), 2.91 (tt, J = 7.0, 0.8 Hz, 2H), 2.74 (qt, J = 12.5, 7.1 Hz, 2H), 2.35 - 2.19 (m, 2H), 1.40 (t, J = 8.0 Hz, 3H). ESI-MS m / z 476.2 [M+H] + 。

[0083] Example A20: Synthesis of Compound A20

Chemical Structure

[0084] Example A21: Synthesis of Compound A21 [ka] Compound 24-1 is used instead of morpholinoyl chloride in Example A1, and the synthesis method is similar to that of Compound A1 to obtain Compound A22. 1 H NMR (500MHz, DMSO-d 6 )δ 8.07(d,J=7.5Hz,1H),7.47(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),6.82(dd,J=7.5,1.5Hz,1H),6.74(d,J=0.6Hz,1H),6.59(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] + .

[0085] Example A22: Synthesis of Compound A22 [ka] Compound 25-1 is used instead of morpholinoyl chloride in Example A1, and the synthesis method is similar to that of Compound A1 to obtain Compound A22. 1 H NMR (500MHz, DMSO-d 6) δ 8.93 (d, J = 7.5 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 1.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.85 - 6.76 (m, 2H), 6.74 (d, J = 0.6 Hz, 1H), 6.60 (t, J = 1.0 Hz, 1H), 4.95 (td, J = 6.9, 0.6 Hz, 1H), 4.08 (qd, J = 8.0, 4.6 Hz, 2H), 3.87 - 3.77 (m, 7H), 2.91 (tt, J = 7.1, 0.9 Hz, 2H), 2.78 (dt, J = 12.3, 7.1 Hz, 1H), 2.72 (dt, J = 12.2, 7.1 Hz, 1H), 2.35 - 2.19 (m, 2H), 1.40 (t, J = 8.0 Hz, 3H). ESI-MS m / z 476.2 [M + H] + 。

[0086] Example A23: Synthesis of Compound A23

Chem.

[0087] Example A24: Synthesis of Compound A24

Chem.

[0088] Example A25: Synthesis of Compound A25 [ka] Use compound 28-1 instead of morpholinoyl chloride in Example A1, and refer to the synthesis method of compound A1 to obtain compound A25. 1 H NMR (500MHz, DMSO-d 6)δ 8.47 (dd, J = 7.5, 1.6 Hz, 1H), 7.72 (dd, J = 7.5, 1.5 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 1.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.82 (dd, J = 7.5, 1.5 Hz, 1H), 6.77 - 6.71 (m, 2H), 6.60 (t, J = 1.0 Hz, 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, 7.1 Hz, 1H), 2.91 (tt, J = 7.1, 0.9 Hz, 2H), 2.70 (dt, J = 12.4, 7.1 Hz, 1H), 2.35 - 2.18 (m, 2H), 1.40 (t, J = 8.0 Hz, 3H). ESI-MS m / z 475.2 [M + H] + 。

[0089] Example A26: Synthesis of Compound A26

Chemical Structure

[0090] Example A27: Synthesis of Compound A27 [ka] Use compound 30-1 instead of morpholinoyl chloride in Example A1, and refer to the synthesis method of compound A1 to obtain compound A27. 1 H NMR (500MHz, DMSO-d 6 )δ 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),6.7 5(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=7.9,4.4Hz,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] + .

[0091] Example A28: Synthesis of Compound A28 [ka] Using compound 31-1 instead of morpholinoyl chloride in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A28. 1 H NMR (500MHz, DMSO-d 6)δ 7.26 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 1.4 Hz, 1H), 7.09 (d, J = 8.4 Hz, 1H), 6.82 (dd, J = 7.5, 1.5 Hz, 1H), 6.75 (d, J = 0.6 Hz, 1H), 6.60 (t, J = 1.0 Hz, 1H), 4.90 - 4.84 (m, 1H), 4.08 (qd, J = 8.0, 2.9 Hz, 2H), 3.80 (d, J = 12.1 Hz, 7H), 3.57 (t, J = 7.1 Hz, 2H), 3.52 - 3.43 (m, 3H), 2.96 (dt, J = 12.3, 7.1 Hz, 1H), 2.91 (tt, J = 7.1, 0.9 Hz, 2H), 2.70 (dt, J = 12.4, 7.1 Hz, 1H), 2.37 - 2.19 (m, 2H), 1.93 (p, J = 7.1 Hz, 2H), 1.40 (t, J = 8.0 Hz, 3H). ESI-MS m / z 464.2 [M + H] + 。

[0092] Example A29: Synthesis of Compound A29

Chem.

[0093] Example A30: Synthesis of Compound A30 [ka] Using compound 1-6 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A30. 1 H NMR (500MHz, DMSO-d 6 )δ 7.42(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] + .

[0094] Example A31: Synthesis of Compound A31 [ka] Using compound 1-7 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A31. 1 H NMR (500MHz, DMSO-d 6)δ 7.26(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),3.55-3.43( 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] + .

[0095] Example A32: Synthesis of Compound A32 [ka] Using compound 1-8 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A32. 1 H NMR (500MHz, DMSO-d 6)δ 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=7.5,1.6Hz,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),3.5 3(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] + .

[0096] Example A33: Synthesis of Compound A33 [ka] Using compound 1-9 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A33. 1 H NMR (500MHz, DMSO-d 6)δ 7.26(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),6.59(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] + .

[0097] Example A34: Synthesis of Compound A34

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[0098] Example A35: Synthesis of Compound A35 [ka] Using compound 1-11 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A35. 1 H NMR (500MHz, DMSO-d 6 )δ 7.26(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=1.0 Hz,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] + .

[0099] Example A36: Synthesis of Compound A36 [ka] Using compound 1-12 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A36. 1 H NMR (500MHz, DMSO-d 6)δ 7.42(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,1 H),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=12.5,1.0Hz,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] + .

[0100] Example A37: Synthesis of Compound A37

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[0101] Example A38: Synthesis of Compound A38

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[0102] Example A39: Synthesis of Compound A39 [ka] Using compound 1-15 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A39. 1 H NMR (500MHz, DMSO-d 6 )δ 7.26(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] + .

[0103] Example A40: Synthesis of compound A40 [ka] Using compound 1-16 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A40. 1 H NMR (500MHz, DMSO-d 6 )δ 7.26(d,J=7.6Hz,1H),7.14(d,J=1.8Hz,1H),7.09(d,J=8.4Hz,1H),6.84-6.79(m,2 H),6.59(t,J=1.0Hz,1H),4.87(t,J=6.9Hz,1H),4.59(hept,J=6.8Hz,1H),3.83-3.7 4(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]+ .

[0104] Example A41: Synthesis of Compound A41 [ka] Using compound 1-17 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A41. 1 H NMR (500MHz, DMSO-d 6 )δ 7.26(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(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),1.32(d,J=6.8Hz,3H),1.27(d,J=6.8Hz,3H). ESI-MS m / z 508.3[M+H] + .

[0105] Example A42: Synthesis of Compound A42 [ka] Using compound 1-18 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A42. 1 H NMR (500MHz, DMSO-d 6)δ 7.26(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=1 2.5,7.1Hz,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] + .

[0106] Example A43: Synthesis of Compound A43

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[0107] Example A44: Synthesis of Compound A44

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[0108] Example A45: Synthesis of Compound A45 [ka] Compound 1-21 is used instead of 1-5 in Example A1, and the synthesis method is similar to that of Compound A1 to obtain Compound A45. 1 H NMR (500MHz, DMSO-d 6)δ 7.26(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),6.70(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 / z 524.3[M+H] + .

[0109] Example A46: Synthesis of Compound A46

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[0110] Example A47: Synthesis of compound A47 [ka] Using compound 1-23 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A47. 1 H NMR (500MHz, DMSO-d 6 )δ 7.26(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] + .

