GLP-1 receptor agonist and use thereof

Abstract

Provided are an agonist of a glucagon-like peptide-1 receptor (GLP-1R) and a use thereof, relating to the field of medicine. The agonist is a compound having a structure represented by formula (I), or an isomer, isotopically labeled compound, prodrug thereof, or a pharmaceutically acceptable salt, ester, hydrate or solvate thereof, can be used for treating metabolic syndrome, and has a significant therapeutic effect in terms of blood glucose lowering or weight loss.

Description

A GLP-1 receptor agonist and uses thereof TECHNICAL FIELD

[0001] The present application relates to the field of chemical pharmacy, and specifically develops a GLP-1R oral small molecule agonist which can reduce blood glucose level by enhancing the secretion of insulin in a glucose-dependent manner. BACKGROUND

[0002] In recent years, with the improvement of people's living standards and the change of eating habits, obesity has gradually become a global health problem, and its prevalence continues to increase worldwide. Obesity is a key risk factor for metabolic complications such as non-alcoholic fatty liver disease (NAFLD), type 2 diabetes (T2DM), cardiovascular disease, high cholesterol, and hypertension.

[0003] Type 2 diabetes accounts for 90-95% of all diabetes patients, and its prevalence continues to increase worldwide. According to the International Diabetes Federation (IDF), 382.5 million people were affected by T2DM in 2015, and this number is expected to exceed 578 million in 20 years.

[0004] Glucagon-like peptide-1 (GLP-1) is an incretin, a 30-amino-acid polypeptide secreted by L cells in the small intestine. GLP-1 participates in the regulation of glucose homeostasis by interacting with GLP-1 receptor (GLP-1R) and transmitting signals. The insulinotropic effect of GLP-1 is glucose-dependent, and once the plasma glucose level drops to the normal range, it will not further stimulate the secretion of insulin, thereby reducing the risk of hypoglycemia. In addition, GLP-1 regulates blood glucose homeostasis mainly by promoting insulin gene transcription, stimulating pancreatic beta cell proliferation and neogenesis, inhibiting beta cell apoptosis, and blocking glucagon release. It can also delay gastric emptying and promote satiety, thereby playing a role in weight loss. In the intestine, GLP-1 can stimulate the division and proliferation of crypt cells, playing a role in intestinal growth promotion. Intestinal intraepithelial lymphocytes can reduce inflammation and protect intestinal tissue under the action of GLP-1. In the brain, GLP-1 can reduce appetite and reduce addictive behavior towards certain foods. In the cardiovascular system, GLP-1R is also expressed, which can increase heart rate and cardiac output, and has a heart-protective function.

[0005] Therefore, GLP-1 receptor agonists can be used to treat obesity and metabolic syndrome with obvious clinical manifestations, and have been widely used in the treatment of type 2 diabetes, with the properties of weight loss, protection of islet beta cells, promotion of islet beta cell proliferation and small side effects; in addition, GLP-1 receptor agonists have multiple biological effects such as reducing neuroinflammation, promoting nerve growth, improving heart function, suppressing appetite, delaying gastric emptying, regulating lipid metabolism and reducing fat deposition. Moreover, GLP-1 receptor agonists have neuroprotective, anti-infective, cardiovascular protective and metabolic regulatory effects, showing good application prospects. The relationship between GLP-1 receptor agonists and the occurrence, development and prognosis of tumors in T2DM patients is also attracting more and more attention.

[0006] GLP-1 receptor agonists (GLP-1RA) can bind to GLP-1R and exert the same effects as GLP-1. All currently approved GLP-1 receptor agonists are synthetic analogs of the endogenous agonist GLP-1 or its paralog exendin-4, mainly to optimize their pharmacokinetic properties by various modification methods to improve proteolytic stability and / or avoid kidney clearance. These FDA-approved polypeptide drugs are mainly used to treat T2DM or obesity, but these polypeptide GLP-1 receptor agonist drugs usually need to be administered by subcutaneous injection, and patient compliance is poor. There is no small molecule GLP-1 receptor agonist drug approved for the market for the treatment of T2DM or obesity, so the present application is committed to developing an orally available small molecule GLP-1 receptor agonist to meet this need.

[0007] Novo Nordisk's oral semaglutide Rybelsus is the first and only marketed oral GLP-1R agonist, but the requirements for taking it are strict and cumbersome. Non-peptide oral small molecule GLP-1R agonists have the advantages of oral administration, high stability, easy storage and low cost, and are the future research trend.

[0008] Patent CN109790161B discloses a pyrazolopyridine derivative with GLP-1 receptor agonist effect, specifically disclosing compound 67, which is an oral small molecule GLP-1R agonist drug Orforglipron (LY3502970) being developed by Lilly. Clinical phase II study reports that at 26 weeks, the body weight of the subjects decreased by 8.6%-12.6%, and the average decrease in HbA1c of type 2 diabetes subjects reached 2.1%; at 36 weeks, the body weight of the subjects decreased by 9.4%-14.7%. Due to the low oral bioavailability of the drug, the dosage is relatively high.

[0009] There is no small molecule GLP-1R agonist drug on the market, and new GLP-1R agonist drugs need to be developed urgently. SUMMARY

[0010] In response to the above-mentioned technological status, this invention provides an oral small-molecule GLP-1 receptor agonist that can enhance insulin secretion and lower blood glucose levels in a glucose-dependent manner. This avoids the risk of hypoglycemia that is common with traditional T2DM treatments, maintaining intelligent and precise blood glucose control. Simultaneously, this molecule possesses functions such as weight loss, lipid reduction, cardiovascular protection, and treatment of non-alcoholic fatty liver disease. Compared to large-molecule peptide drugs, its potential advantages include: tolerability and safety similar to peptide GLP-1 receptor agonists, and convenient oral dosage form; good bioavailability; unlike oral large-molecule GLP-1 receptor agonists (such as oral smegglutide), it is not limited by food or dosage; and it can be developed for monotherapy or combination therapy.

[0011] In addition to the use of this oral small molecule agonist GLP-1R in the fields of diabetes and obesity, as research on this type of drug continues to deepen in the fields of chronic liver disease, kidney disease, and cardiovascular and cerebrovascular diseases, there is strong reason to expect that this type of product can be used to treat a range of indications such as non-alcoholic fatty liver disease (NASH), diabetic nephropathy (DKD), atherosclerotic cardiovascular disease (ASCVD), and Alzheimer's disease (AD).

[0012] This invention provides a compound having the structure of formula (I) and a pharmaceutically acceptable salt thereof:

[0013] in,

[0014] R 1 Selected from C 6-10 Aryl or substituted C 6-10 Aryl, the substituted C 6-10 Aryl groups include C 6-10 One or more hydrogens on the aryl group are each independently selected from halogens, C 1-6 Alkyl, C 3-6 Substituents of cycloalkyl groups;

[0015] R 3 R 4 R 5 R 7 R 8 R 9 R 6 Each is independently selected from hydrogen, deuterium, halogen, or C. 1-6 alkyl;

[0016] R a and R b Each is independently selected from hydrogen, deuterium, halogen, or C. 1-6 Alkyl; or R a and R btogether with the carbon atom to which they are attached form a C 3～10 cycloalkyl; optionally said C 3～10 cycloalkyl is substituted with 1 to 3 substituents independently selected from C 1-6 alkyl;

[0017] R 10 is selected from a 6-membered heterocyclyl or a 6-membered heteroaryl, wherein the 6-membered heterocyclyl or the 6-membered heteroaryl is optionally substituted with one or more (preferably one to three) substituents independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, -NR N1 R N2 and, optionally, two C 1-6 alkyl groups together with the carbon atom to which they are attached can form a C 3-8 cycloalkyl or a 4-8 membered heterocyclyl, R N1 and R N2 are independently selected from H, C 1-6 alkyl;

[0018] R 2 is selected from an optionally substituted 13-18 membered heterocyclyl, an optionally substituted C 13-18 aryl, an optionally substituted 13-18 membered heteroaryl.

[0019] In the present application, as one of the embodiments, the heteroatoms in the 13-18 membered heterocyclyl, the C 13-18 aryl, and the 13-18 membered heteroaryl are selected from N, O, S, P, the number of the heteroatoms in the 13-18 membered heterocyclyl, the C 13-18 aryl, and the 13-18 membered heteroaryl is one or more, wherein when two or more heteroatoms are included, they can be the same, partially the same, or completely different; as an exemplary illustration, one N, O, S, or P can be included; two heteroatoms such as N and O; N and S; N and N; N and P; O and O; O and S; O and P; S and S; S and P can be included; three heteroatoms such as N, N, and O; N, O, and O; N, S, and O; N, N, and N can be included.

[0020] In the present application, as one of the embodiments, R 2 is selected from a 13-18 membered heterocyclyl, a C 13-18 aryl, and a 13-18 membered heteroaryl, wherein optionally the 13-18 membered heterocyclyl, the C 13-18 aryl, and the 13-18 membered heteroaryl is optionally substituted with one or more substituents each independently selected from:

[0021] a) deuterium,

[0022] b) oxo (=O),

[0023] c) Halogens,

[0024] d)OH,

[0025] e) Cyano group

[0026] f) Among them, R 0 Selected from H, C 1-6 alkyl,

[0027] g)-NR N3 R N4 , where R N3 and R N4 Each is independently selected from H and C. 1-6 Alkyl and (C 1-6 alkyl)carbonyl, wherein C 1-6 The alkyl group may be optionally selected independently from one or more deuterium, halogen, hydroxyl, C 1-6 Substitution of alkoxy groups,

[0028] h)-C(=O)R C1 , where R C1 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkylene

[0029] i)C 1-6 Alkyl, wherein C 1-6 The alkyl group may optionally be substituted with one or more substituents independently selected from deuterium, halogen, hydroxyl, cyano, C1-6 alkoxy, and 3- to 12-membered heterocyclic groups, wherein the 3- to 12-membered heterocyclic groups may optionally be substituted with one or more substituents independently selected from C1-6 alkoxy, halogen, hydroxyl, cyano, C1-6 alkoxy, and 3- to 12-membered heterocyclic groups. 1-6 Alkyl substituents,

[0030] j)C 1-6 Alkoxy, where C 1-6 The alkoxy group may optionally be independently selected from halogen, hydroxyl, C. 1-6 Alkyl or C 1-6 Substitution of alkoxy groups,

[0031] k) 3 to 12-membered heterocyclic groups, wherein the 3 to 12-membered heterocyclic groups are optionally selected independently by one or more of deuterium, halogen, hydroxyl, NH2, CN, C 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Substitution of alkyl group 2;

[0032] l) 5- to 10-membered heteroaryl, wherein the 5- to 10-membered heteroaryl is optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxyl, CN, C 1-6 alkyl, C 1-6 haloalkyl, C N5 alkoxy, -NR N6 R N5 and R N6 are independently selected from H, C 1-6 alkyl;

[0033] m) C 3-10 cycloalkyl, wherein the C 3-10 cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxyl, NH2, CN, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -NH(C 1-6 alkyl), -N(C S1 alkyl)2;

[0034] n) -S(O)2-R S1 , wherein R 1-6 is selected from C 1-6 alkyl, C 3-6 haloalkyl, C e cycloalkyl; and

[0035] o) wherein R f , R 1 are each independently selected from H, deuterium or halogen.

[0036] In the present application, as one of the preferred embodiments, the R 6-10 is selected from C 6-10 aryl or substituted C 6-10 aryl, the substituted C 6-10 aryl includes that one or more hydrogens on the C 1-6 aryl are each independently replaced with a substituent selected from halogen, C 3-6 alkyl, C 3 cycloalkyl;

[0037] R 4 , R 5 , R 7 , R 8 , R 9 , R 6 are each independently selected from hydrogen, deuterium, halogen or C 1-6 alkyl;

[0038] R a and R b are each independently selected from hydrogen, deuterium, halogen or C 1-6alkyl; or R a and R b together with the carbon atom to which they are attached form a C 3～10 cycloalkyl; optionally said C 3～10 cycloalkyl is substituted with 1 to 3 substituents independently selected from C 1-6 alkyl;

[0039] R 10 is selected from a 6-membered heterocyclyl or a 6-membered heteroaryl, wherein the 6-membered heterocyclyl or the 6-membered heteroaryl is optionally substituted with one or more substituents independently selected from deuterium, halogen, C 1-6 alkyl, C 1-6 alkoxy, -NR N1 R N2 and, optionally, two C 1-6 alkyl groups as substituents on the 6-membered heterocyclyl or the 6-membered heteroaryl, together with the carbon atom to which they are attached, can form a C 3-8 cycloalkyl or a 4-8 membered heterocyclyl, R N1 and R N2 are independently selected from H, C 1-6 alkyl;

[0040] R 2 is selected from a 13-18 membered heterocyclyl, a C 13-18 aryl, a 13-18 membered heteroaryl, wherein optionally the 13-18 membered heterocyclyl, the C 13-18 aryl and the 13-18 membered heteroaryl is optionally substituted with one or more substituents each independently selected from:

[0041] a) deuterium,

[0042] b) oxo (=0),

[0043] c) halogen,

[0044] d) OH,

[0045] e) cyano,

[0046] f) wherein R 0 is selected from H, C 1-6 alkyl,

[0047] g) -NR N3 R N4 , wherein R N3 and R N4 are each independently selected from H, C 1-6 alkyl and (C 1-6 alkyl)carbonyl, wherein the C 1-6 alkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxyl, C 1-6 alkoxy,

[0048] h) -C(=O)R C1 wherein R C1 is selected from C 1-6 alkyl, C 1-6 haloalkyl,

[0049] i) C 1-6 alkyl, wherein C 1-6 alkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxyl, C 1-6 alkoxy, and 3- to 12-membered heterocyclyl, and wherein 3- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from C 1-6 alkyl,

[0050] j) C 1-6 alkoxy, wherein C 1-6 alkoxy is optionally substituted with one or more substituents independently selected from halogen, hydroxyl, C 1-6 alkyl, or C 1-6 alkoxy,

[0051] k) 3- to 12-membered heterocyclyl, wherein 3- to 12-membered heterocyclyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxyl, NH2, CN, C 1-6 alkyl, C 1-6 alkoxy, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2;

[0052] l) 5- to 10-membered heteroaryl, wherein 5- to 10-membered heteroaryl is optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxyl, CN, C 1-6 alkyl, C 1-6 alkoxy, -NR N5 R N6 , wherein R N5 and R N6 are independently selected from H, C 1-6 alkyl; and

[0053] m) C 3-10 cycloalkyl, wherein C 3-10 cycloalkyl is optionally substituted with one or more substituents independently selected from deuterium, halogen, hydroxyl, NH2, CN, C 1-6 alkyl, C 1-6 alkoxy, -NH(C 1-6 alkyl), -N(C 1-6 alkyl)2.

[0054] In the present application, as one of the embodiments, the R 2 is selected from 13- to 18-membered heterocyclyl, C13-18 aryl, 13-18 membered heteroaryl, wherein optionally the 13-18 membered heterocyclyl, C 13-18 aryl, 13-18 membered heteroaryl optionally substituted with one or more (preferably one to five) substituents each independently selected from:

[0055] deuterium;

[0056] halogen;

[0057] -C 1～6 alkyl;

[0058] =0;

[0059] -(CH2)n-OH;

[0060] -(CH2)n-CN;

[0061] -(CH2)n-O-(CH2)n-CH3;

[0062] -O-(CH2)n-CH3;

[0063] -(CH2)n-CX3, -(CH2)n-CH2X;

[0064] -C 3-10 cycloalkyl, 3-10 membered heterocyclyl;

[0065] -NH2;

[0066] =NH;

[0067] -CO-NH2;

[0068] -CO-(CH2)n-CH3, -CO-CH(CH3)OH;

[0069] -CO-(CH2)n-CX3;

[0070] -SO2-(CH2)n-CH3;

[0071] =CF2, =CHF;

[0072] wherein n is 0-6; said X is F, Cl, Br, or I;

[0073] the 13-18 membered heterocyclyl, C 13-18 the heteroatoms in aryl, 13-18 membered heteroaryl are selected from N, O, S, P, the 13-18 membered heterocyclyl, C 13-18 the number of heteroatoms in aryl, 13-18 membered heteroaryl is one or more, wherein when two or more heteroatoms are included, they can be the same, partially the same, or completely different.

[0074] Preferably, R 2 Selected from 13-18 membered heterocyclic groups, C 13-18 Aryl, 13-18 membered heteroaryl, wherein the 13-18 membered heterocyclic group, C 13-18 The aryl group and the 13-18 membered heteroaryl group are optionally replaced by one or more (preferably one to five) substituents, each independently selected from the following:

[0075] deuterium;

[0076] Halogens (e.g., F, Cl);

[0077] -C 1～4 Alkyl groups (e.g., methyl, ethyl, isopropyl, or tert-butyl);

[0078] =O;

[0079] -(CH2)n-OH (e.g., -(CH2)2-OH);

[0080] -(CH2)n-CN (e.g., -CH2-CN or -(CH2)2-CN);

[0081] -(CH2)nO-(CH2)n-CH3 (e.g., -(CH2)2-OCH3);

[0082] -O-(CH2)n-CH3 (e.g., -O-CH3);

[0083] -(CH2)n-CX3 (e.g., -CH2-CF3), -(CH2)n-CH2X;

[0084] -C 3-6 Cycloalkyl (e.g., cyclopropane) or 4-7 membered heterocyclic groups (e.g., oxobutane);

[0085] -NH2;

[0086] =NH;

[0087] -CO-NH2;

[0088] -CO-(CH2)n-CH3 (e.g., -CO-CH3), -CO-CH(CH3)OH;

[0089] -CO-(CH2)n-CX3 (e.g., -CO-CF3);

[0090] -SO2-(CH2)n-CH3 (e.g., -SO2-CH3);

[0091] =CF2, =CHF;

[0092] wherein n is 0-6; X is F, Cl, Br, or I;

[0093] the 13-18 membered heterocyclyl, C 13-18 the heteroatoms in the aryl, 13-18 membered heteroaryl are selected from N, O, S, P, the 13-18 membered heterocyclyl, C 13-18 the number of heteroatoms in the aryl, 13-18 membered heteroaryl is one or more, wherein when two or more heteroatoms are included, they can be the same, partially the same, or completely different.

[0094] In the present application, as one of the preferred schemes, R 2 the 13-18 membered heterocyclyl, C 13-18 the 13-18 membered heterocyclyl, C 13-18 the aryl, 13-18 membered heteroaryl is optionally substituted by one or more (preferably one to five) substituents each independently selected from the following:

[0095] deuterium;

[0096] halogen;

[0097] -C 1～4 alkyl;

[0098] =O;

[0099] -(CH2)n-OH;

[0100] -(CH2)n-O-(CH2)n-CH3;

[0101] -O-(CH2)n-CH3; -(CH2)n-CH2X; X is F, Cl, Br, or I;

[0102] -C 3-6 cycloalkyl, 4-7 membered heterocyclyl;

[0103] -NH2;

[0104] =NH;

[0105] -CO-NH2;

[0106] -CO-(CH2)n-CH3

[0107] wherein n is 0-6;

[0108] the 13-18 membered heterocyclyl, C 13-18 the heteroatoms in the aryl, 13-18 membered heteroaryl are selected from N, O, S, P, the 13-18 membered heterocyclyl, C 13-18the number of heteroatoms in the aryl group, 13-18-membered heteroaryl group is one or more, wherein when two or more heteroatoms are included, they can be the same, partially the same or completely different.

[0109] In the present application, as one of the preferred embodiments, the R 2 selected from a 13-18-membered heterocyclic group, C 13-18 aryl group, 13-18-membered heteroaryl group, wherein the 13-18-membered heterocyclic group, C 13-18 aryl group, 13-18-membered heteroaryl group is optionally substituted by one or more (preferably one to five) substituents each independently selected from the group consisting of:

[0110] deuterium;

[0111] halogen;

[0112] -C 1～3 alkyl group (e.g., methyl isopropyl group);

[0113] =O;

[0114] -(CH2)n-OH;

[0115] -(CH2)n-O-(CH2)n-CH3;

[0116] -O-(CH2)n-CH3;

[0117] -(CH2)n-CH2X;

[0118] -C 3-6 cycloalkyl group (e.g., cyclopropane group) or 4-7-membered heterocyclic group (e.g., cyclobutanone group);

[0119] -NH2;

[0120] =NH;

[0121] -CO-NH2;

[0122] -CO-(CH2)n-CH3

[0123] wherein n is 0-6;

[0124] the 13-18-membered heterocyclic group, C 13-18 the number of heteroatoms in the aryl group, 13-18-membered heteroaryl group is one or more, wherein when two or more heteroatoms are included, they can be the same, partially the same or completely different. 13-18

[0125] In the present application, as one of the embodiments, the R 1 selected from a C​6-10 aryl or substituted C 6-10 aryl, substituted C 6-10 aryl includes C 6-10 one or more hydrogens on the aryl group are each independently replaced with a substituent selected from the group consisting of halogen, SF5, C 1-6 alkyl, C 1-6 deuteroalkyl, C 3-6 cycloalkyl; preferably, R

[0126] In the present application, as one of the embodiments, the R 1 is selected from the group consisting of phenyl, optionally the phenyl includes one or more (preferably 1 to 5) hydrogens on the phenyl group each independently replaced with a substituent selected from the group consisting of halogen, SF5, C 1-6 alkyl, C 1-6 deuteroalkyl, C 3-6 cycloalkyl; preferably, R 1 is

[0127] In the present application, as one of the embodiments, the R 1 is selected from the group consisting of phenyl, optionally the phenyl includes one or more (preferably 1 to 5) hydrogens on the phenyl group each independently replaced with a substituent selected from the group consisting of halogen, C 1-6 alkyl, C 3-6 cycloalkyl; preferably, R 1 is

[0128] In the present application, as one of the preferred embodiments, the R 1 is selected from the group consisting of 3,5-dimethyl-4-fluorophenyl.

[0129] In the present application, as one of the embodiments, the R 3 , R 4 , R 5 are each independently selected from the group consisting of hydrogen, deuterium, or C 1-6 alkyl; R 7 , R 8 , R 9 , R 6 are each independently selected from the group consisting of hydrogen, deuterium, or halogen.

[0130] In the present application, as one of the embodiments, the R 3 , R 4 is hydrogen, R 5 is CH3, R 7 is hydrogen, R 8 is hydrogen, F, R 9 is hydrogen, R 6 is hydrogen.

[0131] In the present application, as one of the preferred embodiments, R 3 is hydrogen, R 4 is CH3, R 5 is CH3, R 7 is hydrogen, R 8 is hydrogen, R 9 is hydrogen, R 6 is hydrogen.

[0132] In the present application, as one of the embodiments, R a and R b are each independently selected from hydrogen, deuterium, halogen, or C 1-6 alkyl; or R a and R b together with the carbon atom to which they are attached form a C3cycloalkyl; optionally the C3cycloalkyl is substituted with one or more (preferably 1 to 3) independently C 1-6 alkyl.

[0133] In the present application, as one of the embodiments, R a and R b are each independently selected from hydrogen, deuterium, halogen, or C 1-6 alkyl; or R a and R b together with the carbon atom to which they are attached form a C3cycloalkyl; optionally the C3cycloalkyl is substituted with one or more (preferably 1 to 3) independently C 1-6 alkyl.

[0134] Preferably, R a and R b are each independently selected from hydrogen, deuterium, halogen, or C 1-6 alkyl; or R a and R b together with the carbon atom to which they are attached form a cyclopropyl, 2-methylcyclopropyl (e.g. ).

[0135] In the present application, as one of the preferred embodiments, R a and R b are each independently selected from hydrogen, deuterium, halogen, or C 1-6 alkyl; or R a and R b together with the carbon atom to which they are attached form a 2-methylcyclopropyl (e.g. ).

[0136] In the present application, as one of the embodiments, R 10 is selected from a 6-membered heterocyclyl, a 6-membered heteroaryl, wherein optionally the 6-membered heterocyclyl, the 6-membered heteroaryl is optionally substituted with one or more (preferably one to three) independently selected from deuterium, halogen, C 1-3alkyl, C 1-3 alkoxy or -NR N1 R N2 substituted with two C 1-3 alkyl groups together with the carbon atom to which they are attached form a C 3-6 cycloalkyl (e.g. cyclopropanyl) or 4-7 membered heterocyclyl; R N1 and R N2 are independently selected from H, C 1-3 alkyl.

[0137] In the present application, as one of the embodiments, said R 10 is selected from 6-membered heterocyclyl, 6-membered heteroaryl, wherein optionally the 6-membered heterocyclyl, 6-membered heteroaryl is optionally substituted with one or more (preferably one to three) substituents independently selected from deuterium, halogen, C 1-3 alkyl, C 1-3 alkoxy or -NR N1 R N2 substituted with two C 1-3 alkyl groups together with the carbon atom to which they are attached form a C 3-6 cycloalkyl (e.g. cyclopropanyl) or 4-7 membered heterocyclyl; R N1 and R N2 are independently selected from H, C 1-3 alkyl;

[0138] Preferably, R 10 is 3,3-dimethyl-cyclo-4-oxa-hexane (e.g. ) or

[0139] In the present application, as one of the embodiments, said R 10 is 3,3-dimethyl-cyclo-4-oxa-hexane (e.g. ).

[0140] In the present application, as one of the embodiments, said R 2 is selected from:

[0141] wherein Q1is selected from N or CR 13 ; Q2is selected from N or CR 15 ; Q3is selected from N or CR 14 ;

[0142] R 13 , R 14 , R 15 , R 30 are each independently selected from H, deuterium, C1-6 alkyl or halogen;

[0143] M1, M2, M3, M4, M5, M6, M7, M8, M9, M 10 M 11 M 12 M 13 M 14 M 15 M 16 M 17 M 18 M 19 M 20 M 21 M 22 M 23 each independently selected from C, N, O, P or S,

[0144] M 24 M 25 each independently selected from CH, N, CH2, NH, O or S; M 26 selected from CH, N, O or S;

[0145] between M1and M2, between M2and M3, between M4and M5, between M5and M6, between M6and M7, between M 10 and M 11 and M 11 and M 12 and M 11 and M 16 and M 12 and M 13 and M 13 and M 14 and M 14 and M 15 and M 15 and M 16 and M 17 and M 18 and M 18 and M 19 and M 19 and M 20 and M 19 and M 23 and M 20 and M 21 and M 21 and M 22 and M 22 and M 23 and M 24 and M 25 M 25 M 26each independently is a single or double bond, wherein the two adjacent chemical bonds are not both double bonds;

[0146] said R 11 ,R 12 ,R 21 ,R 22 ,R 31 ,R 32， R 41 ,R 42 ,R 51 ,R 52 ,R 61 ,R 62 ,R 71 ,R 72 ,R 16 ,R 17 ,R 18 ,R 19 ,R 23 ,R 24 ,R 81 ,R 82 ,R 91 ,R 92 ,R 101 ,R 102 ,R 121 ,R 131 ,R 141 ,R 211 ,R 221 ,R 261 each independently is selected from: nothing, hydrogen, deuterium, halogen, -C 1～6 alkyl (preferably methyl or isopropyl), =O, -(CH2)n-OH, -(CH2)n-CN, -(CH2)n-O-(CH2)n-CH3, -O-(CH2)n-CH3, -(CH2)n-CX3, -(CH2)n-CH2X, C 3-10 cycloalkyl (preferably cyclopropanyl), 3-10 membered heterocyclyl (preferably oxetanyl), -NH2, =NH, -CO-NH2, -CO-(CH2)n-CH3, -CO-CH(CH3)OH, -CO-(CH2)n-CX3, -SO2-(CH2)n-CH3, =CF2or =CHF; wherein, said X is F, Cl, Br or I; said n is 0-6; and (I)-O satisfies one of the following conditions:

[0147] 1)R 11 ,R 12 and the atom to which it is attached forms a C 5-10 cycloalkyl, 5-10 membered heterocyclyl;

[0148] 2)R 21 ,R 22 and the atom to which it is attached forms a C5-10 cycloalkyl, 5- to 10-membered heterocyclyl;

[0149] 3) R 31 R 32 with the atom to which it is attached to form C 5-10 cycloalkyl, 5- to 10-membered heterocyclyl;

[0150] (I)-2 satisfies one of the following conditions:

[0151] 4) R 41 R 42 with the atom to which it is attached to form C 4-9 cycloalkyl, 4- to 9-membered heterocyclyl;

[0152] 5) R 51 R 52 with the atom to which it is attached to form C 4-9 cycloalkyl, 4- to 9-membered heterocyclyl;

[0153] 6) R 61 R 62 with the atom to which it is attached to form C 4-9 cycloalkyl, 4- to 9-membered heterocyclyl;

[0154] 7) R 71 R 72 with the atom to which it is attached to form C 4-9 cycloalkyl, 4- to 9-membered heterocyclyl;

[0155] (I)-3 satisfies one of the following conditions:

[0156] 8) R 16 R 17 with the atom to which it is attached to form C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl;

[0157] 9) R 18 R 19 with the atom to which it is attached to form C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl;

[0158] 10) R 23 R 24 with the atom to which it is attached to form C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl;

[0159] 11) R 81 R 82 with the atom to which it is attached to form C 3-8 cycloalkyl, 3- to 8-membered heterocyclyl;

[0160] 12) R 91 R 92 with the atom to which it is attached to form C3-8 cycloalkyl groups, 3- to 8-membered heterocyclic groups;

[0161] Wherein, C is optionally mentioned 3-8 cycloalkyl, C 4-9 cycloalkyl, C 5-10 Cycloalkyl, 3-8 membered heterocyclic, 4-9 membered heterocyclic, and 5-10 membered heterocyclic groups are substituted by one or more of the following substituents: deuterium; halogen; -C 1～6 Alkyl group (preferably methyl or isopropyl); =O; -(CH2) n -OH;-(CH2)n-CN;-(CH2) n -O-(CH2) n -CH3; -O-(CH2) n -CH3; -(CH2) n -CX3; -(CH2) n -CH2X; -NH2; =NH; -CO-NH2; -CO-(CH2) n -CH3; -CO-(CH2)n-CX3; -SO2-(CH2)n-CH3; -CO-CH(CH3)OH, =CF2, =CHF; where n is independently 0 to 6; and X is F, Cl, Br, or I;

[0162] The C 3-8 cycloalkyl, C 4-9 cycloalkyl, C 5-10 Cycloalkyl, 3-8 membered heterocyclic groups, 4-9 membered heterocyclic groups, and 5-10 membered heterocyclic groups include spirocyclic (e.g., spiroheterocyclic or spirocarbon-cyclic) or fused-ring (e.g., fused-heterocyclic or fused-carbon-cyclic);

[0163] The 3-8 membered heterocyclic group, 4-9 membered heterocyclic group, and 5-10 membered heterocyclic group include one or more heteroatoms each independently selected from N, O, and S, wherein when there are more than two heteroatoms, the heteroatoms are the same, partially the same, or completely different.