[0111] Example A48: Synthesis of compound A48 [ka] Using compound 1-24 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A48. 1 H NMR (500MHz, DMSO-d 6)δ 7.26(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),3.52-3.4 3(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] + .

[0112] Example A49: Synthesis of Compound A49

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[0113] Example A50: Synthesis of Compound A50

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[0114] Example A51: Synthesis of Compound A51 [ka] Using compound 1-27 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A51. 1 H NMR (500MHz, DMSO-d 6 )δ 7.26(d,J=7.6Hz,1H),7.14(d,J=1.4Hz,1H),7.12-7.06(m,2H),6.82(dd,J=7.5,1.6H z,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,4 H),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] + .

[0115] Example A52: Synthesis of Compound A52 [ka] Using compound 1-28 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A52. 1 H NMR (500MHz, DMSO-d 6 )δ 7.26(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,7 H),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] + .

[0116] Example A53: Synthesis of Compound A53 [ka] Using compound 1-29 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A53. 1 H NMR (500MHz, DMSO-d 6)δ 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=7.5,1.5Hz,1H),6.75(d,J=0.6Hz,1 H),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=12.4,7.0Hz,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] + .

[0117] Example A54: Synthesis of Compound A54

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[0118] Example A55: Synthesis of Compound A55 [ka] Using compound 2-7 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A55. 1 H NMR (500MHz, DMSO-d 6 )δ 7.26(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=12 .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] + .

[0119] Example A56: Synthesis of Compound A56 [ka] Using compound 2-8 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A56. 1 H NMR (500MHz, DMSO-d 6)δ 7.26(d,J=7.6Hz,1H),7.17-7.13(m,1H),7.10(d,J=8.4Hz,1H),6.82(dd,J=7.4,1.5 Hz,1H),6.74(d,J=0.7Hz,1H),6.59(t,J=1.0Hz,1H),4.90-4.83(m,1H),4.06(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),2.97-2.86 (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] + .

[0120] Example A57: Synthesis of Compound A57

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[0121] Example A58: Synthesis of Compound A58

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[0122] Example A59: Synthesis of Compound A59 [ka] Using compound 2-11 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A59. 1 H NMR (500MHz, DMSO-d 6 )δ 7.29(s,1H),7.07(d,J=8.4Hz,1H),6.81(s,1H),6.74(d,J=0.7Hz,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] + .

[0123] Example A60: Synthesis of compound A60 [ka] Using compound 2-12 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A60. 1 H NMR (500MHz, DMSO-d 6 )δ 7.48(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] + .

[0124] Example A61: Synthesis of Compound A61 [ka] Using compound 2-13 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A61. 1 H NMR (500MHz, DMSO-d 6)δ 7.74-7.70(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] + .

[0125] Example A62: Synthesis of Compound A62

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[0126] Example A63: Synthesis of Compound A63

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[0127] Example A64: Synthesis of compound A64 [ka] Using compound 2-16 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A64. 1 H NMR (500MHz, DMSO-d 6 )δ 7.37(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),3.02-2.9 4(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] +.

[0128] Example A65: Synthesis of Compound A65 [ka] Using compound 2-17 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A65. 1 H NMR (500MHz, DMSO-d 6 )δ 9.72(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,2H),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),3.02-2.94 (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] + .

[0129] Example A66: Synthesis of Compound A66 [ka] Using compound 2-18 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A66. 1 H NMR (500MHz, DMSO-d 6)δ 7.69-7.63(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] + .

[0130] Example A67: Synthesis of Compound A67

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[0131] Example A68: Synthesis of Compound A68 [ka] Using compound 2-20 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A68. 1 H NMR (500MHz, DMSO-d 6 )δ 7.91(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),3.83-3.73( 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] + .

[0132] Example A69: Synthesis of Compound A69 [ka] Using compound 2-21 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A69. 1 H NMR (500MHz, DMSO-d 6)δ 9.94(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=7.5Hz,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] + .

[0133] Example A70: Synthesis of Compound A70

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[0134] Example A71: Synthesis of Compound A71 [ka] Using compound 2-23 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A71. 1 H NMR (500MHz, DMSO-d 6 )δ 6.94(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] + .

[0135] Example A72: Synthesis of Compound A72 [ka] Using compound 2-24 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A72. 1 H NMR (500MHz, DMSO-d 6)δ 8.51-8.46(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] + .

[0136] Example A73: Synthesis of Compound A73

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[0137] Example A74: Synthesis of Compound A74

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[0138] Example A75: Synthesis of Compound A75

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[0139] Example A76: Synthesis of Compound A76 [ka] Use iodomethane instead of 1-2 in Example (S)-A1, use compound 2-28 instead of 2-5 in Example (S)-A1, and use compound 33-1 instead of morpholinoyl chloride in Example (S)-A1. The synthesis method is similar to that of compound (S)-A1 to obtain compound A76. 1 H NMR(500MHz,Chloroform-d)δ 9.91(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),3.69(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] +

[0140] Example A77: Synthesis of Compound A77 [ka] Use iodomethane instead of 1-2 in Example A1, use compound 2-29 instead of 2-5 in Example A1, use compound 10-1 instead of morpholinoyl chloride in Example A1, and refer to compound A1 for the synthesis method to obtain compound A77. 11H NMR (500 MHz, Chloroform-d) δ 9.94 (d, J = 8.4 Hz, 1H), 8.70 - 8.65 (m, 2H), 7.78 - 7.73 (m, 2H), 7.60 (dd, J = 7.3, 1.6 Hz, 1H), 7.36 (dd, J = 7.4, 1.7 Hz, 1H), 7.18 - 7.12 (m, 2H), 7.09 (td, J = 7.4, 1.5 Hz, 1H), 6.82 (s, 1H), 6.58 (t, J = 1.0 Hz, 1H), 4.93 - 4.86 (m, 1H), 3.84 (d, J = 4.4 Hz, 6H), 3.75 - 3.63 (m, 2H), 3.18 (dt, J = 12.2, 7.1 Hz, 1H), 3.02 (dt, J = 12.5, 7.1 Hz, 1H), 2.90 (td, J = 7.0, 0.9 Hz, 2H), 2.35 - 2.18 (m, 2H). ESI-MS m / z 442.2 [M+H] + 。

[0141] Example A80: Synthesis of Compound A80

Chem.

[0142] Example A83: Synthesis of Compound A83 [ka] Use iodomethane instead of 1-2 in Example A1, use compound 2-32 instead of 2-5 in Example A1, and 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 for 5 hours under argon gas protection. Cool, evaporate the solvent to dryness, dilute with dichloromethane, and wash twice with saturated ammonium chloride and sodium chloride. Combine the organic phases, dry with anhydrous sodium sulfate, spin-dry the solvent, and then perform column chromatography (petroleum ether: ethyl acetate 1:1) to obtain an off-white solid, with a yield of 90%. Obtain compound A83. 1 H NMR(500MHz,Chloroform-d)δ 7.62(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(dt,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] + .

[0143] Example A84: Synthesis of compound A84 [ka] Using compound 36-1 instead of morpholinoyl chloride in Example A1, the synthesis method is similar to that of compound A83 to obtain compound A84. 1 H NMR (500MHz, DMSO-d 6 )δ 7.25(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=4.0 Hz,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] + .

[0144] Example A85: Synthesis of Compound A85 [ka] Use compound 37-1 instead of morpholinoyl chloride in Example A1, and refer to the synthesis method of compound A1 to obtain compound A85. 1 H NMR (500MHz, DMSO-d 6 )δ 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,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),3.84-3.80(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] + .