[0164] The structure shown in equation (Ⅰ)-0 includes R 11 ,R 12 R 21 ,R 22 The ring formed by the atoms connected to it, or R 31 ,R 32 The ring formed by the atoms connected to it;

[0165] The structure shown in equation (Ⅰ)-2 includes R 41 ,R 42 R 51 ,R 52 The ring formed by the atoms connected to it, R61 ,R 62 The ring formed by the atoms connected to it, or R 71 ,R 72 The ring formed by the atoms connected to it;

[0166] The structure shown in equation (Ⅰ)-3 includes R 16 ,R 17 R 18 ,R 19 R 23 ,R 24 R 81 ,R 82 The ring formed by the atoms connected to it, or R 91 ,R 92 A ring formed by atoms connected to it.

[0167] In this invention, as one of the preferred embodiments, the R 2 Selected from:

[0168] Among them, R 13 ,R 14 ,R 15 Each is independently selected from H, deuterium, and C. 1-6 Alkyl or halogen;

[0169] M1, M2, M3, M4, M5, M6, M7, M8, M9, M 10 M 11 M 12 M 13 M 14 M 15 M 16 M 17 M 18 M 19 M 20 M 21 M 22 M 23 Each is independently selected from C, N, O, P, or S.

[0170] Between M1 and M2, between M2 and M3, between M4 and M5, between M5 and M6, between M6 and M7, M 10 and M 11 Between, M 11 and M 12 Between, M 11 and M 16 Between, M 12 and M 13 Between, M 13 and M 14between M 14 and M 15 between M 15 and M 16 between M 17 and M 18 between M 18 and M 19 between M 19 and M 20 between M 19 and M 23 between M 20 and M 21 between M 21 and M 22 between M 22 and M 23 are each independently a single or double bond, wherein the two adjacent chemical bonds are not both double bonds;

[0171] said R 11 , R 12 , R 21 , R 22 , R 31 , R 32， R 41 , R 42 , R 51 , R 52 , R 61 , R 62 , R 71 , R 72 , R 16 , R 17 , R 18 , R 19 , R 23 , R 24 , R 81 , R 82 , R 91 , R 92 , R 101 , R 102 , R 121 , R 131 , R 141 , R 211 , R 221 , R 261 are each independently selected from the group consisting of: nothing, hydrogen, deuterium, halogen, -C 1～6 alkyl (preferably methyl or isopropyl), =0, -(CH2)n-OH, -(CH2)n-O-(CH2)n-CH3, -O-(CH2)n-CH3, -(CH2)n-CH2X, C 3-10cycloalkyl (preferably cyclopropane), 3-10 membered heterocyclyl (preferably dioxetane), -NH2, =NH, -CO-NH2, or -CO-(CH2)n-CH3; wherein said X is F, Cl, Br or I; said n is 0-6; or

[0172] 1) R 11 ,R 12 with the atom connecting them forming a C 3-10 cycloalkyl, 3-10 membered heterocyclyl;

[0173] 2) R 21 ,R 22 with the atom connecting them forming a C 3-10 cycloalkyl, 3-10 membered heterocyclyl;

[0174] 3) R 31 ,R 32 with the atom connecting them forming a C 3-10 cycloalkyl, 3-10 membered heterocyclyl;

[0175] 4) R 41 ,R 42 with the atom connecting them forming a C 3-10 cycloalkyl, 3-10 membered heterocyclyl;

[0176] 5) R 51 ,R 52 with the atom connecting them forming a C 3-10 cycloalkyl, 3-10 membered heterocyclyl;

[0177] 6) R 61 ,R 62 with the atom connecting them forming a C 3-10 cycloalkyl, 3-10 membered heterocyclyl;

[0178] 7) R 71 ,R 72 with the atom connecting them forming a C 3-10 cycloalkyl, 3-10 membered heterocyclyl;

[0179] 8) R 16 ,R 17 with the atom connecting them forming a C 3-10 cycloalkyl, 3-10 membered heterocyclyl;

[0180] 9) R 18 ,R 19 with the atom connecting them forming a C 3-10 cycloalkyl, 3-10 membered heterocyclyl;

[0181] 10) R 23 ,R 24 with the atom connecting them forming a C 3-10cycloalkyl, 3-10 membered heterocyclyl;

[0182] 11)R 81 ,R 82 with the connecting atom to form a C 3-10 cycloalkyl, 3-10 membered heterocyclyl;

[0183] 12)R 91 ,R 92 with the connecting atom to form a C 3-10 cycloalkyl, 3-10 membered heterocyclyl; or

[0184] 13)R 101 ,R 102 with the connecting atom to form a C 3-10 cycloalkyl, 3-10 membered heterocyclyl;

[0185] wherein, optionally, the C 3-10 cycloalkyl, 3-10 membered heterocyclyl is substituted with one or more of the following substituents: deuterium; halogen; -C 1～6 alkyl (preferably methyl or isopropyl); =0; -(CH2) n -OH; -(CH2) n -O-(CH2) n -CH3; -O-(CH2) n -CH3; -(CH2) n -CH2X; said X is F, Cl, Br, or I; -NH2; =NH; -CO-NH2 or -CO-(CH2) n -CH3 wherein each n is independently 0-6;

[0186] said 3-10 membered heterocyclyl or substituted 3-10 membered heterocyclyl comprises one or more heteroatoms each independently selected from N, O, S, wherein when there are more than one heteroatom, said heteroatoms are the same, partially the same or completely different;

[0187] said structure represented by formula (I)-1 comprises R 11 ,R 12 a ring formed with the connecting atom, R 21 ,R 22 a ring formed with the connecting atom, or R 31 ,R 32 a ring formed with the connecting atom;

[0188] said structure represented by formula (I)-2 comprises R 41 ,R 42 a ring formed with the connecting atom, R 51 ,R 52 a ring formed with the connecting atom, R 61 ,R62 a ring formed with the atom to which it is attached, or R 71 a ring formed with the atom to which it is attached 72 a ring formed with the atom to which it is attached

[0189] the structure represented by formula (I)-3 includes R 16 a ring formed with the atom to which it is attached 17 a ring formed with the atom to which it is attached, R 18 a ring formed with the atom to which it is attached 19 a ring formed with the atom to which it is attached, R 23 a ring formed with the atom to which it is attached 24 a ring formed with the atom to which it is attached, R 81 a ring formed with the atom to which it is attached 82 a ring formed with the atom to which it is attached, or R 91 a ring formed with the atom to which it is attached 92 a ring formed with the atom to which it is attached

[0190] In the present application, as one of the embodiments, the R 2 is selected from:

[0191] M1, M2, M3 are each independently selected from C, N, O, P or S;

[0192] in the structure represented by formula (I)-1, R 11 a ring formed with the atom to which it is attached 12 a ring formed with the atom to which it is attached 21 a ring formed with the atom to which it is attached 22 a ring formed with the atom to which it is attached 31 a ring formed with the atom to which it is attached 32 are each independently selected from: nothing, hydrogen, deuterium, halogen, -C 1～6 alkyl (preferably methyl or tert-butyl), CF3, =O, -(CH2)n-OH, -(CH2)n-O-(CH2)n-CH3, -O-(CH2)n-CH3, -(CH2)n-CX3, -(CH2)n-CH2X, C 3-6 cycloalkyl (preferably cyclopropane), 4-7-membered heterocyclyl (preferably oxetanyl), =NH, -NH2, -CO-NH2, or -CO-(CH2)n-CH3, wherein the X is F, Cl, Br, or I, and the n is 0-6; and one of the following conditions is satisfied:

[0193] 1) R 11 a ring formed with the atom to which it is attached 12 a ring formed with the atom to which it is attached, the ring being selected from C 5-10 cycloalkyl, 5-10-membered heterocyclyl (preferably C 5-9 cycloalkyl, 5-9-membered heterocyclyl);

[0194] 2) R 21 a ring formed with the atom to which it is attached 22 a ring formed with the atom to which it is attached, the ring being selected from C5-10 cycloalkyl, 5-10 membered heterocyclyl (preferably C 5-7 cycloalkyl, 5-7 membered heterocyclyl);

[0195] 3) R 31 R 32 forming a ring with the atom to which it is attached, said ring being selected from C 5-10 cycloalkyl, 5-10 membered heterocyclyl (preferably C 5-9 cycloalkyl, 5-9 membered heterocyclyl, more preferably 6 membered heterocyclyl);

[0196] wherein said structure of formula (I)-1 includes R 11 R 12 forming a ring with the atom to which it is attached, R 21 R 22 forming a ring with the atom to which it is attached, or R 31 R 32 forming a ring with the atom to which it is attached;

[0197] said 5-10 membered heterocyclyl includes one or more heteroatoms each independently selected from N, O, S; optionally said C 5-10 cycloalkyl, 5-10 membered heterocyclyl is substituted with one or more of the following substituents: deuterium, halogen, -C 1～6 alkyl (preferably methyl, ethyl or isopropyl), =0, -(CH2) n -OH, -(CH2)n-CN, -(CH2) n -O-(CH2) n -CH3, -O-(CH2) n -CH3, -(CH2) n -CX3, -(CH2) n -CH2X, -NH2, =NH, -CO-NH 2、 -CO-(CH2)n-CX3, -CO-(CH2) n -CH3, -SO2-(CH2)n-CH3, -CO-CH(CH3)OH, =CF2 or =CHF wherein said X is F, Cl, Br, or I, and said n is 0-6.

[0198] In the present invention, as one of the embodiments, said R 2 is selected from:

[0199] M1, M2, M3 are each independently selected from C, N, O, P or S;

[0200] In the structure of formula (I)-1, R 11 R 12 R 21 R22 ,R 31 ,R 32 each independently selected from the group consisting of: nothing, hydrogen, deuterium, halogen, methyl, isopropyl, tert-butyl, =O, -(CH2)n-OH, -(CH2)n-O-(CH2)n-CH3, -O-(CH2)n-CH3, -(CH2)n-CX3, -(CH2)n-CH2X, C 3-6 cycloalkyl (preferably cyclopropane), 4-7 membered heterocyclyl (preferably oxetanyl); =NH, -NH2, -CO-NH2, or -CO-(CH2)n-CH3, wherein the X is F, Cl, Br, or I, and the n is 0-6; and one of the following conditions is satisfied:

[0201] 1) R 11 ,R 12 and the ring formed with the atom to which it is attached, 2) R 21 ,R 22 and the ring formed with the atom to which it is attached, or 3) R 31 ,R 32 and the ring formed with the atom to which it is attached, each independently selected from the group consisting of:

[0202] In the present invention, as one of the preferred embodiments, the R 2 is selected from the group consisting of:

[0203] M1, M2, M3 are each independently selected from C, N, O, P or S;

[0204] In the structure represented by formula (I)-1, R 11 ,R 12 ,R 21 ,R 22 ,R 31 ,R 32 each independently selected from the group consisting of: nothing, hydrogen, deuterium, halogen, -C 1～6 alkyl (preferably methyl or isopropyl), =O, -(CH2)n-OH, -(CH2)n-O-(CH2)n-CH3, -O-(CH2)n-CH3, -(CH2)n-CH2X, C 3-10 cycloalkyl (preferably cyclopropane), 3-10 membered heterocyclyl (preferably oxetanyl); =NH, -NH2, -CO-NH2, or -CO-(CH2)n-CH3, wherein the X is F, Cl, Br, or I, and the n is 0-6; or

[0205] R 11 ,R 12 and the ring formed with the atom to which it is attached, the ring being selected from C 3-10cycloalkyl, 3-10 membered heterocyclyl;

[0206] R 21 R 22 form a ring with the atom to which they are attached, said ring being selected from C 3-10 cycloalkyl, 3-10 membered heterocyclyl;

[0207] R 31 R 32 form a ring with the atom to which they are attached, said ring being selected from C 3-10 cycloalkyl, or 3-10 membered heterocyclyl;

[0208] wherein the structure represented by formula (I)-1 includes R 11 R 12 form a ring with the atom to which they are attached, R 21 R 22 form a ring with the atom to which they are attached, or R 31 R 32 form a ring with the atom to which they are attached;

[0209] said 3-10 membered heterocyclyl or 3-10 membered heterocyclyl includes one or more heteroatoms each independently selected from N, O, S; optionally said C 3-10 cycloalkyl, 3-10 membered heterocyclyl is substituted with one or more of the following substituents: deuterium, halogen, -C 1～6 alkyl (preferably methyl or isopropyl), =O, -(CH2) n -OH, -(CH2) n -O-(CH2) n -CH3, -O-(CH2) n -CH3, -(CH2) n -CH2X, -NH2, =NH, -CO-NH2 or -CO-(CH2) n -CH3, wherein said X is F, Cl, Br, or I, and said n is 0-6.

[0210] In the present application, as one of the preferred schemes, said R 2 is selected from:

[0211] M1, M2, M3 are each independently selected from C, N, O, P or S;

[0212] in the structure represented by formula (I)-1, R 11 R 12 R 21 R 22 R 31 R 32each independently selected from: nothing, hydrogen, deuterium, halogen, methyl or isopropyl; =O; -(CH2)n-OH; -(CH2)n-O-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X, C 3-10 cycloalkyl (preferably cyclopropane), 3-10 membered heterocyclyl (preferably oxetane); =NH, -NH2, -CO-NH2, or -CO-(CH2)n-CH3, wherein the X is F, Cl, Br, or I, and the n is 0-6; or

[0213] R 11 R 12 with the atom to which it is attached forming a ring, R 21 R 22 with the atom to which it is attached forming a ring, or R 31 R 32 with the atom to which it is attached forming a ring, each of which is independently selected from:

[0214] In the present application, as one of the embodiments, the R 2 is selected from:

[0215] wherein the R 13 R 14 R 15 each independently selected from: H, deuterium, C 1-6 alkyl or halogen;

[0216] M4, M5, M6, M7 are each independently selected from C, N, O, P or S;

[0217] each independently a single bond or a double bond, wherein no two adjacent chemical bonds are both double bonds;

[0218] In the structure shown in formula (I)-2, the R 41 R 42 R 51 R 52 R 61 R 62 R 71 R 72 each independently selected from: nothing; hydrogen; deuterium; halogen; -C 1～6 alkyl (preferably methyl or isopropyl); =O; -(CH2)n-OH; -(CH2)n-O-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X; C 3-6cycloalkyl (preferably cyclopropane), 4-7 membered heterocyclyl (preferably oxetanyl), =NH; -NH2; -CO-NH2; or -CO-(CH2)n-CH3; wherein, said X is F, Cl, Br, or I, said n is 0-6; and one of the following conditions is met:

[0219] 1) R 41 ,R 42 and the atoms connecting them form a ring selected from C 4-9 cycloalkyl, 4-9 membered heterocyclyl (preferably C 4-6 cycloalkyl, 4-6 membered heterocyclyl);

[0220] 2) R 51 ,R 52 and the atoms connecting them form a ring selected from C 4-9 cycloalkyl, 4-9 membered heterocyclyl (preferably C 4-6 cycloalkyl, 4-6 membered heterocyclyl);

[0221] 3) R 61 ,R 62 and the atoms connecting them form a ring selected from C 4-9 cycloalkyl, 4-9 membered heterocyclyl (preferably C 4-6 cycloalkyl, 4-6 membered heterocyclyl, more preferably 6 membered heterocyclyl);

[0222] 4) R 71 ,R 72 and the atoms connecting them form a ring selected from C 4-9 cycloalkyl, 4-9 membered heterocyclyl (preferably C 4-6 cycloalkyl, 4-6 membered heterocyclyl);

[0223] said 4-9 membered heterocyclyl includes one or more heteroatoms each independently selected from N, O, S, and when including more than two heteroatoms, they can be the same, partially the same, or completely different;

[0224] said structure of (I)-2 includes R 41 ,R 42 and the atoms connecting them form a ring, R 51 ,R 52 and the atoms connecting them form a ring, R 61 ,R 62 and the atoms connecting them form a ring, or R 71 ,R 72 and the atoms connecting them form a ring;

[0225] optionally said C 4-9 cycloalkyl, 4-9 membered heterocyclyl is substituted with one or more of the following: deuterium; halogen; -C 1～6alkyl (preferably methyl or isopropyl); =O; -(CH2)n-OH; -(CH2)n-O-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X; C n -OH; -(CH2)n-OH; -(CH2)n-O-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X; C n -OH; -(CH2)n-OH; -(CH2)n-O-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X; C n -OH; -(CH2)n-OH; -(CH2)n-O-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X; C n -OH; -(CH2)n-OH; -(CH2)n-O-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X; C n -OH; -(CH2)n-OH; -(CH2)n-O-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X; C n -OH; -(CH2)n-OH; -(CH2)n-O-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X; C

[0226] In the present application, as one of the embodiments, the R 2 is selected from:

[0227] In the present application, as one of the embodiments, the R 13 is selected from: 14 is selected from: 15 are each independently selected from: H, deuterium, C 1-6 alkyl or halogen;

[0228] M4, M5, M6, M7 are each independently selected from C, N, O, P or S;

[0229] M4and M5, M5and M6, M6and M7are each independently single bond or double bond, wherein the adjacent two chemical bonds are not double bond at the same time;

[0230] In the structure shown in formula (I)-2, the R 41 is selected from: 42 is selected from: 51 is selected from: 52 is selected from: 61 is selected from: 62 is selected from: 71 is selected from: 72 are each independently selected from: nothing; hydrogen; deuterium; halogen; -C 1～6 alkyl (preferably methyl or isopropyl); =O; -(CH2)n-OH; -(CH2)n-O-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X; C 3-6 cycloalkyl (preferably cyclopropane), 4-7 membered heterocyclyl (preferably oxetanyl); =NH; -NH2; -CO-NH2; or -CO-(CH2)n-CH3; wherein, the X is F, Cl, Br, or I, the n is 0-6; and one of the following conditions is met:

[0231] 1) the R 41 is selected from: 42 forms a ring with the atom to which it is connected; 2) the R 51 is selected from: 52with the atom to which it is attached forming a ring; 3) R 61 , 62 with the atom to which it is attached forming a ring; or 4) R 71 , 72 with the atom to which it is attached forming a ring;

[0232] each of said rings is independently selected from:

[0233] In the present application, as one of the embodiments, said R 2 is selected from:

[0234] wherein said R 13 , 14 , 15 each independently is selected from H, deuterium, C 1-6 alkyl or halogen;

[0235] said M8, M9are independently selected from C, N, O, P or S;

[0236] Preferably, in the structure represented by formula (I)-3, R 16 , 17, R 18 , 19 , 23 , 24 , 81 , 82 , 91 , 92 , each independently is selected from: nothing; hydrogen; deuterium; halogen; -C 1～6 alkyl (preferably methyl or isopropyl); =O; -(CH2)n-OH; -(CH2)n-O-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X, said X being F, Cl, Br, or I; C 3-6 cycloalkyl (preferably cyclopropane), 4-7 membered heterocyclyl (preferably oxetanyl); =NH-NH2; =NH; -CO-NH2; or -CO-(CH2)n-CH3, wherein n is 0-6; and one of the following conditions is met:

[0237] 1) R 16 , 17 with the atom to which it is attached forming a ring, said ring being selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl (preferably 4 membered heterocyclyl);

[0238] 2) R 18 , 19 with the atom to which it is attached forming a ring, said ring being selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl (preferably 4 membered heterocyclyl);

[0239] 3)R 23 ,R 24 with the connecting atom forms a ring selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl (preferably 4 membered heterocyclyl);

[0240] 4)R 81 ,R 82 with the connecting atom forms a ring selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl;

[0241] 5)R 91 ,R 92 with the connecting atom forms a ring selected from C 3-8 cycloalkyl, 3-8 membered heterocyclyl;

[0242] the structure represented by formula (I)-3 includes R 16 ,R 17 with the connecting atom forms a ring, R 18 ,R 19 with the connecting atom forms a ring, R 23 ,R 24 with the connecting atom forms a ring, R 81 ,R 82 with the connecting atom forms a ring, or R 91 ,R 92 with the connecting atom forms a ring;

[0243] each of said 3-8 membered heterocyclyl independently includes one or more heteroatoms each independently selected from N, O, S, and when including two or more heteroatoms, they are the same, partially the same or completely different;

[0244] said C 3-8 cycloalkyl, 3-8 membered heterocyclyl, each independently is substituted with one or more of the following substituents: deuterium; halogen; -C 1～6 alkyl, preferably methyl or isopropyl; =O; -(CH2) n -OH; -(CH2) n -O-(CH2) n -CH3; -O-(CH2) n -CH3; -(CH2) n -CH2X, said X being F, Cl, Br, or I; -NH2; -CO-NH2; or -CO-(CH2) n -CH3, wherein said n is 0-6.

[0245] In the present application, as one of the embodiments, said R 2 is selected from:

[0246] wherein,

[0247] said R 13 ,R 14 ,R 15 each independently selected from H, deuterium, C 1-6 alkyl or halogen;

[0248] said M8, M9are independently selected from C, N, O, P or S;

[0249] Preferably, in the structure shown in formula (I)-3, R 16 ,R 17, R 18 ,R 19 ,R 23 ,R 24 ,R 81 ,R 82 ,R 91 ,R 92 each independently selected from: nothing; hydrogen; deuterium; halogen; -C 1～6 alkyl (preferably methyl or isopropyl); =O; -(CH2)n-OH; -(CH2)n-O-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X, C 3-6 cycloalkyl (preferably cyclopropane), 4-7 membered heterocyclyl (preferably oxetanyl); =NH; -NH2; -CO-NH2; or -CO-(CH2) n -CH3, wherein said X is F, Cl, Br, or I; said n is 0-6; and one of the following conditions is met:

[0250] 1) R 16 ,R 17 and the atom to which it is attached form a ring; 2) R 18 ,R 19 and the atom to which it is attached form a ring; 3) R 23 ,R 24 and the atom to which it is attached form a ring; 4) R 81 ,R 82 and the atom to which it is attached form a ring; or 5) R 91 ,R 92 and the atom to which it is attached form a ring;

[0251] each of said rings is independently selected from:

[0252] In the present application, as one of the embodiments, said R 2 is selected from:

[0253] wherein,

[0254] said R 13 ,R 14 ,R 15 ,R 30 each independently is selected from H, deuterium, C 1-6 alkyl or halogen;

[0255] said M 10 ,M 11 ,M 12 ,M 13 ,M 14 ,M 15 ,M 16 each independently is selected from C, N, O, P or S;

[0256] M 10 and M 11 , M 11 and M 12 , M 11 and M 16 , M 12 and M 13 , M 13 and M 14 , M 14 and M 15 , M 15 and M 16 each independently is a single or double bond, wherein no two adjacent chemical bonds are double bonds; R 101 ,R 102 ,R 121 ,R 131 ,R 141 each independently is selected from: nothing; hydrogen; deuterium; halogen; -C 1～6 alkyl (preferably methyl or isopropyl); =O; -(CH2)n-OH; -(CH2)n-O-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X; C 3-10 cycloalkyl (preferably cyclopropane), 3-10 membered heterocyclyl (preferably oxetanyl); -NH2; =NH; -CO-NH2; -CO-(CH2) n -CH3, wherein said X is F, Cl, Br, or I, and said n is 0-6.

[0257] In the present application, as one of the embodiments, said R 2 is selected from:

[0258] wherein, R 13 ,R 14 ,R 15 each independently is selected from H, deuterium, C1-6 alkyl or halogen;

[0259] M 17 M 18 M 19 M 20 M 21 M 22 M 23 each independently selected from C, N, O, P or S;

[0260] M 17 and M 18 between M 18 and M 19 between M 19 and M 20 between M 19 and M 23 between M 20 and M 21 between M 21 and M 22 between M 22 and M 23 each independently a single or double bond, wherein no two adjacent chemical bonds are simultaneously double bonds;

[0261] In the structure shown in formula (II)-2, R 211 R 221 each independently selected from hydrogen, deuterium; halogen; -C 1～6 alkyl (preferably methyl or isopropyl); =O; -(CH2)n-OH; -(CH2)n-O-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X; C 3-10 cycloalkyl (preferably cyclopropane), 3-10 membered heterocyclyl (preferably oxetanyl); =NH; -NH2; -CO-NH2; -CO-(CH2) n -CH3, wherein the X is F, Cl, Br, or I, and the n is 0-6.

[0262] In the present application, as one of the embodiments, the R 13 R 14 R 15 each independently selected from H or F.

[0263] In the present application, as one of the embodiments, the R 2 is selected from:

[0264] wherein R 13 R 14 R 15 each independently selected from H, deuterium, C 1-6 alkyl or halogen;

[0265] M 24 、M 25 each independently selected from CH or N; M 26 is selected from N, O or S;

[0266] M 24 and M 25 ,M 25 and M 26 each independently is a single or double bond, wherein the two adjacent chemical bonds are not simultaneously double bonds;

[0267] R 261 is selected from the group consisting of: hydrogen, deuterium, halogen, -C 1～6 alkyl.

[0268] In the present invention, as one of the embodiments, the R 2 is selected from the group consisting of:

[0269] wherein Q1is selected from N or CR 13 ; Q2is selected from N or CR 15 ; Q3is selected from N or CR 14 ; preferably Q1is selected from CR 13 ; Q2is selected from CR 15 ; Q3is selected from CR 14 ;

[0270] R 13 , R 14 , R 15 each independently is selected from H, deuterium, C 1-6 alkyl or halogen; preferably R 13 is selected from H, R 14 is selected from H or halogen (e.g. F), R 15 is selected from H; more preferably R 13 , R 14 , R 15 is selected from H;

[0271] R 11 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, hydroxyC 1-6 alkylene-, C 1-6 alkoxyC 1-6 alkylene-, C 3-6 cycloalkyl, 4-7 membered heterocyclyl; preferably R 11 is selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyC 1-4 alkylene-, C 3-6saturated cycloalkyl, 4-7 membered saturated heterocyclyl;

[0272] R 31 , R 32 together with the carbon atom to which they are attached form a C 3-6 monocyclic cycloalkyl, 4-7 membered monocyclic heterocyclyl, C 7-9 fused bicyclic cycloalkyl, 7-9 membered fused bicyclic heterocyclyl, C 7-9 spiro bicyclic cycloalkyl, 7-9 membered spiro bicyclic heterocyclyl; said C 3-6 monocyclic cycloalkyl, 4-7 membered monocyclic heterocyclyl, C 7-9 fused bicyclic cycloalkyl, 7-9 membered fused bicyclic heterocyclyl, C 7-9 spiro bicyclic cycloalkyl, 7-9 membered spiro bicyclic heterocyclyl optionally substituted with one or more halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -CO-C 1-6 alkyl, -CO-C 1-6 alkylhydroxy, -CO-C 1-6 haloalkyl, -SO2-C 1-6 alkyl, cyano C 1-6 alkylene-; wherein R e , R f are each independently selected from H or halogen;

[0273] Preferably, R 31 , R 32 together with the carbon atom to which they are attached form a 5-6 membered monocyclic oxygen heterocyclyl; optionally said 5-6 membered monocyclic oxygen heterocyclyl is substituted with one or more of the following substituents: deuterium, halogen, -C 1～6 alkyl (preferably methyl or ethyl), =O, -(CH2) n -OH, -(CH2)n-CN, -(CH2) n -O-(CH2) n -CH3, -O-(CH2) n -CH3, -(CH2) n -CX3, -(CH2) n -CH2X, -NH2, =NH, -CO-NH 2、 -CO-(CH2)n-CX3, -CO-(CH2) n -CH3, -SO2-(CH2)n-CH3 or -CO-CH(CH3)OH, =CF2, =CHF; wherein said X is F, Cl, Br, or I, and said n is 0-6.