[0145] Example A86: Synthesis of compound A86 [ka] Using compound 38-1 instead of morpholinoyl chloride in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A86. 1 H NMR (500MHz, DMSO-d 6 )δ 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),4.92-4.86(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] + .

[0146] Example A87: Synthesis of compound A87 [ka] Use compound 39-1 instead of morpholinoyl chloride in Example A1, and refer to the synthesis method of compound A1 to obtain compound A87. 1 H NMR (500MHz, DMSO-d 6) δ 7.25 (d, J = 7.4 Hz, 1H), 7.13 - 7.08 (m, 2H), 6.82 (dd, J = 7.3, 2.0 Hz, 1H), 6.74 (s, 1H), 6.61 (t, J = 1.0 Hz, 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, 1.0 Hz, 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 = 6.3 Hz, 3H). ESI-MS m / z 520.3 [M + H] + 。

[0147] Example A88: Synthesis of Compound A88

Chem.

[0148] Example A89: Synthesis of Compound A89

Chem.

[0149] Example A90: Synthesis of compound A90 [ka] Using compound 41-1 instead of morpholinoyl chloride in Example A1, the synthesis method is similar to that of compound A83 to obtain compound A90. 1 H NMR (500MHz, DMSO-d 6) δ 7.25 (d, J = 7.4 Hz, 1H), 7.13 - 7.08 (m, 2H), 6.82 (dd, J = 7.3, 2.0 Hz, 1H), 6.74 (s, 1H), 6.61 (t, J = 1.0 Hz, 1H), 4.66 - 4.59 (m, 1H), 4.56 (d, J = 1.0 Hz, 2H), 4.11 (q, J = 6.2 Hz, 2H), 3.83 (d, J = 4.0 Hz, 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 = 6.3 Hz, 3H). ESI-MS m / z 492.3 [M + H] + 。

[0150] Example A96: Synthesis of Compound A96

Chem.

[0151] Example A97: Synthesis of Compound A97

Chem.

[0152] Example A98: Synthesis of Compound A98 [ka] Using compound 49-1 instead of morpholinoyl chloride in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A98. 1 H NMR (500MHz, DMSO-d 6)δ 7.25 (d, J = 7.4 Hz, 1H), 7.13 - 7.08 (m, 2H), 6.82 (dd, J = 7.3, 2.0 Hz, 1H), 6.74 (s, 1H), 6.61 (t, J = 1.0 Hz, 1H), 4.83 (t, J = 6.1 Hz, 1H), 4.11 (q, J = 6.2 Hz, 2H), 3.91 (m, 1H), 3.83 (d, J = 4.0 Hz, 6H), 3.76 - 3.66 (m, 5H), 3.60 (dt, J = 12.3, 4.6 Hz, 2H), 3.51 - 3.43 (m, 2H), 2.94 - 2.83 (m, 2H), 2.69 (td, J = 7.8, 2.5 Hz, 2H), 2.21 - 2.04 (m, 2H), 1.41 (t, J = 6.2 Hz, 3H). ESI-MS m / z 518.3 [M + H] + 。

[0153] Example A99: Synthesis of Compound A99

Chem.

[0154] Example A100: Synthesis of Compound A100

Chem.

[0155] Example A101: Synthesis of Compound A101 [ka] Using compound 52-1 instead of morpholinoyl chloride in Example A1, the synthesis method is similar to that of compound A83 to obtain compound A101. 1 H NMR (500MHz, DMSO-d 6)δ 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),4.92-4.86(m,1H),4.24(d,J=5.0Hz,1H),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(p,J=4.9Hz,1H),3.53(m,2H),3.35(m,2H),2.92(td,J=5.6,1.0H z,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] + .

[0156] Example A102: Synthesis of Compound A102

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[0157] Example A103: Synthesis of Compound A103

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[0158] Example A104: Synthesis of compound A104 [ka] Using compound 1-32 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A104. 1 H NMR (500MHz, DMSO-d 6 )δ 7.84(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),3.27 -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] + .

[0159] Example A105: Synthesis of compound A105 [ka] Using compound 1-33 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A105. 1 H NMR (500MHz, DMSO-d 6 )δ 7.81(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=4.8Hz,0H),3 .89(s,1H),3.82(s,1H),3.75(dt,J=12.5,5.5Hz,0H),3.64-3.57(m,2H),3.27-3.13 (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 687.3[M+H] + .

[0160] Example A106: Synthesis of compound A106 [ka] Using compound 1-34 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A106. 1 H NMR (500MHz, DMSO-d 6 )δ 7.28-7.22(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] + .

[0161] Example A107: Synthesis of compound A107 [ka] Using compound 1-35 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A107. 1 H NMR (500MHz, DMSO-d 6 )δ 7.25(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] + .

[0162] Example A108: Synthesis of compound A108 [ka] Using compound 1-36 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A108. 1 H NMR (500MHz, DMSO-d 6)δ 7.52(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),4.4 9(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] + .

[0163] Example A109: Synthesis of Compound A109

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[0164] Example A110: Synthesis of Compound A110

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[0165] Example A111: Synthesis of Compound A111 [ka] Compound 1-39 is used instead of 1-5 in Example A1, and the synthesis method is similar to that of Compound A1 to obtain Compound A111. 1 H NMR (500MHz, DMSO-d 6)δ 7.25(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] + .

[0166] Example A112: Synthesis of Compound A112

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[0167] Example A113: Synthesis of Compound A113 [ka] Using compound 1-41 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A113. 1 H NMR (500MHz, DMSO-d 6 )δ 7.25(d,J=7.4Hz,1H),7.13-7.08(m,2H),6.82(dd,J=7.3,2.0Hz,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] + .

[0168] Example A114: Synthesis of compound A114 [ka] Using compound 1-42 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A114. 1 H NMR (500MHz, DMSO-d 6 )δ 7.25(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,5 H),3.79-3.71(m,1H),3.65-3.55(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). ESI-MS m / z 537.3[M+H] + .

[0169] Example A115: Synthesis of compound A115 [ka] Using compound 1-43 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A115. 1 H NMR (500MHz, DMSO-d 6 )δ 7.25(d,J=7.4Hz,1H),7.13-7.08(m,2H),6.82(dd,J=7.3,2.0Hz,1H),6.76(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=5.5,1.0 Hz,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] + .

[0170] Example A116: Synthesis of compound A116 [ka] Using compound 1-44 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A116. 1 H NMR (500MHz, DMSO-d 6)δ 7.25(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=2.0H z,6H),3.79-3.71(m,1H),3.65-3.55(m,4H),3.36(d,J=6.2Hz,0H),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 504.2[M+H] + .

[0171] Example A117: Synthesis of Compound A117

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[0172] Example A118: Synthesis of Compound A118

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[0173] Example A119: Synthesis of compound A119 [ka] Using compound 2-33 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A119. 1 H NMR (500MHz, DMSO-d 6 )δ 7.49(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,1H),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] + .

[0174] Example A120: Synthesis of compound A120 [ka] Using compound 2-34 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A120. 1 H NMR (500MHz, DMSO-d 6 )δ 7.84(t,J=1.2Hz,1H),7.53(d,J=1.3Hz,2H),6.74(s,1H),6.61(t,J=1.0Hz,1 H),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 543.2[M+H] + .

[0175] Example A121: Synthesis of compound A121 [ka] Using compound 2-35 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A121. 1 H NMR (500MHz, DMSO-d 6)δ 7.54(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,2 H),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] + .

[0176] Example A122: Synthesis of Compound A122

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[0177] Example A123: Synthesis of Compound A123

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[0178] Example A124: Synthesis of compound A124 [ka] Using compound 2-38 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A124. 1 H NMR (500MHz, DMSO-d 6 )δ 7.77-7.73(m,1H),7.66(d,J=7.9Hz,1H),7.49(dd,J=7.9,2.0Hz,1H),7.43(s,1H),6.7 4(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] + .