[0274] In the present application, as one of the embodiments, said R2 is selected from (I)-0-1-1, (I)-0-1-2 or (I)-0-1-3:

[0275] wherein, represents a single or double bond; preferably, represents a single bond;

[0276] Z0is selected from CH, CH2, O, S, NH or N; preferably, Z0is selected from O;

[0277] Z1, Z2, Z3are each independently selected from CH2or O;

[0278] v1, v2, v3, v4, v5are each independently selected from 0 or 1; preferably, v1is selected from 1;

[0279] s is selected from 0, 1 or 2; preferably, s is selected from 0;

[0280] ring D is selected from C 3-6 cycloalkyl or phenyl;

[0281] R ’ is selected from halogen, oxo, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, -CO-C 1-6 alkyl, -CO-C 1-6 haloalkyl, -SO2-C 1-6 alkyl, cyano C 1-6 alkylene-, -CO-C 1-6 alkylhydroxy; wherein R e , R f are each independently selected from H or halogen;

[0282] R" is selected from H or C 1-6 alkyl;

[0283] wherein, Q1is selected from N or CR 13 ; Q2is selected from N or CR 15 ; Q3is selected from N or CR 14 ; preferably, Q1is selected from CR 13 ; Q2is selected from CR 15 ; Q3is selected from CR 14 ;

[0284] R 13 , R 14 , R 15 are each independently selected from H, deuterium, C 1-6 alkyl or halogen; preferably, R 13 is selected from H, R14 selected from H or halogen (e.g. F), R 15 selected from H; more preferably, R 13 , R 14 , R 15 selected from H;

[0285] R 11 selected from H, C 1-6 alkyl, C 1-6 haloalkyl, hydroxyC 1-6 alkylene-, C 1-6 alkoxyC 1-6 alkylene-, C 3-6 cycloalkyl, 4-7 membered heterocyclyl; preferably, R 11 selected from H, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxyC 1-4 alkylene-, C 3-6 saturated cycloalkyl, 4-7 membered saturated heterocyclyl.

[0286] In the present application, as one of the embodiments, said R 2 is selected from:

[0287] said Q1, Q2, Q3, R 11 , R’, s, v1are as defined in any embodiment of the present application.

[0288] In the present application, as one of the embodiments, said R 2 is selected from:

[0289] wherein:

[0290] Q1is selected from N or CR 13 ; Q2is selected from N or CR 15 ; Q3is selected from N or CR 14 ;

[0291] Preferably, Q1is selected from CR 13 ; Q2is selected from CR 15 ; Q3is selected from CR 14 ;

[0292] R 13 , R 14 , R 15 are each independently selected from H or halogen (e.g. F);

[0293] Preferably, R 13 , R 14 , R 15 one of which is selected from halogen (e.g. F) and the rest are H;

[0294] R 13 , R 14 , R 15 are each H;

[0295] R 11 is selected from H, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 deuteroalkyl, hydroxyC 1-6 alkylene-, C 1-4 alkoxyC 1-4 alkylene-, C 3-6 saturated cycloalkyl, 4-7 membered saturated heterocyclyl;

[0296] R 11 is selected from C 1-6 alkyl;

[0297] v3, v4, v5 are each independently selected from 0 or 1 ;

[0298] Preferably, v3, v4 are each 0;

[0299] Preferably, v3, v4 are each 1 ;

[0300] Preferably, v5 is 0;

[0301] Preferably, v5 is 1.

[0302] In the present application, as one of the embodiments, the R 2 is selected from:

[0303] wherein R 13 , R 14 , R 15 are each independently selected from H, deuterium, C 1-6 alkyl or halogen; preferably, R 13 , R 14 , R 15 are each independently selected from H or halogen (e.g. F); preferably, R 13 , R 14 , R 15 one is selected from halogen (e.g. F) and the rest are selected from H; or, preferably, R 13 , R 14 , R 15 are selected from H;

[0304] Z4 is selected from CH2, CF2 or O; preferably, Z4 is selected from O;

[0305] Z5 is selected from CH2, CF2, NR 71or O; preferably, Z5is selected from CH2, 71 or O; preferably, Z5is selected from CH2,

[0306] Preferably, for formula I-2-A, when Z5is selected from NR 71 or O; preferably, Z4is selected from O;

[0307] Preferably, for formula I-2-A, when Z5is selected from CH2or CF2, Z4is selected from CH2, CF2or O, preferably CF2or O, more preferably O;

[0308] R 41 , R 71 are each independently selected from C 1-6 alkyl; preferably, R 41 , R 71 are each independently selected from C 1-4 alkyl (e.g., methyl);

[0309] V6, v7are each independently selected from 0 or 1; preferably, V6, v7are both selected from 0 or V6, v7are both selected from 1.

[0310] In the present application, as one of the embodiments, the R 2 is selected from:

[0311] wherein the R 13 , R 14 , R 15 are each independently selected from H, deuterium, C 1-6 alkyl or halogen; preferably, R 13 , R 14 , R 15 are each independently selected from H or halogen (e.g., F); preferably, R 13 , R 14 , R 15 one is selected from halogen (e.g., F) and the rest is selected from H; or, preferably, R 13 , R 14 , R 15 are all H;

[0312] R 41 is C 1-6 alkyl (e.g., methyl).

[0313] In the present application, as one of the embodiments, the R 2 is selected from:

[0314] wherein:

[0315] R 13 , R 14 and R15 each independently selected from hydrogen or halogen (e.g. F), preferably R 13 , R 14 and R 15 one of which is halogen (e.g. F) and the others are hydrogen; or, more preferably R 13 , R 14 and R 15 are all hydrogen;

[0316] M 10 is selected from N, O or S, preferably N;

[0317] R 101 is selected from absent, hydrogen, C 1-6 alkyl; with the proviso that when M 10 is selected from O or S, R 101 is selected from absent;

[0318] M 12 , M 13 , M 14 , M 15 are each independently selected from C or N; preferably M 12 , M 13 , M 14 , M 15 one of which is N; more preferably M 12 , M 13 , M 14 , M 15 are all C;

[0319] R 121 , R 131 , R 141 are each independently selected from absent, hydrogen, halogen (e.g. F or CI), C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy; preferably R 121 , R 131 , R 141 are each independently selected from absent, hydrogen, halogen (e.g. F or CI); with the proviso that when M 12 , M 13 , M 14 is selected from N, R 121 , R 131 , R 141 is selected from absent.

[0320] In the present application, as one of the embodiments, said R 2 is selected from:

[0321] In the present application, as one of the embodiments, the R 2 selected from the group consisting of:

[0322] In the present application, as one of the embodiments, the R 2 selected from the group consisting of: preferably

[0323] In the present application, as one of the embodiments, the R 2 selected from the group consisting of:

[0324] In the present application, as one of the embodiments, the R 2 selected from the group consisting of:

[0325] In the present application, as one of the embodiments, the C 1～6 alkyl or C 1-6 Cycloalkyl, as an illustrative example, includes, but is not limited to, methyl, ethyl, propyl, isopropyl, cyclopropyl, isobutyl, n-butyl, sec-butyl, t-butyl, cyclobutyl, pentyl, isopentyl, cyclopentyl, hexyl, isohexyl, 3-methylpentyl, 2-ethylbutyl, 2,2-dimethylbutyl, 2,3-dimethylbutyl, or cyclohexyl, and the like.

[0326] In the present application, as one of the embodiments, the C 1-6 alkoxy or C 1-6 Cycloalkoxy, as an illustrative example, includes, but is not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropoxy, isobutoxy, n-butoxy, sec-butoxy, t-butoxy, cyclobutoxy, pentoxy, isopentoxy, cyclopentoxy, hexoxy, isohexoxy, 3-methylpentoxy, 2-ethylbutoxy, 2,2-dimethylbutoxy, 2,3-dimethylbutoxy, or cyclohexoxy, and the like.

[0327] In the present application, as one of the embodiments, the C 1-6 haloalkyl or C 1-6 halocycloalkyl, includes, but is not limited to, halomethyl, haloethyl, halopropyl, haloisopropyl, halocyclopropyl, haloisobutyl, halonormal butyl, halosec butyl, halotert butyl, halocyclobutyl, halopentyl, haloisopentyl, halocyclopentyl, halo hexyl, haloisohexyl, halo 3-methylpentyl, halo 2-ethylbutyl, halo 2,2-dimethylbutyl, halo 2,3-dimethylbutyl, or halocyclohexyl, and the like.

[0328] In the present application, as one of the embodiments, the saturated or unsaturated C 3-8 cycloalkyl, C 3-8 heterocyclyl, haloC 3-8 cycloalkyl, haloC 3-8 heterocyclyl, as an illustrative example, can be cyclopropane, cyclopropene, cyclobutane, cyclobutene, cyclopentane, cyclopentene, cyclohexane, cyclohexene, cycloheptane, cycloheptene, cyclooctane, cyclooctene, etc., in which one, two or more of the carbon atoms are each independently replaced with O, N, S.

[0329] In the present application, as one of the embodiments, the halogen or halo includes, but is not limited to, F, Cl, Br or I substitution.

[0330] In the present application, as one of the embodiments, the C 2～6 alkenyl, as an illustrative example, can be a linear chain alkenyl group having 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and having at least one double bond at any position, including, for example, ethenylene, alkenylene, propenylene, butenylene, isoprenylene, butadienylene, pentenylene, pentadienylene, hexenylene, hexadienylene, etc.

[0331] In the present application, as one of the embodiments, the C 2～6 alkynyl, as an illustrative example, can be a linear chain alkynyl group having 2 to 4 carbon atoms, preferably 2 to 4 carbon atoms, and having at least one triple bond at any position, including, for example, ethynylene, propynylene, butynylene, pentynylene, hexynylene, etc.

[0332] The "isomers" refer to chemical compounds having the same chemical composition but different structures and properties, including, but not limited to, enantiomers, diastereomers, racemates, stereoisomers, tautomers, geometric isomers.

[0333] The "isotope-labeled compound" refers to a compound in which one or more atoms in its molecule are substituted by its isotope or other easily identifiable nuclide.

[0334] The "alkyl" refers to a saturated aliphatic hydrocarbon group, with C 1～6 As an example, the alkyl is a straight chain or branched chain group containing 1-6 carbon atoms, including, but not limited to, methyl, ethyl, propyl, pentyl, hexyl, t-butyl, s-butyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, 1,1,2-trimethylpropyl, etc. aliphatic alkyl groups.

[0335] The term "cycloalkyl" refers to saturated or partially unsaturated monocyclic or polycyclic ring carbon chain structures, preferably containing 3 to 6 carbon atoms, including but not limited to cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like.

[0336] The term "heterocyclyl" refers to saturated or partially unsaturated monocyclic or polycyclic ring hydrocarbon substituent groups containing 3 to 20 ring atoms, one or more of which are heteroatoms selected from nitrogen, oxygen, or S(O)z(where z is selected from 0, 1, or 2), but excluding ring moieties of -O-O-, -O-S-, or -S-S-, the remainder of which are carbon. Preferably, 3 to 12 ring atoms are contained, of which 1 to 4 are heteroatoms; more preferably, 3 to 6 ring atoms are contained. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, imidazolidinyl, tetrahydrofuranyl, tetrahydrothienyl, dihydroimidazolyl, dihydrofuranyl, dihydropyrazolyl, dihydropyrrolyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, and the like.

[0337] The term "alkoxy," "cycloalkoxy" refers to -O-alkyl and -O-(cycloalkyl), where alkyl and cycloalkyl are as defined above. Included, but not limited to, methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, and the like.

[0338] The term "aryl" refers to a 6- to 14-membered all-carbon monocyclic or fused polycyclic (that is, rings which share adjacent pairs of carbon atoms) ring systems having a conjugated pi-electron system, preferably 6- to 10-membered, such as phenyl and naphthyl. "Aryl ring" refers to the ring system in aryl groups.

[0339] The term "heteroaryl" (also "heteroaromatic") refers to a heteroaromatic system containing heteroatoms selected from oxygen, sulfur, and nitrogen. Heteroaryl groups are preferably 5- to 12-membered, such as imidazolyl, furanyl, thienyl, thiazolyl, pyrazolyl, oxazolyl, pyrrolyl, tetrazolyl, pyridyl, pyrimidinyl, thiadiazolyl, pyrazinyl, carbazolyl, indolyl, and the like. "Heteroaromatic ring" (also "heteroaromatic ring") refers to the ring system in heteroaryl groups.

[0340] The term "spirocyclic" refers to a polycyclic group of 5- to 20-membered rings sharing a single carbon atom (termed a spiro atom) between single rings, which can contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. Preferably, 5- to 14-membered. Spirocyclic alkyl groups are classified as mono-, bi-, or polyspirocyclic, preferably mono- and bi-spirocyclic, depending on the number of spiro atoms between rings. More preferably, 3-membered / 3-membered, 3-membered / 4-membered, 3-membered / 5-membered, or 3-membered / 6-membered mono-spirocyclic.

[0341] The term "halo" refers to a group capable of being substituted with any one or more F, Cl, Br, I atoms.

[0342] In the present application, the "*" involved in the structure of the compound indicates that the atom marked is a chiral atom, which is one of R or S configuration.

[0343] The "prodrug" refers to a compound which is inactive or less active in vitro after chemical structure modification by a person skilled in the art, and exerts a pharmaceutical effect by releasing an active drug of the compound of the present application in vivo through enzymatic or non-enzymatic conversion. It includes but is not limited to all prodrugs of the compound of the present application, which can provide the compound of the present application or its active metabolites or residues (directly or indirectly) after being administered to the human or animal body.

[0344] The "pharmaceutically acceptable salt" used in the present application refers to anionic and cationic salts of the compound of the present application, including but not limited to, more specifically, the compound with a specific substituent discovered in the present application is prepared with a relatively non-toxic acid or base. The pharmaceutically acceptable acid addition salt includes but is not limited to hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, phosphoric acid, sulfuric acid, phosphinic acid, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and the like. The base salt includes but is not limited to metal salt, alkaline earth metal salt, ammonium salt and the like, or salt formed with an organic base, such as trialkylamine, pyridine, quinoline, piperidine, imidazole, methylpyridine, dimethylaminopyridine, dimethylphenylamine, N-alkylmorpholine, 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), 1,4-diazabicyclo[2.2.2]octane (DABCO) and the like;

[0345] The "pharmaceutically acceptable ester" refers to an ester formed by the active ingredient of the present application with an acid or an alcohol, which is suitable for use as a drug, and is an ester formed by one or more hydroxyl groups of the active ingredient of the present application with an acid. The acid suitable for forming an ester includes but is not limited to phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, picric acid, methanesulfonic acid, benzenesulfonic acid, benzenesulfonic acid and the like; the alcohol suitable for forming an ester includes but is not limited to C1-C6 alkyl-OH, such as methanol, ethanol, n-propanol, isopropanol and the like.

[0346] The complex formed by the pharmaceutically acceptable solvent includes but is not limited to water, ethanol, acetic acid, N,N-dimethylformamide, dimethyl sulfoxide, isopropanol, acetonitrile, tetrahydrofuran, acetone or propylene glycol and the like;

[0347] In the present application, as one of the embodiments, the compound is selected from:

[0348] The present application provides a pharmaceutical composition comprising any of the above-mentioned compounds, salts thereof, or solvates of the compounds or the salts thereof as an active ingredient.

[0349] The present application also provides the use of any of the above-mentioned compounds, salts thereof, or solvates of the compounds or the salts thereof, or a pharmaceutical composition containing the same for the manufacture of a medicament for treating non-insulin dependent diabetes (type 2 diabetes), hyperglycemia, impaired glucose tolerance, insulin dependent diabetes (type 1 diabetes), diabetic complications, obesity, cardiovascular diseases, chronic kidney disease, non-alcoholic steatohepatitis, Parkinson's disease, or dementia. As one of the embodiments, the use for the manufacture of a medicament for treating non-insulin dependent diabetes (type 2 diabetes) or obesity.

[0350] The present application provides a pharmaceutical composition comprising any of the above-mentioned compounds, isomers thereof, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof as an active ingredient.

[0351] The present application provides the use of any of the above-mentioned compounds, isomers thereof, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates thereof, or a pharmaceutical composition containing the same for the manufacture of a medicament for treating metabolic diseases, cardiovascular diseases, liver diseases, kidney diseases, neurodegenerative diseases, and other diseases regulated by GLP-1 receptor.

[0352] As one of the embodiments in the present application, the metabolic diseases include diabetes, diabetic complications, obesity; the cardiovascular diseases include hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, cerebral infarction; the liver diseases include non-alcoholic steatohepatitis; the kidney diseases include type 2 diabetes combined with chronic kidney disease; the neurodegenerative diseases include Parkinson's disease or dementia.

[0353] The compounds of the present application can significantly increase the accumulation of cAMP in hGLP-1R CHO-K1 cells. They have excellent human liver microsomal metabolic stability. The inhibitory activity on CYP 2C8 and CYP 2C9 is low, which can reduce the risk of drug-drug interactions (DDI). They have excellent pharmacokinetic properties, and the bioavailability and exposure are significantly improved. DETAILED DESCRIPTION

[0354] The following examples and test examples are used to further illustrate the present application, but in no way limit the effective scope of the present application.

[0355] Example: Synthesis of compounds

[0356] The control compound LY3502970 was prepared according to patent CN109790161B; the structure of the control compound LY3502970 is as follows:

[0357] Example 1: Preparation of compound G-S

[0358] Synthetic route:

[0359] Step 1: Preparation of compounds G-S-2 and G-S-2A

[0360] Under nitrogen protection, a solution of compound G-S-1 (100 g, 780 mmol) in tetrahydrofuran (1000 mL) was added dropwise with lithium bis(trimethylsilyl)amide (1.0 M, 937 mL, 937 mmol) at -78 degrees Celsius. After the addition was completed, the mixture was stirred at -78 degrees Celsius for 1 hour, then N-phenyl bis(trifluoromethanesulfonyl)imide (306 g, 858 mmol) was added, and the temperature was increased to 25 degrees Celsius, and the reaction was carried out for 18 hours. After the reaction was completed, the reaction solution was quenched with saturated ammonium chloride (100 mL), diluted with water (1000 mL) and extracted with ethyl acetate (1000 mL x 2), the organic phase was washed with saturated brine (400 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain a mixture of compounds G-S-2 and G-S-2A. 1 H NMR (400 MHz, CDCl3) δ 5.79-5.62 (m, 1H), 4.24-3.80 (m, 2H), 2.36-2.22 (m, 2H), 1.26-1.22 (m, 6H).

[0361] Step 2: Synthesis of compounds G-S-3 and G-S-3A

[0362] To a mixture of compound G-S-2 and G-S-2A (60.0 g, 231 mmol), potassium acetate (45.4 g, 461 mmol) and bis(pinacolato)diboron (64.5 g, 254 mmol) in 1,4-dioxane (100 mL) was added [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (16.9 g, 23.1 mmol) under nitrogen atmosphere. After three times of nitrogen replacement, the reaction was heated to 90 °C and stirred for 10 hours. The reaction was diluted with water (1000 mL) and extracted with ethyl acetate (1000 mL x 2). The organic phase was washed with saturated brine (400 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give a mixture of compound G-S-3 and G-S-3A. 1 H NMR (400 MHz, CDC13) δ 6.47-6.31 (m, 1H), 4.14-4.12 (m, 1H), 3.68 (t, J = 5.4 Hz, 1H), 2.08-2.01 (m, 2H), 1.20 (s, 12H), 1.18 (s, 3H), 1.13 (s, 3H).

[0363] Step 3: Synthesis of compound G-S-5 and G-S-5A:

[0364] To a mixture of compound G-S-3 and G-S-3A (50.0 g, 210 mmol), potassium carbonate (48.4 g, 350 mmol) and compound G-S-4 (46.9 g, 175 mmol) in a mixture of 1,4-dioxane (500 mL) and water (100 mL) was added [1,1'-bis(diphenylphosphino)ferrocene] palladium dichloride (12.9 g, 17.5 mmol) under nitrogen atmosphere. After three times of nitrogen replacement, the reaction was heated to 100 °C and stirred for 10 hours. The reaction was diluted with water (1000 mL) and extracted with ethyl acetate (1000 mL x 2). The organic phase was washed with saturated brine (400 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 5) to give a mixture of compound G-S-5 and G-S-5A. MS m / z (ESI): 300.2 [M+H] + . 1H NMR (400 MHz, CDC13) δ 8.83 (s, 1H), 7.62-7.54 (m, 1H), 7.37-7.29 (m, 2H), 7.13 (d, J = 2.0 Hz, 1H), 6.05-5.89 (m, 1H), 4.37-4.28 (m, 3H), 3.90 (t, J = 5.2 Hz, 1H), 2.45-2.37 (m, 2H), 1.35 (t, J = 7.2 Hz, 3H), 1.26-1.29 (m, 6H).

[0365] Step 4: Synthesis of compound G-S-6

[0366] To a mixture of compound G-S-5 and G-S-5A (40.0 g, 133.6 mmol) in methanol (150 mL) and N,N-dimethylformamide (150 mL) was added 10% palladium carbon (4.0 g), replaced with hydrogen gas for three times, and the reaction was stirred at 25 °C for 10 hours. After the reaction was filtered through celite, the filter cake was washed with ethyl acetate for three times, diluted with water (500 mL), and extracted with ethyl acetate (500 mL x 2). The organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound G-S-6. MS m / z (ESI): 302.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.47 (s, 1H), 7.38 (d, J = 8.4 Hz, 1H), 7.18 (dd, J = 8.4, 1.6 Hz, 1H), 7.08 (dd, J = 2.4, 0.8 Hz, 1H), 4.33 (q, J = 7.2 Hz, 2H), 3.70 (dd, J = 8.8, 2.0 Hz, 2H), 2.99-2.94 (m, 1H), 1.72-1.64 (m, 2H), 1.60-1.46 (m, 2H), 1.34 (t, J = 7.2 Hz, 3H), 1.26 (s, 3H), 1.18 (s, 3H).

[0367] Step 5: Synthesis of compound G-S-7

[0368] To a solution of compound G-S-6 (34.0 g, 112.8 mmol) in methanol (250 mL) and water (50 mL) was added sodium hydroxide (13.5 g, 338.4 mmol) at 25 °C. The reaction was stirred at 25 °C for 1 h. Then the reaction was warmed to 50 °C for 2 h. The reaction was adjusted to pH about 3 with 2M dilute hydrochloric acid. The solid was precipitated and filtered. The filter cake was washed with water for 3 times and concentrated under reduced pressure to give compound G-S-7. MS m / z (ESI): 274.2 [M+H] + .

[0369] Step 6: Synthesis of compound G-S-8

[0370] To a solution of compound G-S-7 (26.0 g, 95.1 mmol) and N-methylaniline (12.2 g, 114 mmol) in N,N-dimethylacetamide (200 mL) was added N-methylimidazole (15.6 g, 190 mmol), N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (32.0 g, 114 mmol). The reaction was stirred at room temperature for 2 h. After the reaction was completed, the solid was precipitated and filtered. The filter cake was washed with water for 3 times and concentrated under reduced pressure to give compound G-S-8. MS m / z (ESI): 363.2 [M+H] + .

[0371] Step 7: Synthesis of compound F

[0372] To a solution of compound G-S-8 (10.0 g, 27.6 mmol) and potassium tert-butoxide (9.3 g, 82.8 mmol) in N,N-dimethylacetamide (150 mL) was added bromoacetonitrile (6.6 g, 55.2 mmol). The reaction was stirred at 90 °C for 10 h. After the reaction was cooled to room temperature, it was diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 2). The organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 4) to give compound F. MS m / z (ESI): 402.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.56 (d, J = 8.4 Hz, 1H), 7.37-7.33 (m, 4H), 7.28-7.20 (m, 3H), 5.95 (s, 1H), 5.62 (s, 2H), 3.69-3.63 (m, 2H), 3.43 (s, 3H), 2.98-2.90 (m, 1H), 1.65-1.57 (m, 2H), 1.56-1.40 (m, 2H), 1.22 (s, 3H), 1.14 (s, 3H).

[0373] Step 8: Synthesis of compound G-S-11

[0374] To a solution of compound F (7.3 g, 18.2 mmol) and compound G-S-10 (7.53 g, 55.5 mmol) in N,N-dimethylformamide (120 mL) was added lithium bis(trimethylsilyl)amide (1.0 M, 109 mL, 109 mmol) dropwise at -10 °C under nitrogen protection. After the addition was completed, the mixture was stirred at -10 °C for 1 h, then warmed to 25 °C and stirred for 18 h. The reaction was quenched with saturated ammonium chloride (100 mL), diluted with water (500 mL) and extracted with ethyl acetate (500 mL x 2). The organic phase was washed with saturated brine (200 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 1) to give compound G-S-11. MS m / z (ESI): 442.2 [M+H] + .

[0375] Step 9: Synthesis of compound G-S-12

[0376] To a solution of compound G-S-11 (5.0 g, 11.3 mmol) and hydroxylamine hydrochloride (1.6 g, 22.6 mmol) in dimethyl sulfoxide (50 mL) was added sodium bicarbonate (4.7 g, 56.5 mmol) and the reaction was stirred at 60 °C for 10 h under nitrogen protection. After the reaction was cooled to room temperature, water (100 mL) was added to dilute the reaction and extract with ethyl acetate (100 mL x 2). The organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound G-S-12, which was used directly in the next step. MS m / z (ESI): 475.2 [M+H] + .

[0377] Step 10: Synthesis of compound G-S-13

[0378] To a solution of compound G-S-12 (5.0 g, 10.5 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (4.8 g, 31.6 mmol) in dimethyl sulfoxide (50 mL) was added N,N'-carbonyldiimidazole (2.6 g, 15.8 mmol) and the reaction was protected by nitrogen for three times. The reaction was stirred at 25 °C for 3 h. After the reaction was cooled to room temperature, water (100 mL) was added to dilute the reaction and extracted with ethyl acetate (100 mL x 2). The organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 1) to give compound G-S-13. MS m / z (ESI): 501.2 [M+H] + .

[0379] Step 11: Synthesis of compound G-S-14

[0380] Compound G-S-13 (2.7 g, 5.39 mmol) was separated by SFC (separation column: ChiralPak AD 250 x 30 mm I.D., 5 pm, mobile phase: A for CO2 and B for Methanol (0.1% DEA), flow rate: 100 mL / min, column temperature: 35 °C, ABPR: 100 psi) to give the first peak as compound G-S-14A (retention time: 2.458 min) and the second peak as compound G-S-14 (retention time: 2.724 min). Compound G-S-14: 1 H NMR (400 MHz, DMSO-d6) d 12.21 - 11.69 (m, 1H), 7.47 - 7.10 (m, 8H), 6.00 - 5.89 (m, 1H), 3.67 - 3.65 (m, 1H), 3.45 - 3.38 (m, 1H), 2.96 - 2.89 (m, 1H), 2.04 - 2.00 (s, 1H), 1.82 - 1.25 (m, 9H), 1.22 (s, 3H), 1.14 (s, 3H).

[0381] Step 12: Synthesis of compound G-S

[0382] To a solution of compound G-S-14 (1.2 g, 2.4 mmol) in ethylene glycol monomethyl ether (12 mL) was added potassium hydroxide (1.35 g, 24.0 mmol), and the reaction was stirred at 120 °C for 12 h. After the reaction was cooled to room temperature, ice water was added for dilution, 1M dilute hydrochloric acid was added dropwise to adjust the pH to about 3, and ethyl acetate (50 mL x 2) was added for extraction. The organic phase was dried over anhydrous sodium sulfate and concentrated, the residue was slurried with methyl tert-butyl ether, and the filter cake was concentrated and dried to obtain compound G-S. MS m / z (ESI): 412.2 [M+H] + .