[0179] Example A125: Synthesis of compound A125 [ka] Using compound 2-39 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A125. 1 H NMR (500MHz, DMSO-d 6 )δ 7.91(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),3.92-3.84( 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),2.77(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] + .

[0180] Example A126: Synthesis of compound A126 [ka] Using compound 2-40 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A126. 1 H NMR (500MHz, DMSO-d 6)δ 7.76(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),3.92-3.85(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] + .

[0181] Example A127: Synthesis of Compound A127

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[0182] Example A128: Synthesis of Compound A128

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[0183] Example A129: Synthesis of compound A129 [ka] Using compound 2-43 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A129. 1 H NMR (500MHz, DMSO-d 6 )δ 7.33-7.26(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] + .

[0184] Example A130: Synthesis of compound A130 [ka] Using compound 2-44 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A130. 1 H NMR (500MHz, DMSO-d 6 )δ 9.91(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] + .

[0185] Example A131: Synthesis of compound A131 [ka] Using compound 2-45 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A131. 1 H NMR (500MHz, DMSO-d 6 )δ 7.31-7.24(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,2 H),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] + .

[0186] Example A132: Synthesis of compound A132 [ka] Using compound 2-46 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A132. 1 H NMR (500MHz, DMSO-d 6 )δ 7.30(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),6.7 4(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),4.1 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=5.6,1.0Hz,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] + .

[0187] Example A133: Synthesis of compound A133 [ka] Using compound 2-47 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A133. 1 H NMR (500MHz, DMSO-d 6)δ 7.25(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(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 479.3[M+H] + .

[0188] Example A134: Synthesis of Compound A134

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[0189] Example A135: Synthesis of Compound A135

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[0190] Example A136: Synthesis of compound A136 [ka] Using compound 2-50 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A136. 1 H NMR (500MHz, DMSO-d 6 )δ 8.38(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] + .

[0191] Example A137: Synthesis of compound A137 [ka] Using compound 2-51 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A137. 1 H NMR (500MHz, DMSO-d 6 )δ 8.41(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=7.1 Hz,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),3.83(s,2H),3.79-3.71(m,1H),3.65-3.57(m,4H),3.27-3.13(m,4H),2.9 2(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] + .

[0192] Example A138: Synthesis of compound A138 [ka] Using compound 2-52 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A138. 1 H NMR (500MHz, DMSO-d 6)δ 9.45(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,2 H),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] + .

[0193] Example A139: Synthesis of Compound A139

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[0194] Example A140: Synthesis of Compound A140 [ka] Using compound 2-54 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A140. 1 H NMR (500MHz, DMSO-d 6 )δ 9.48(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] + .

[0195] Example A141: Synthesis of compound A141 [ka] Using compound 2-55 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A141. 1 H NMR (500MHz, DMSO-d 6)δ 9.98(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] + .

[0196] Example A142: Synthesis of Compound A142

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[0197] Example A143: Synthesis of Compound A143

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[0198] Example A144: Synthesis of compound A144 [ka] Using compound 2-58 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A144. 1 H NMR (500MHz, DMSO-d 6)δ 9.98(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),3.65-3.55(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] + .

[0199] Example A145: Synthesis of Compound A145

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[0200] Example A146: Synthesis of compound A146 [ka] Using compound 2-60 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A146. 1 H NMR (500MHz, DMSO-d 6 )δ 9.15(s,1H),7.01(d,J=7.3Hz,1H),6.95(d,J=2.3Hz,1H),6.74(s,1H),6.61(t,J=1.0H z,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] + .

[0201] Example A147: Synthesis of compound A147 [ka] Using compound 2-61 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A147. 1 H NMR (500MHz, DMSO-d 6)δ 8.65(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] + .

[0202] Example A148: Synthesis of Compound A148

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[0203] Example A149: Synthesis of Compound A149

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[0204] Example A150: Synthesis of compound A150 [ka] Using compound 2-64 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A150. 1 H NMR (500MHz, DMSO-d 6)δ 9.73(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=6.2Hz,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] + .

[0205] Example A151: Synthesis of Compound A151

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[0206] Example A152: Synthesis of Compound A152

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[0207] Example A153: Synthesis of compound A153 [ka] Using compound 2-67 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A153. 1 H NMR (500MHz, DMSO-d 6 )δ 7.63(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] + .

[0208] Example A154: Synthesis of compound A154 [ka] Using compound 2-68 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A154. 1 H NMR (500MHz, DMSO-d 6 )δ 9.95(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=7.7H z,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),4.11(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,4 H),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] + .

[0209] Example A155: Synthesis of compound A155 [ka] Using compound 2-69 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A155. 1 H NMR (500MHz, DMSO-d 6)δ 7.37(m,2H),7.12(d,J=7.0Hz,1H),7.07(m,1H),6.74(s,1H),6.61(t,J=1.0 Hz,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] + .

[0210] Example A156: Synthesis of Compound A156

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[0211] Example A157: Synthesis of Compound A157

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[0212] Example A158: Synthesis of compound A158 [ka] Using compound 2-72 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A158. 1 H NMR (500MHz, DMSO-d 6)δ 7.29(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,2 H),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] + .

[0213] Example A159: Synthesis of Compound A159

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[0214] Example A160: Synthesis of compound A160 [ka] Using compound 2-74 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A160. 1 H NMR (500MHz, DMSO-d 6 )δ 7.25(d,J=7.3Hz,1H),7.15-7.10(m,2H),6.82(dd,J=7.3,2.0Hz,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=6.2Hz,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] + .

[0215] Example A161: Synthesis of compound A161 [ka] Using compound 2-75 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A161. 1 H NMR (500MHz, DMSO-d 6)δ 9.18(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,1 H),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] + .

[0216] Example A162: Synthesis of Compound A162

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[0217] Example A163: Synthesis of Compound A163

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[0218] Example A164: Synthesis of compound A164 [ka] Using compound 2-78 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A164. 1 H NMR (500MHz, DMSO-d 6 )δ 9.44(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] + .

[0219] Example A165: Synthesis of compound A165 [ka] Using compound 2-79 instead of 2-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A165. 1 H NMR (500MHz, DMSO-d 6)δ 9.01(d,J=6.7Hz,1H),7.37(d,J=6.7Hz,1H),7.27(d,J=7.3Hz,1H),7.14(d,J=2.1Hz,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),4.1 1(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] + .

[0220] Example A166: Synthesis of Compound A166

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[0221] Example A167: Synthesis of Compound A167 [ka] Using compound 1-48 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A167. 1 H NMR (500MHz, DMSO-d 6 )δ 7.25(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=6.2Hz,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] + .

[0222] Example A168: Synthesis of compound A168 [ka] Using compound 1-49 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A168. 1 H NMR (500MHz, DMSO-d 6)δ 7.25(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=6.1Hz,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] + .

[0223] Example A169: Synthesis of Compound A169

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[0224] Example A170: Synthesis of Compound A170

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[0225] Example A171: Synthesis of compound A171 [ka] Using compound 1-52 instead of 1-5 in Example A1, the synthesis method is similar to that of compound A1 to obtain compound A171. 1 H NMR (500MHz, DMSO-d 6 )δ 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=1.1Hz,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(dq ,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] + .

[0226] Biological activity test 1. Detection method: Measurement of intracellular cAMP concentration 1.1. Test materials and equipment cAMP detection kit (PerkinElmer), cell incubator (Thermo Fisher Scientific), EnVision multifunction microplate reader (PerkinElmer), Forskolin (Sigma-Aldrich), IBMX (Sigma-Aldrich), DSMO (Sigma-Aldrich), hINSL5 (Genova, human insulin-like peptide 5), hRXFP4-CHO stably transfected cell line stably expressing human RXFP4, and test compounds.