[0383] Example 2: Preparation of compound K

[0384] The structural formula of compound K is as follows:

[0385] Synthetic route:

[0386] Step 1: Synthesis of compound D-2

[0387] To a solution of compound D-1 (100 g, 492.5 mmol) in tetrahydrofuran (1000 mL) was slowly added n-butyllithium (197 mL, 492.5 mmol, 2.5 M) dropwise under nitrogen protection at -78 °C, and the reaction mixture was stirred at -78 °C for 1 h, then di-tert-butyl azodicarboxylate (113.5 g, 492.5 mmol) was added, and the mixture was stirred at room temperature for 18 h. The reaction was quenched with saturated ammonium chloride (300 mL) and extracted with ethyl acetate (1000 mL x 2), and the organic phase was washed with saturated brine (600 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain compound D-2. MS m / z (ESI): 377.0 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ 9.60 (s, 1H), 7.00 (t, J = 6.8 Hz, 2H), 2.19 (d, J = 2.4 Hz, 6H), 1.42 (d, J = 6.0 Hz, 18H).

[0388] Step 2: Synthesis of compound D-4

[0389] To a solution of compound D-2 (50.0 g, 141.24 mmol) in dichloromethane (500 mL) was added trifluoroacetic acid (250 mL), the reaction mixture was stirred at room temperature for 2 hours, the reaction was concentrated to dryness, then a solution of pyridine hydrochloride (1.65 g, 14.12 mmol) and (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (33.6 g, 141.24 mmol) in ethanol (500 mL) was added, the reaction mixture was stirred at 85 degrees Celsius for 2 hours. The reaction was quenched with water (200 mL) and extracted with ethyl acetate (500 mL x 2), the organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 4) to give compound D-4. MS m / z (ESI): 375.2 [M+H] + .

[0390] Step 3: Synthesis of compound D-5

[0391] To a solution of aminoacetaldehyde dimethyl acetal (12.0 g, 114 mmol) in tetrahydrofuran (160 mL) was added N,N-diisopropylethylamine (5.92 g, 45.80 mmol) and p-nitrophenyl chloroformate (16.0 g, 79.38 mmol), the reaction mixture was stirred at 40 degrees Celsius for 6 hours under nitrogen protection, the reaction was concentrated to dryness under reduced pressure, then a solution of compound D-4 (5.0 g, 13.35 mmol) in pyridine (50 mL) was added, the reaction was stirred at 40 degrees Celsius for 48 hours. The reaction was quenched with water (100 mL) and extracted with ethyl acetate (200 mL x 2), the organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 1) to give compound D-5. MS m / z (ESI): 506.2 [M+H] + .

[0392] Step 4: Synthesis of compound K

[0393] To a solution of compound D-5 (5.0 g, 9.90 mmol) in tetrahydrofuran (50 mL) was added methanesulfonic acid (761 mg, 7.92 mmol), the reaction mixture was stirred at 60 degree Celsius for 2 hours. After cooling to room temperature, the pH of the reaction solution was adjusted to about 9 by adding saturated potassium phosphate solution, then di-tert-butyl dicarbonate (864 mg, 3.96 mmol) was added to the above mixture, after stirring at room temperature for 1 hour, diluted with water (40 mL), extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain compound K. MS m / z (ESI): 442.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (d, J = 2.4 Hz, 1H), 7.07 (d, J = 6.4 Hz, 2H), 6.57 (dt, J = 16.4, 2.8 Hz, 2H), 5.05 (s, 1H), 3.30 (d, J = 2.8 Hz, 2H), 2.75-2.56 (m, 2H), 2.20 (d, J = 2.0 Hz, 6H), 1.43 (s, 9H), 1.13 (d, J = 6.4 Hz, 3H).

[0394] Example 3: Preparation of compound 1

[0395] Synthetic route:

[0396] Step 1: Synthesis of compound 1-2

[0397] To a solution of compound K (150 mg, 0.34 mmol) in N-methylpyrrolidone (3 mL) was added compound 1-1 (125 mg, 0.51 mmol), potassium carbonate (140 mg, 1.02 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (24 mg, 0.17 mmol) and cuprous iodide (13 mg, 0.07 mmol). The reaction solution was stirred at 130 degree Celsius for 16 hours. Water (3 mL) was added to the reaction solution, extracted with ethyl acetate (2 mL x 3), the combined organic phase was washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to obtain compound 1-2. MS m / z (ESI): 607.4 [M+H] + . 1H NMR (400 MHz, CDC13) δ 8.25 (s, 1H), 8.00 (dd, J = 12.0, 8.0 Hz, 2H), 7.78 (s, 1H), 7.35 (d, J = 2.8 Hz, 2H), 7.16 (d, J = 4.0 Hz, 2H), 7.04 (d, J = 6.4 Hz, 2H), 6.73 (d, J = 3.2 Hz, 1H), 6.24 (d, J = 2.8 Hz, 1H), 5.33-5.12 (m, 1H), 3.15-2.61 (m, 4H), 2.15 (d, J = 2.0 Hz, 6H), 1.43 (s, 9H), 1.27-1.24 (m, 3H).

[0398] Step 2: Synthesis of compound 1-3

[0399] To a solution of compound 1-2 (190 mg, 0.31 mmol) in dichloromethane (2 mL) was added 4 M hydrochloric acid in dioxane (1 mL), and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure to give compound 3, which was used directly in the next step. MS m / z (ESI): 507.2 [M+H] + .

[0400] Step 3: Synthesis of compound 1

[0401] To a solution of compound G-S (20 mg, 0.05 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (50 mg, 0.40 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (55 mg, 0.15 mmol). After the reaction was stirred at room temperature for 30 minutes, compound 1-3 (37 mg, 0.08 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The reaction was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with saturated brine (4 mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC (waters-xbridge-C18-10um-19*250mm, Mobile phase: 0.1% TFA / H20 B:CH3CN, Gradient: 50% B-70% B, Ret 12.48 min) to give compound 1. MS m / z (ESI): 900.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.57 (d, J = 142.4 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.13 (d, J = 8.0 Hz, 1H), 7.90 (s, 1H), 7.57 - 7.46 (m, 2H), 7.41 - 7.37 (m, 4H), 7.29 - 7.15 (m, 5H), 6.98 (d, J = 15.6 Hz, 2H), 5.63 - 5.61 (m, 1H), 4.41 - 4.38 (m, 1H), 3.72 (d, J = 8.4 Hz, 2H), 3.28 - 2.98 (m, 2H), 2.95 - 2.66 (m, 2H), 2.23 (m, 6H), 1.68 (m, 2H), 1.63 - 1.55 (m, 3H), 1.42 (d, J = 6.8 Hz, 3H), 1.26 (d, J = 16.8 Hz, 6H), 1.19 (s, 3H), 1.17 - 1.07 (m, 3H).

[0402] Example 4: Preparation of compound 2

[0403] Synthetic route:

[0404] Step 1: Synthesis of compound 2-2

[0405] To a solution of compound 2-1 (500 mg, 2.04 mmol) in tetrahydrofuran (10 mL) was added sodium hydride (163 mg, 4.08 mmol) under ice-bath, after stirring for 30 min, iodomethane (580 mg, 16.67 mmol) in tetrahydrofuran (4 mL) was added dropwise. The reaction was stirred at room temperature for 1 h. After the reaction was completed, water (10 mL) was added to quench the reaction, and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 4 / 1) to give compound 2-2. MS m / z (ESI): 260.0, 262.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 7.6 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.48 (d, J = 1.6 Hz, 1H), 7.46 - 7.40 (m, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.26 (dd, J = 8.0, 1.6 Hz, 1H), 7.19 - 7.16 (m, 1H), 3.75 (s, 3H).

[0406] Step 2: Synthesis of compound 2-3

[0407] To a solution of compound K (200 mg, 0.45 mmol) in N-methylpyrrolidine (3 mL) was added compound 2-2 (176 mg, 0.68 mmol), potassium carbonate (188 mg, 1.35 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (32 mg, 0.23 mmol) and cuprous iodide (17 mg, 0.09 mmol). The reaction was stirred at 130 °C for 3 h. Water (5 mL) was added to the reaction, which was extracted with ethyl acetate (5 mL x 3), washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate before being concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 3 / 1) to give compound 2-3. MS m / z (ESI): 621.4 [M+H] + . 1 H NMR (400 MHz, CDC13) δ 8.03 (dd, J = 12.0, 8.0 Hz, 2H), 7.71 (s, 1H), 7.43 (t, J = 7.6 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.20 (d, J = 6.8 Hz, 1H), 7.17 (d, J = 4.4 Hz, 1H), 7.06 (d, J = 6.4 Hz, 2H), 6.74 (d, J = 3.2 Hz, 1H), 6.25 (s, 1H), 5.40-5.11 (m, 1H), 4.54-4.16 (m, 1H), 3.80 (s, 3H), 3.17-2.97 (m, 1H), 2.85-2.66 (m, 2H), 2.16 (d, J = 1.6 Hz, 6H), 1.44 (s, 9H), 1.28 (d, J = 6.8 Hz, 3H).

[0408] Step 3: Synthesis of compound 2-4

[0409] To a solution of compound 2-3 (270 mg, 0.44 mmol) in dichloromethane (3 mL) was added 4 M hydrochloric acid in dioxane (1 mL) and the reaction was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure to give compound 2-4, which was used directly in the next step. MS m / z (ESI): 521.2 [M+H] + .

[0410] Step 4: Synthesis of compound 2

[0411] To a solution of compound G-S (30 mg, 0.07 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (75 mg, 0.56 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (83 mg, 0.23 mmol). After the reaction solution was stirred at room temperature for 30 min, compound 2-4 (57 mg, 0.11 mmol) was added, and the reaction solution was stirred at room temperature for 16 h. The reaction solution was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with saturated brine (4 mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC (waters-xbridge-C18-10um-19*250mm, Mobile phase: 0.1% TFA / H2O B:CH3CN, Gradient: 50% B-70% B, Ret 12.98 min) to give compound 2. MS m / z (ESI): 914.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.11 (dd, J = 23.6, 8.0 Hz, 1H), 7.89 (dd, J = 67.6, 8.0 Hz, 1H), 7.71 - 7.35 (m, 5H), 7.34 - 7.09 (m, 5H), 6.97 (dd, J = 22.4, 5.6 Hz, 1H), 6.89 - 6.55 (m, 2H), 5.79 - 5.42 (m, 1H), 4.48 (d, J = 11.6 Hz, 1H), 3.85 (s, 3H), 3.80 - 3.61 (m, 2H), 3.29 - 2.64 (m, 4H), 2.30 - 2.22 (m, 6H), 1.69 (m, 4H), 1.56 (d, J = 7.2 Hz, 3H), 1.36 - 1.23 (m, 6H), 1.20 (s, 3H), 1.11 - 0.85 (m, 3H).

[0412] Example 5: Preparation of compound 3

[0413] Synthetic route:

[0414] Step 1: Synthesis of compound 3-2

[0415] To a solution of compound 3-1 (250 mg, 0.89 mmol) in NMP (10 mL) was added compound K (471 mg, 1.07 mmol), trans-N,N'-dimethylcyclohexane-1,2-diamine (126 mg, 0.89 mmol), potassium carbonate (307 mg, 2.23 mmol) and cuprous iodide (85 mg, 0.045 mmol), the mixture was warmed to 130 Celsius and stirred for 16 hours. The reaction was diluted with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with saturated brine (6 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 3-2. MS m / z (ESI): 643.3 [M+H] + .

[0416] Step 2: Synthesis of compound 3-3

[0417] To a solution of compound 3-2 (200 mg, 0.31 mmol) in DMF (5 mL) was added sodium hydride (25 mg, 0.62 mmol) under ice-bath, the mixture was stirred at room temperature for 30 min, then iodomethane (88 mg, 0.62 mmol) was added, the reaction was stirred at room temperature for 3 hours. The reaction was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with saturated brine (6 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 3-3. MS m / z (ESI): 657.4 [M+H] + .

[0418] Step 3: Synthesis of compound 3-4

[0419] To a solution of compound 3-3 (150 mg, 0.23 mmol) in dichloromethane (5 mL) was added hydrogen chloride in dioxane solution (4.0 M, 0.5 mL), the reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure, the residue was washed with dichloromethane for 3 times and dried to give compound 3-4. MS m / z (ESI): 557.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.65 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 3.2 Hz, 1H), 7.34 - 7.27 (m, 2H), 7.14 (d, J = 6.2 Hz, 2H), 6.94 (d, J = 3.3 Hz, 1H), 4.58 (d, J = 7.2 Hz, 1H), 4.05 (dt, J = 11.6, 5.6 Hz, 2H), 3.83 (dt, J = 11.2, 5.1 Hz, 2H), 3.62 (d, J = 11.2 Hz, 1H), 3.11 (s, 3H), 3.08 - 2.95 (m, 2H), 2.21 (d, J = 2.2 Hz, 6H), 1.73 (t, J = 5.4 Hz, 3H), 1.38 (d, J = 6.4 Hz, 3H), 1.31 - 1.20 (m, 2H).

[0420] Step 4: Synthesis of compound 3

[0421] To a solution of compound G-S (30.00 mg, 0.07 mmol) in N,N- dimethylformamide (0.6 mL) was added N,N-diisopropylethylamine (75 mg, 0.56 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl) uronium hexafluorophosphate (83 mg, 0.21 mmol). After the reaction solution was stirred at room temperature for 30 min, compound 3-4 (61 mg, 0.11 mmol) was added, and the reaction solution was stirred at room temperature for 16 h. The reaction solution was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC (waters-xbridge-C18-10um-19*250mm, Mobile phase: 0.1% TFA / H2O B:CH3CN, Gradient: 50% B-70% B, Ret 11.57 min) to give compound 3. MS m / z (ESI): 950.4 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 7.62-7.37 (m, 3H), 7.31-7.24 (m, 2H), 7.14 (dd, J = 11.6, 4.8 Hz, 2H), 7.07 (s, 1H), 6.99-6.54 (m, 3H), 5.57 (m, 1H), 4.50-3.57 (m, 8H), 3.23-2.94 (m, 6H), 2.27-2.22 (m, 6H), 1.80 (d, J = 28.8 Hz, 8H), 1.66-1.57 (m, 3H), 1.52 (d, J = 6.8 Hz, 3H), 1.36-1.24 (m, 6H), 1.20 (d, J = 5.2 Hz, 2H), 1.06 (d, J = 5.6 Hz, 1H).

[0422] Example 6: Preparation of compound 4

[0423] Synthetic route:

[0424] Step 1: Synthesis of compound 4-1

[0425] To a solution of compound 3-2 (150 mg, 0.23 mmol) in dichloromethane (5 mL) was added hydrogen chloride in dioxane (4.0 M, 0.5 mL), and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure, washed with dichloromethane for 3 times and dried to give compound 4-1. MS m / z (ESI): 543.4 [M+H] + .