[0227] 1.2. Test Method Stably transduced hRXFP4-CHO cells were cultured at 2.5 × 10 5 Inoculate cells at 1000 cells / mL, so that the cells in the culture dish reach a growth density of 70%-80% the next day. On the day of the experiment, use trypsin-free digestion solution or 0.02% EDTA in PBS solution to digest the cells, discard the supernatant after centrifuging the cells, and use 1x HBSS (calcium and magnesium-free) solution to prepare cAMP experiment buffer (0.5mM IBMX+5mM HEPES+0.1% BSA). Resuspend the cells and inoculate them into a 384-well plate at 4000 cells / well, dilute the compounds to different concentrations using DMSO, then add them to the above 384-well plate, add 500nM Forskolin at the same time, and incubate at room temperature for 40 minutes, then add Eu-cAMP and ULight-anti-cAMP working solutions according to the instructions of the cAMP detection kit, respectively, and read them using an EnVision multifunctional microplate reader after incubating at room temperature for 40 minutes (excitation light wavelength is 320 or 340nm, detection emission light is 665nm).

[0228] 1.3.Test Results The results of the in vitro RXFP4 agonist activity test of the compounds are shown in Table 1. Table 1. Results of in vitro RXFP4 agonist activity testing of compounds [Table 1]

[0229] 2. Detection method: Ligand-receptor affinity detection 2.1. Test materials and equipment Stably transfected cells with hRXFP4-CHO and Eu-R 3 / I5 (Lanthanide europium-labeled chimeric peptide R 3 / I5), a BMG POLARstar plate reader (BMG Labtech) and test compounds.

[0230] 2.2. Test Method hRXFP4-CHO was seeded into a 96-well plate at 80,000 cells / well, and cultured in a cell incubator for 24 hours. The supernatant was discarded, and the plate was washed once with PBS. A binding buffer containing 1% BSA was added, and the plate was incubated at room temperature for 1 hour. The plate was washed once with PBS, and then the positive control, test compound and 5 nM Eu-R at different concentrations were added. 3 Add / I5 and incubate together at room temperature for 1 hour. Wash the cell plate once with PBS, then add enhancement solution, and measure the fluorescence value after 45 minutes using a BMG POLARstar plate reader (excitation light wavelength is 340 nm, detection emission light is 614 nm).

[0231] 2.3.Test Results The results of the in vitro ligand receptor affinity test of the compounds are shown in Table 2. Table 2. Results of in vitro ligand-receptor affinity testing of compounds. [Table 2]

[0232] In vivo Pharmacodynamic Evaluation of Compounds Promoting intestinal peristalsis in mice with constipation 1. Experimental Reagents, Equipment, and Animals 1.1. Experimental materials Samopride 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 Scientifi), anti-AQP3 antibody, goat anti-rabbit IgG H&L (Alexa FluorR 488), goat anti-mouse IgG H&L (Alexa FluorR 488) (Abcam), mouse VIP ELISA kit (LSBio), mouse 5-HT ELISA kit (mlbio).

[0233] 1.2.Experimental Equipment FORMA700 ultra-low temperature refrigerator (Thermo Fisher Scientific), YC-300L drug storage cabinet (Zhongke Meiling Cryogenics Company Limited), Direct-Q with pump ultrapure water meter (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 Dichuang Technology Development Co., Ltd.), Y-3102 mouse metabolic cage (Shanghai YUYAN Scientific Instrument Co., Ltd.), paraffin embedding machine, microtome (LEICA), Olympus inverted phase contrast microscope (Olympus); Zeiss LSM laser confocal microscope (Zeiss, Germany), Berthold LB941 microplate multifunction microplate reader (Berthold).

[0234] 1.3. Laboratory animals SPF grade ICR mice, male, 6-8 weeks old, weighing 20±2g, provided by Changzhou Cavens Laboratory Animal Co., Ltd., Animal Certificate Number: SCXK(Su)2022-0010, were kept in an SPF grade environment, the indoor temperature was controlled at 22±2°C, and food and water were available ad libitum.

[0235] 2. Animal Models and Dosing Regimen 2.1. Construction of mouse model The ICR mice were raised in an SPF-grade animal room, and the environmental conditions were controlled at 20°C to 26°C and relative humidity 40% to 70%, and they were exposed to 12 hours of light and dark with alternating light and dark. They were allowed to eat and drink freely. After one week of adaptive feeding, the mice in the model group were intragastrically administered 3 mg / kg loperamide, with the intragastric dose being 0.1 mL / 10 g, once a day for five consecutive days, and the mice in the normal control group were intragastrically administered an equal amount of saline every day.

[0236] 2.2. Experimental Grouping Control group: Mice were intragastrically administered an equal amount of saline once a day for 7 consecutive days (n=8). Model group: After the establishment of the mouse constipation model, an equal amount of saline was administered intragastrically once a day for 7 consecutive days (n=8). Positive control group: After establishing the mouse constipation model, 10 mg / kg of Mosapride Citrate was administered intragastrically at a dose of 0.1 mL / 10 g once a day for 7 consecutive days (n=8). Experimental group: After establishing the mouse constipation model, the mice in the experimental group were divided into three groups, and compound (S)-A1 was administered intragastrically at 1 mg / kg, 5 mg / kg, and 25 mg / kg at a dose of 0.1 ml / 10 g once a day for 7 consecutive days (n=8 in each group).

[0237] 3. Detection Indicators and Methods After the modeling and the last administration, the mice of each group were placed in metabolic cages and allowed to move freely for 1 hour. The feces of the mice were collected, and the weight, number, hardness, and water content were calculated. The effect of the compound on the colon function of the mice was evaluated through the bead excretion experiment. After the bead excretion experiment was completed, the mice were euthanized by CO2 method, and the colon tissue (the colon tissue with a length of about 2 cm near the anus) was collected. HE staining was used to observe the morphological changes of the mouse colon, and the thickness of the colon muscle layer, the thickness of the mucosa, the number of goblet cells and Libeco's gland were statistically obtained. Blood was collected, and the kit was used to detect the nitric oxide (NO), serotonin (5-HT), and vasoactive intestinal peptide (VIP) levels in the mouse serum. Immunohistochemistry experiments were performed 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 mouse colon tissue.

[0238] 3.1. Detection of Fecal Moisture Content Each group of mice was placed in a metabolic cage and allowed to move freely for 2 hours. The feces of the mice were collected in a dry EP tube, weighed, and the wet weight of the feces was recorded. The feces were then placed in a drying box, set at 50°C and baked for 4 hours, after which they were taken out and weighed. Then they were placed in the drying box again, and weighed once every 2 hours. If the weight of the feces did not change, the dry weight of the feces was calculated. The formula for the moisture content of the feces was: Fecal moisture content (%) = [(wet weight of feces - dry weight of feces) / wet weight of feces] × 100%.

[0239] 3.2.Bead excretion experiment After anesthetizing the mouse using a small animal anesthesia machine, insert a glass bead with a diameter of 1.5 mm into the terminal colon approximately 3 cm away from the anal opening. After the glass bead is inserted into the terminal colon of the mouse, place the mouse in a separate cage, and record the time from when the mouse wakes up to when the glass bead is excreted as the bead excretion time.

[0240] 3.3.HE staining 1) Grill slices: Place the prepared tissue paraffin slices in an electric thermostatic drying oven and bake at 60°C for 3 hours. 2) Dried paraffin sections were deparaffinized in conventional xylene, hydrated in descending gradients of ethanol, and washed in distilled water; 3) Stain the nuclei with hematoxylin for 2 minutes, then stain with hydrochloric acid and alcohol for a few seconds, and wash with water until the nuclei return to a blue color. 4) Stain with eosin dye for 1 minute, then wash with water to remove residual dye. 5) The sections were dehydrated through graded alcohols and dried, cleared in xylene, and sealed in neutral gum. 6) Using a phase contrast microscope, one field is randomly selected and photographed at 400x magnification.

[0241] 3.4. Immunohistofluorescence 1) Wash paraffin sections of mouse colon tissue with PBS for 5 minutes three times. 2) Wipe off the liquid around the sectioned tissue and use an immunohistochemistry pen to draw a circle 2 mm away from the tissue to prevent dilution of the various liquid components that will be added later. 3) Incubate in 0.4% Trion X-100 at room temperature for 10 minutes, wash with PBS for 5 minutes x 3 times, 4) Repair the antigen (1.5 minutes after the pressure limiting valve of the high pressure cooker releases air, cool the water to reduce the pressure). After natural cooling, wash with PBS for 5 minutes x 3 times, 5) Sealed with 5% sheep serum at 37°C for 10 minutes; 6) Discard the serum, drop the primary antibody (see Table 1 for specific primary antibodies and their dilutions), place in a humid box, and react overnight at 4°C. 7) Remove the antibody reaction solution by aspiration, wash with PBS for 5 minutes x 3 times, 8) Add fluorescently labeled secondary antibody (see Table 1 for dilution rates) and incubate in a humidified box at 37°C in the dark for 1-2 hours. 9) Remove the antibody reaction solution by aspiration, wash with PBS for 5 minutes x 3 times, 10) Place the 90% glycerin sealed slide in a light-proof box. 11) Observe under a laser confocal microscope at a magnification of 630x and take photographs. Table 3. Antibodies and their dilutions [Table 3]

[0242] 3.4. Detection of NO content Serum: Take 100 μL of serum stock solution, add 200 μL of Reagent 1, mix evenly, add 100 μL of Reagent 2, vortex to mix completely and evenly, leave for 10 minutes, centrifuge at 3500-4000 rpm / min for 15 minutes, and take 160 μL of supernatant. Operation sheet [Table 4]

[0243] Preparation of standard curve Dilute the 2mmol / L sodium nitrite standard solution with double distilled water to 1:39, 1:79, 1:99, 1:159, 1:319, and 1:39, that is, the concentrations of the sodium nitrite standard solution are 0.05mm, 0.025mm, 0.02mm, 0.0125mm, 0.00625mm, and 0.003125mm, respectively. Operation sheet [Table 5]

[0244] 3.5. ELISA detection of serum VIP content 1) Equilibrate all reagents and samples to room temperature and mix thoroughly (avoid foaming) and prepare all reagents, working solutions, controls and samples; 2) Add 50 μL of standard, blank or sample to each well. The concentrations of the standard are 6.173, 18.52, 55.57, 166.7, and 500 pg / mL, respectively. 3) Immediately add 50 μL of Detection Reagent A Working Solution to each well, cover the plate, gently swirl to ensure complete mixing, and incubate at 37°C for 1 hour. 4) Aspirate the liquid from each well and wash three times. Using a spray bottle, multichannel pipette or automatic washer, add approximately 350 μL of wash buffer and wash. Leave for 1-2 minutes after each wash, aspirate the remaining wash buffer after the last wash, then invert the wash plate and dab the excess liquid dry with absorbent paper. 5) Add 100 μL of Detection Reagent B Working Solution to each well, gently swirl to thoroughly mix, cover with fresh plate sealant, and incubate at 37°C for 30 minutes. 6) Aspirate the liquid from each well and wash five times as described in step 4; 7) Add 90 μL of TMB substrate solution to each well, gently swirl to mix thoroughly, cover with new plate sealant, and incubate at 37°C for 10-20 minutes. Keep out of light and monitor regularly until optimal color development is achieved. 8) Add 50μL of stop solution to each well according to the same order and time as TMB substrate solution, mix evenly, and the solution will turn from blue to yellow. 9) Using a microplate reader, measure the optical density (OD value) of each well in sequence at a wavelength of 450 nm.

[0245] 3.7. ELISA detection of serum 5-HT content 1) Before use, mix all the reagents thoroughly and equilibrate them at room temperature. 2) Adding standard samples: Set up standard wells and sample wells, and add 50 μL of standard of different concentrations to each standard well. The standard concentrations are 240, 120, 60, 30, and 15 ng / mL, respectively. 3) Sample addition: Set up blank wells (no sample or enzyme-labeled reagent is added to the blank control wells, the remaining steps are the same) and test sample wells. First, add 40 μL of sample dilution solution to the test sample wells on the enzyme-labeled coated plate, then add 10 μL of the test sample (the final dilution rate of the sample is 5 times). Sample addition: Add the sample to the bottom of the enzyme plate well, shake gently to mix evenly without touching the wall of the well, 4) Incubation: After sealing the plate with sealing film, incubate at 37°C for 30 minutes. 5) Liquid preparation: Dilute the 30-fold concentrated cleaning solution with distilled water and store it. 6) Washing: Carefully peel off the sealing film, discard the liquid, centrifuge dry, fill each well with washing solution, leave for 30 seconds and discard, repeat 5 times, pat dry, 7) Add enzyme: Add 50 μL of enzyme labeling reagent to each well except the blank well. 8) Incubation: Same as step 4; 9) Washing: Same as step 6, 10) Color development: First, add 50 μL of color developer A to each well, then add 50 μL of color developer B, gently shake to mix evenly, and allow to develop color in a dark place at 37°C for 15 minutes. 11) Stop: Add 50 μL of stop solution to each well, the solution will turn from blue to yellow, 12) Measurement: Adjust the blank well to zero, and measure the absorbance (OD value) of each well sequentially at a wavelength of 450 nm.

[0246] 4. Experimental Results Compared with the control group, in the mice of the model group, the fecal volume was decreased, the water content of feces was decreased, the fecal pellets were decreased, the hardness was increased, the bead excretion time was increased, the arrangement of intestinal villi in the colon tissue of the mice was disrupted, a large amount of inflammatory infiltration was observed, the colon muscle layer and mucosa were thinned, the number of goblet cells and Libek's gland was decreased, 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 being orally treated with the compound, the mice's fecal volume increased, fecal water content increased, the number of fecal particles increased, hardness decreased, bead excretion time decreased, intestinal peristalsis increased (Figure 1), the phenomenon of thinning of the colonic muscle layer and mucosa was significantly improved, the number of goblet cells and Liberko's gland increased to different degrees (Figure 2), the expression levels of AQP3 protein, TRPV1 protein and CGRP in colonic tissue were significantly decreased (Figure 3), serum 5-HT level increased, and VIP and NO levels decreased (Figure 4).

[0247] All documents mentioned in the present invention are incorporated by reference in this application as if each document was incorporated by reference individually. Furthermore, 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 these equivalents are also included in the scope defined by the appended claims of this application.

Claims

1. A nitrogen-containing heterocyclic compound represented by general formula (I) or a pharma- ceutically acceptable salt, enantiomer, diastereomer or racemate thereof, 【Chemistry 1】 Where: the chiral carbon atom C* is independently S, R, racemic, or a combination thereof; n=0, 1 or 2; X １ and X ２ are each independently selected from the group consisting of O or NH; X ３ is a chemical bond, CHR ６ or (CHR ６ ) ２ and R １ and R ２ are each independently hydrogen, deuterium, tritium, a halogen, a hydroxyl group, a carboxyl group, a substituted or unsubstituted C １ ~C ６ Alkyl group, substituted or unsubstituted C １ ~C ６ Alkoxy group, substituted or unsubstituted C ２ ~C ６ Alkenyl group, substituted or unsubstituted C ２ ~C ６ Alkynyl group, substituted or unsubstituted C ６ ~C １０ an aryl group, a substituted or unsubstituted 5- to 7-membered heterocycle, a substituted or unsubstituted C １ ~C ６ Alkylphenyl group, substituted or unsubstituted C １ ~C ６ alkyl 5-7 membered heteroaryl group, substituted or unsubstituted C ３ ~C １２ Cycloalkyl groups, substituted or unsubstituted C ２ ~C １０ Acyl group, substituted or unsubstituted C ２ ~C １０ Ester group, amino group, substituted or unsubstituted C １ ~C ６ Alkylamino group, substituted or unsubstituted C １ ~C ６ Amide, -SOR ５ , -OSOR ５ , -OCOR ５ , C(=NH)NH ２ , Fmoc, allyloxycarbonyl group (Alloc); When n=0, R １ and R ２ is not a methyl group, and when n=1, the R １ and R ２ is not hydrogen at the same time, Or the above R １ and R ２ is adjacent (CH ２ ) ｎ together with O and C═C, form a substituted or unsubstituted 5- to 7-membered heterocycle, said heterocycle being fully saturated, partially unsaturated or aromatic; X is O, S, or CHR ６ , C ２ H ４ (i.e., forming a cyclopropyl group at the substitution position of X) or NR ６ wherein R ６ H, CN, C １ ~C ６ Alkyl group, C １ ~C ６ alkoxy groups; Y is a chemical bond, C １ ~C ６ Linear or branched alkyl group, -CH ２ NH-, C ２ ~C ６ Linear or branched alkenyl group, -CH ２ O-, -CH ２ S-, -CONH-, -NHCO-, -COO-, -OOC-, 【Chemistry 2】 is a linking group selected from the group consisting of Ring A is a 5-12 membered nitrogen-containing heterocyclic group (including monocyclic, fused polycyclic, bridged or spirocyclic, where the linking site is preferably on the nitrogen atom); ６ ~C １２ An aryl group (preferably ６ ~C １０ a substituted or unsubstituted group selected from the group consisting of a heterocyclic group, a 5-12 membered heteroaryl group (preferably a 5-7 membered heteroaryl group), wherein the heterocyclic group or heteroaryl group is selected from the group consisting of N, NH, S, O, S(O) ２ The ring skeleton contains a heteroatom selected from the group consisting of R ４ is unsubstituted or substituted by 1 to 3 substituents, ３ C to C cycloalkyl group, 5 to 12 membered heterocyclic group, C ６ ~C １２ aryl, 5-12 membered heteroaryl (preferably 5-7 membered heteroaryl, or benzo 5-7 membered heteroaryl), wherein each of said heterocyclic or heteroaryl groups contains 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, and said substituents are each independently selected from halogen, C １ ~C ６ Linear or branched alkyl group, C ２ ~C ６ A linear or branched alkenyl group, C ２ ~C ６ A straight or branched chain alkynyl group, C １ ~C ６ Linear or branched alkoxy group, C １ ~C ６ A straight-chain or branched-chain alkylcarbonyloxy group, a cyano group, a nitro group, a hydroxy group, an amino group, a hydroxymethyl group, a trifluoromethyl group, a trifluoromethoxy group, a carboxy group, a thiol group, C １ ~C ４ Acyl group, amide, sulfonyl group, aminosulfonyl group, C １ ~C ４ alkyl-substituted sulfonyl groups or two substituents located on adjacent ring atoms together with the carbon atoms to which they are attached form a 5- to 7-membered ring; R ３ and R ５ are each independently hydrogen, deuterium, tritium, halogen, or C unsubstituted or substituted with 1 to 3 halogens. １ ~C ６ an alkyl group or a C unsubstituted or substituted with 1 to 3 halogens; ３ ~C ６ Cycloalkyl groups, unsubstituted or substituted with 1 to 3 halogens ６ ~C １０ Aryl group, unsubstituted or substituted by 1 to 3 halogens １ -C ３ Alkyl-C ６ ~C １０ aryl groups, and 5-7 membered heteroaryl groups unsubstituted or substituted by 1-3 halogens; Unless otherwise specified, the term "substituted" refers to one or more hydrogen atoms on a group being replaced with a C １ ~C １０ Alkyl group, C １ ~C １０ Alkoxy group, C ３ ~C １０ Cycloalkyl group, C １ ~C １０ Alkoxy group, 5-12 membered heterocyclic group, halogen, hydroxy group, carboxy group (-COOH), C １ ~C １０ Aldehyde group, C ２ ~C １０ Acyl group, C ２ ~C １０ The phenyl group includes an unsubstituted phenyl group or a substituted phenyl group having 1 to 3 substituents, and the substituents are selected from the group consisting of halogen, C １ -C １０ Alkyl group, cyano group, hydroxy group, nitro group, C ３ ~C １０ Cycloalkyl group, C １ ~C １０ is selected from an alkoxy group, an amino group, And the compound is 【Chemistry 3】 The nitrogen-containing heterocyclic compound represented by the general formula (I), or a pharma- ceutically acceptable salt, enantiomer, diastereomer or racemate thereof, characterized in that the structure is not selected from the group consisting of:

2. A nitrogen-containing heterocyclic compound represented by general formula (I) or a pharma- ceutically acceptable salt, enantiomer, diastereomer or racemate thereof, 【Chemistry 4】 Where: the chiral carbon atom C* is independently S, R, racemic, or a combination thereof; n=0, 1 or 2; R １ and R ２ are each independently hydrogen, deuterium, tritium, a halogen, a hydroxyl group, a carboxyl group, a substituted or unsubstituted C １ ~C ６ Alkyl group, substituted or unsubstituted C １ ~C ６ Alkoxy group, substituted or unsubstituted C ６ ~C １０ an aryl group, a substituted or unsubstituted 5- to 7-membered heterocycle, a substituted or unsubstituted C １ ~C ６ Alkylphenyl group, substituted or unsubstituted C １ ~C ６ alkyl 5-7 membered heteroaryl group, substituted or unsubstituted C ３ ~C １２ Cycloalkyl groups, substituted or unsubstituted C ２ ~C １０ Acyl group, substituted or unsubstituted C ２ ~C １０ Ester group, amino group, substituted or unsubstituted C １ ~C ６ Alkylamino group, substituted or unsubstituted C １ ~C ６ Amide, -SOR ５ , -OSOR ５ , -OCOR ５ is selected from the group consisting of When n=0, R １ and R ２ is not a methyl group, and when n=1, the R １ and R ２ is not hydrogen at the same time, Or the above R １ and R ２ is adjacent (CH ２ ) ｎ together with O and C═C, form a substituted or unsubstituted 5- to 7-membered heterocycle, said heterocycle being fully saturated, partially unsaturated or aromatic; X is O or S; Y is a chemical bond, C １ ~C ６ Linear or branched alkyl group, -CH ２ NH-, C ２ ~C ６ Linear or branched alkenyl group, -CH ２ O-, -CH ２ S-, -CONH-, -NHCO-, -COO-, -OOC-, 【Chemistry 5】 is a linking group selected from the group consisting of The A ring is a 5- to 12-membered azaheterocyclyl group (wherein the attachment site is preferably on the nitrogen atom); ６ ~C １２ An aryl group (preferably ６ ~C １０ a substituted or unsubstituted group selected from the group consisting of a heterocyclic group, a 5-12 membered heteroaryl group (preferably a 5-7 membered heteroaryl group), wherein the heterocyclic group or heteroaryl group is selected from the group consisting of N, NH, S, O, S(O) ２ The ring skeleton contains a heteroatom selected from the group consisting of R ４ is unsubstituted or substituted by 1 to 3 substituents, ３ ~C ７ Cycloalkyl group, 5- to 12-membered heterocyclic group, C ６ ~C １２ aryl, 5-12 membered heteroaryl (preferably 5-7 membered heteroaryl, or benzo 5-7 membered heteroaryl), wherein each of said heterocyclic or heteroaryl groups contains 1-3 heteroatoms selected from oxygen, sulfur and nitrogen, and said substituents are each independently selected from halogen, C １ ~C ６ Linear or branched alkyl group, C ２ ~C ６ A linear or branched alkenyl group, C ２ ~C ６ A straight or branched chain alkynyl group, C １ ~C ６ Linear or branched alkoxy group, C １ ~C ６ A straight-chain or branched-chain alkylcarbonyloxy group, a cyano group, a nitro group, a hydroxy group, an amino group, a hydroxymethyl group, a trifluoromethyl group, a trifluoromethoxy group, a carboxy group, a thiol group, C １ ~C ４ Acyl group, amide, sulfonyl group, aminosulfonyl group, C １ ~C ４ alkyl-substituted sulfonyl groups or two substituents located on adjacent ring atoms together with the carbon atoms to which they are attached form a 5- to 7-membered ring; R ３ and R ５ are each independently hydrogen, deuterium, tritium, halogen, or C unsubstituted or substituted with 1 to 3 halogens. １ ~C ６ an alkyl group or a C unsubstituted or substituted with 1 to 3 halogens; ３ ~C ６ Cycloalkyl groups, unsubstituted or substituted with 1 to 3 halogens ６ ~C １０ Aryl group, unsubstituted or substituted by 1 to 3 halogens １ -C ３ Alkyl-C ６ ~C １０ A nitrogen-containing heterocyclic compound represented by the above general formula (I), characterized in that the nitrogen-containing heterocyclic compound is selected from the group consisting of an aryl group, and a 5- to 7-membered heteroaryl group unsubstituted or substituted by 1 to 3 halogens, or a pharma- ceutically acceptable salt, enantiomer, diastereomer or racemate thereof.

3. The A ring is an aziridinyl group, an azetidinyl group, a pyrrolidinyl group, a piperidinyl group, an azepanyl group, a morpholinyl group, a piperazinyl group, a homopiperazinyl group, a thiomorpholinyl group, a thiomorpholinyl group in which the ring sulfur is substituted with a sulfoxide or a sulfone, an imidazolidinyl group, a pyrazinyl group, a hexahydropyrimidinyl group, or 【Chemistry 6】 wherein the A ring is optionally selected from the group consisting of hydrogen, C １ -C ３ Linear or branched alkyl groups, halogens, hydroxyl groups and C １ -C ４ substituted with 1 to 2 groups selected from alkoxycarbonyl groups; 2. The nitrogen-containing heterocyclic compound of claim 1, or a pharma- ceutically acceptable salt, enantiomer, diastereomer or racemate thereof.

4. R １ and R ２ are each independently hydrogen, deuterium, tritium, a halogen, a hydroxyl group, a carboxyl group, a phenyl group, a substituted or unsubstituted C １ ~C ６ Alkyl group, substituted or unsubstituted C １ ~C ６ an alkoxy group, a substituted or unsubstituted 5- to 7-membered heterocycle, a substituted or unsubstituted C １ ~C ６ alkyl 5-7 membered heteroaryl group, substituted or unsubstituted C ３ ~C ８ Cycloalkyl groups, substituted or unsubstituted C ２ ~C １０ Acyl group, substituted or unsubstituted C ２ ~C １０ Ester group, amino group, substituted or unsubstituted C １ ~C ６ Alkylamino group, substituted or unsubstituted C １ ~C ６ Amide, -SOR ５ , -OSOR ５ , -OCOR ５ The compound is selected from the group consisting of 2. The nitrogen-containing heterocyclic compound of claim 1, or a pharma- ceutically acceptable salt, enantiomer, diastereomer or racemate thereof.

5. X is O; Y is -CH ２ --, --CH ２ -CH ２ --, --CH ２ -CH ２ -CH ２ --, --CH ２ NH-, -CH ２ O- or -CH ２ S- 2. The nitrogen-containing heterocyclic compound of claim 1, or a pharma- ceutically acceptable salt, enantiomer, diastereomer or racemate thereof.

6. R ４ is unsubstituted or substituted by 1 to 3 substituents, ６ -C １０ aryl group, 5-7 membered heteroaryl group, or benzo 5-7 membered heteroaryl group, preferably the heterocyclic and heteroaromatic ring moieties in said group are selected from the group consisting of indole group, benzodioxole, isoxazole, pyridine, pyrazole, dihydroimidazopyridine, imidazopyridine, benzothiophene, dihydrobenzodioxane, quinoxaline, pyrrole, benzofuran, indazole, benzimidazole, quinoline, and 1,3-dioxoisoindoline.

2. The nitrogen-containing heterocyclic compound of claim 1, or a pharma- ceutically acceptable salt, enantiomer, diastereomer or racemate thereof.

7. Hydrogen, deuterium, tritium, halogen, unsubstituted or substituted with 1 to 3 halogens １ ~C ６ an alkyl group or a C unsubstituted or substituted with 1 to 3 halogens; ３ ~C ６ Characterized by a cycloalkyl group 2. The nitrogen-containing heterocyclic compound of claim 1, or a pharma- ceutically acceptable salt, enantiomer, diastereomer or racemate thereof.

8. The tetrahydroisoquinoline compound is the following compound: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 【Table 1-5】 【Table 1-6】 【Table 1-7】 【Table 1-8】 【Table 1-9】 【Table 1-10】 【Table 1-11】 【Table 1-12】 【Table 1-13】 【Table 1-14】 【Table 1-15】 【Table 1-16】 【Table 1-17】 【Table 1-18】 【Table 1-19】 【Table 1-20】 【Table 1-21】 【Table 1-22】 【Table 1-23】 【Table 1-24】 【Table 1-25】 【Table 1-26】 【Table 1-27】 【Table 1-28】 【Table 1-29】 characterized in that it is selected from 2. The nitrogen-containing heterocyclic compound of claim 1, or a pharma- ceutically acceptable salt, enantiomer, diastereomer or racemate thereof.

9. A process for preparing a compound of formula (I) according to claim 1, comprising the steps of: The method comprises the steps of: (1) Reacting a compound of formula II with a compound of formula I in the presence of a condensing agent in an inert solvent. ｃ with a compound of formula I ｄ Preferably, the condensing agent is EDCI (1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride), 【Chemistry 7】 (2) In an inert solvent, ｄ to carry out a Bischler-Napieralski ring closure reaction using a compound of formula I ｅ Preferably, the ring closure reaction is carried out using phosphorus oxychloride as Lewis acid, 【Chemistry 8】 (3) reacting a compound of formula I in an inert solvent ｅ to carry out a reduction reaction using a compound of formula I ｆ Preferably, the reduction reaction uses borohydride as a reducing agent or Noyori's catalyst as an asymmetric reduction catalyst; 【Chemistry 9】 (4) In an inert solvent, reacting a compound of formula I ｆ Compounds of and 【Chemistry 10】 to carry out a condensation reaction to obtain a compound of formula (I), 【Chemistry 11】 A method for preparing a compound of formula (I) according to claim 1, characterized in that in each of the above formulas, the definition of each group is as described in any one of claims 1 to 8.

10. 1. A pharmaceutical composition comprising:

11. The pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

11. Use of a compound of formula (I) according to claim 1, Use of the compound of formula (I) described in claim 1, characterized in that it is used for the preparation of a pharmaceutical composition for treating a disease or condition associated with the activity or expression level of relaxin family peptide receptor 4.

12. The compound is characterized in that it is used for preparing a pharmaceutical composition for treating a disease or condition selected from the group consisting of constipation, anorexia, or glucose and lipid metabolism-related disorders.

12. The use according to claim 11.

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