[0426] Step 2: Synthesis of compound 4

[0427] To a solution of compound G-S (40.0 mg, 0.10 mmol) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (100 mg, 0.80 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (111 mg, 0.30 mmol). The reaction was stirred at room temperature for 30 min, then compound 4-1 (79 mg, 0.15 mmol) was added. The reaction was stirred at room temperature for 16 h. The reaction was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with saturated brine (6 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC (waters-xbridge-C18-10um-19*250mm, Mobile phase: 0.1% TFA / H20 B:CH3CN, Gradient: 50% B-70% B, Ret 11.57 min) to give compound 4. MS m / z (ESI): 936.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.64-7.32 (m, 3H), 7.31-6.33 (m, 8H), 5.82-5.30 (m, 1H), 4.59-3.40 (m, 8H), 3.24-2.91 (m, 3H), 2.24 (d, J = 14.4 Hz, 6H), 1.94-1.43 (m, 14H), 1.35-1.25 (m, 6H), 1.14 (m, 3H).

[0428] Example 7: Preparation of compound 5

[0429] Synthetic route:

[0430] Step 1: Synthesis of compound 5-1

[0431] To a solution of compound 3-2 (50 mg, 0.078 mmol) in DMF (5 mL) was added sodium hydride (5 mg, 0.12 mmol) at ice bath. The reaction was stirred at room temperature for 30 min, then 1-iodo-2-methoxyethane (22 mg, 0.12 mmol) was added. The reaction was stirred at room temperature for 5 h. The reaction was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with saturated brine (6 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 5-1. MS m / z (ESI): 701.4 [M+H] + .

[0432] Step 2: Synthesis of compound 5-2

[0433] To a solution of compound 5-1 (50 mg, 0.07 mmol) in dichloromethane (5 mL) was added hydrogen chloride in dioxane (0.5 mL, 4.0 M), and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure to give compound 5-2, which was used directly in the next step. MS m / z (ESI): 601.4 [M+H] + .

[0434] Step 3: Synthesis of compound 5

[0435] To a solution of compound G-S (21 mg, 0.05 mmol) in N,N-dimethylformamide (3 mL) was added triethylamine (0.03 mL, 0.25 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (38 mg, 0.1 mmol). After the reaction was stirred at room temperature for 30 minutes, compound 5-2 (50 mg, 0.08 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The reaction was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC (waters-xbridge-C18-10um-19*250mm, Mobile phase: 0.1% TFA / H2O B:CH3CN, Gradient: 50% B-70% B, Ret 11.67 min) to give compound 5. MS m / z (ESI): 994.4 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 7.63-7.55 (m, 1H), 7.54-7.43 (m, 2H), 7.38 (s, 1H), 7.27 (dd, J = 8.4, 1.8 Hz, 2H), 7.16 (d, J = 6.3 Hz, 2H), 7.09 (t, J = 6.2 Hz, 1H), 6.91 (d, J = 16.2 Hz, 1H), 6.85-6.77 (m, 1H), 5.38-5.31 (m, 1H), 4.5-4.44 (m, 1H), 4.22-4.16 (m, 2H), 3.95-3.80 (m, 6H), 3.64 (t, J = 5.2 Hz, 2H), 3.56-3.50 (m, 1H), 3.08-2.95 (m, 2H), 2.27-2.22 (m, 6H), 2.19 (t, J = 7.6 Hz, 2H), 2.03 (d, J = 5.8 Hz, 2H), 1.84 (d, J = 4.8 Hz, 3H), 1.80-1.72 (m, 5H), 1.64-1.60 (m, 2H), 1.52 (d, J = 6.8 Hz, 2H), 1.37-1.33 (m, 6H), 1.24-1.18 (m, 3H), 0.90 (t, J = 6.8 Hz, 2H).

[0436] Example 8: Preparation of compound 6

[0437] Synthetic route:

[0438] Step 1: Synthesis of compound 6-2

[0439] To a solution of compound 6-1 (1.0 g, 5.29 mmol) and cyclopentanone (0.89 g, 10.6 mmol) in toluene (10 mL) was added phosphorous tribromide (0.57 g, 2.12 mmol) dropwise under nitrogen protection with ice-bath cooling. After the addition was completed, the mixture was stirred at room temperature for 0.5 hours. The reaction solution was quenched with saturated sodium bicarbonate (50 mL), diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to obtain compound 6-2. 1 H NMR (400 MHz, CDCl3) δ 6.83-6.81 (m, 1H), 6.78 (d, J = 2.0 Hz, 1H), 6.52 (d, J = 8.0 Hz, 1H), 2.03-1.97 (m, 4H), 1.77-1.73 (m, 4H).

[0440] Step 2: Synthesis of compound 6-3

[0441] To a solution of compound 6-2 (240 mg, 0.54 mmol) and compound K (346 mg, 1.36 mmol) in N-methylpyrrolidone (5 mL) was added potassium carbonate (225 mg, 1.63 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (39 mg, 0.27 mmol) and cuprous iodide (21 mg, 1.63 mmol) at room temperature. After the addition was completed, the mixture was stirred at 130 °C for 2 hours. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 1) to give compound 6-3. MS m / z (ESI): 616.3 [M+H] + .

[0442] Step 3: Synthesis of compound 6-4

[0443] To compound 6-3 (100 mg, 0.16 mmol) was added a solution of hydrogen chloride in dioxane (3 mL, 12 mmol, 4 M) at room temperature. The reaction was stirred at room temperature for 0.5 hours. The reaction was concentrated under reduced pressure to give compound 6-4, which was used directly in the next step. MS m / z (ESI): 516.2 [M+H] + .

[0444] Step 4: Synthesis of compound 6

[0445] To a solution of compound 6-4 (63 mg, 0.12 mmol) and compound G-S (50 mg, 0.12 mmol) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (47 mg, 0.36 mmol) and 2-(7-azobenzo-triazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (69 mg, 0.18 mmol). The reaction was stirred at room temperature for 1 hour. The reaction was filtered and the filtrate was purified by preparative HPLC (waters-xbridge-C18-10um-19*250mm, mobile phase: A: 0.1% FA; B: ACN, gradient: 68-98%, retention time: 12.5 min) to give compound 6. MS m / z (ESI): 909.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.53 (s, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.8 Hz, 1H), 7.19 (s, 1H), 7.15-7.13 (m, 3H), 7.04 (d, J = 8.4 Hz, 1H), 6.94 (d, J = 8.0 Hz, 2H), 6.76-6.68 (m, 1H), 5.55 (d, J = 7.2 Hz, 1H), 4.37 (d, J = 13.6 Hz, 1H), 3.72-3.62 (m, 3H), 3.19-3.15 (m, 1H), 3.06-3.00 (m, 1H), 2.89-2.85 (m, 1H), 2.22-2.19 (m, 6H), 2.07-2.05 (m, 4H), 1.80-1.75 (m, 5H), 1.67-1.52 (m, 6H), 1.37 (d, J = 6.4 Hz, 2H), 1.30-1.24 (m, 5H), 1.18-1.14 (m, 5H).

[0446] Example 9: Preparation of compound 7

[0447] Synthetic route:

[0448] Step 1: Synthesis of compound 7-1

[0449] To a solution of compound 6-1 (1.0 g, 5.29 mmol) and cyclohexanone (1.04 g, 10.58 mmol) in toluene (10 mL) was added phosphorous tribromide (0.57 g, 2.12 mmol) dropwise under nitrogen protection and ice bath. After the addition was completed, the mixture was stirred at room temperature for 0.5 hours. The reaction solution was quenched with saturated sodium bicarbonate (50 mL), diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2), the combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 10) to give compound 7-1. 1 H NMR (400 MHz, CDCl3) δ 6.91-6.88 (m, 2H), 6.61 (d, J = 8.0 Hz, 1H), 1.93-1.90 (m, 4H), 1.77-1.71 (m, 4H), 1.54-1.50 (m, 2H).

[0450] Step 2: Synthesis of compound 7-2

[0451] To a solution of compound 7-1 (90 mg, 0.20 mmol) and compound K (137 mg, 0.51 mmol) in N-methylpyrrolidone (5 mL) was added potassium carbonate (84.5 mg, 0.61 mmol), (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (14 mg, 0.10 mmol) and cuprous iodide (7.8 mg, 0.04 mmol) at room temperature. After the addition was completed, the mixture was stirred at 130 °C for 2 hours. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 7-2. MS m / z (ESI): 630.3 [M+H] + .

[0452] Step 3: Synthesis of compound 7-3

[0453] To compound 7-2 (113 mg, 0.18 mmol) was added a solution of hydrogen chloride in dioxane (3 mL, 12 mmol, 4 M) at room temperature. The reaction solution was stirred at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure to give compound 7-3, which was used directly in the next step. MS m / z (ESI): 530.2 [M+H] + .

[0454] Step 4: Synthesis of compound 7

[0455] To a solution of compound 7-3 (90 mg, 0.17 mmol) and compound G-S (50 mg, 0.12 mmol) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (47 mg, 0.36 mmol) and 2-(7-azobenzo-triazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (69 mg, 0.18 mmol). The reaction solution was stirred at room temperature for 1 hour. The reaction solution was filtered, and the filtrate was purified by preparative HPLC (waters-xbridge-C18-10um-19*250mm, mobile phase: A: 0.1% FA; B: ACN, gradient: 68-98%, retention time: 12.5 min) to give compound 7. MS m / z (ESI): 923.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.53 (s, 1H), 7.40 (d, J = 8.8 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 3.2 Hz, 1H), 7.15-7.13 (m, 3H), 7.04-7.02 (m, 1H), 6.94-6.92 (m, 2H), 6.76-6.66 (m, 1H), 5.55 (d, J = 6.8 Hz, 1H), 4.37 (d, J = 13.2 Hz, 1H), 3.72-3.59 (m, 3H), 3.21-3.18 (m, 1H), 3.06-3.00 (m, 1H), 2.90-2.86 (m, 1H), 2.22-2.19 (m, 6H), 1.91-1.88 (m, 4H), 1.66-1.47 (m, 13H), 1.38 (d, J = 6.4 Hz, 2H), 1.30-1.23 (m, 5H), 1.18-1.14 (m, 5H).

[0456] Example 10: Preparation of compound 8

[0457] Synthetic route:

[0458] Step 1: Synthesis of compound 8-1

[0459] Compound 3-2 (100 mg, 0.16 mmol) was dissolved in 1,2-dichloroethane (5 mL), and copper acetate (56 mg, 0.31 mmol), pyridine (49 mg, 0.62 mmol) and cyclopropylboronic acid (40 mg, 0.47 mmol) were added successively. The reaction solution was stirred at 50 degrees Celsius for 10 hours. After the reaction solution was naturally cooled to room temperature, it was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 8-1. MS m / z (ESI): 683.4 [M+H] + .

[0460] Step 2: Synthesis of compound 8-2

[0461] To a solution of compound 8-1 (70 mg, 0.10 mmol) in dichloromethane (2 mL) was added hydrogen chloride dioxane solution (0.5 mL, 2.0 mmol, 4M), and the reaction solution was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain compound 8-2, which was directly used in the next step. MS m / z (ESI): 583.2 [M+H] + .

[0462] Step 3: Synthesis of compound 8

[0463] To a solution of compound G-S (30.0 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (19 mg, 0.15 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (33 mg, 0.09 mmol). After the reaction solution was stirred at room temperature for 30 min, compound 8-2 (42 mg, 0.07 mmol) was added, and the reaction solution was stirred at room temperature for 16 h. The reaction solution was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by preparative HPLC (waters-xbridge-C18-10um-19*250mm, Mobile phase: 0.1% TFA / H2O B:CH3CN, Gradient: 50% B-70% B, Ret 10.42 min) to give compound 8. MS m / z (ESI): 976.5 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.61-7.30 (m, 4H), 7.29-7.05 (m, 4H), 6.97-6.52 (m, 3H), 5.79-5.39 (m, 1H), 4.50 (d, J = 13.6 Hz, 1H), 4.18-4.14 (m, 2H), 3.97-3.76 (m, 4H), 3.73-3.51 (m, 1H), 3.23-2.94 (m, 3H), 2.74-2.44 (m, 1H), 2.30-2.19 (m, 6H), 1.81-1.74 (m, 8H), 1.68-1.45 (m, 6H), 1.35 (s, 3H), 1.30-1.19 (m, 5H), 1.72-1.68 (m, 2H), 0.86-0.71 (m, 3H).

[0464] Example 11: Preparation of compound 9

[0465] Compound 9 was synthesized by a similar method to compound 5 in Example 8.

[0466] Compound 9: MS m / z (ESI): 1018.4 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 7.64-6.90 (m, 9H), 6.89-6.54 (m, 2H), 5.55 (m, 1H), 4.52 (m, 2H), 4.20 (m, 2H), 3.97-3.47 (m, 5H), 3.29-2.84 (m, 4H), 2.23 (d, J = 14.0 Hz, 6H), 2.04-1.49 (m, 14H), 1.36-1.25 (m, 6H), 1.23-1.17 (m, 2H), 1.10-0.89 (m, 1H).

[0467] Example 12: Preparation of compound 10

[0468] Synthetic route:

[0469] Step 1: Synthesis of compound 10-2

[0470] To a solution of compound 10-1 (500 mg, 2.36 mmol) in tetrahydrofuran (1 mL) was added LDA (3.54 mL, 7.07 mmol, 2M solution in tetrahydrofuran) dropwise at -45 °C under nitrogen protection. After the addition was completed, it was stirred for 1 hour, then 1,4-dibromobutane (22.9 g, 99.0 mmol) in tetrahydrofuran (1 mL) was added dropwise. The mixture was stirred at 20 °C for 16 hours. The reaction solution was cooled to 0 °C, quenched with saturated ammonium chloride (10 mL), diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 25%) to obtain compound 10-2. MS m / z (ESI): 266.0, 268.0 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.15 (dd, J = 8.0, 1.6 Hz, 1H), 7.07 (d, J = 1.6 Hz, 1H), 7.03 (d, J = 8.0 Hz, 1H), 2.24-2.12 (m, 2H), 2.11-2.01 (m, 2H), 2.00-1.90 (m, 2H), 1.89-1.80 (m, 2H).

[0471] Step 2: Synthesis of compound 10-3

[0472] To a solution of compound 10-2 (300 mg, 1.13 mmol) in DMF (4.5 mL) was added sodium hydride (90 mg, 2.25 mmol) portion wise at 0 °C under nitrogen atmosphere. The mixture was stirred for 30 min before the dropwise addition of iodomethane (0.1 mL, 1.13 mmol). The mixture was stirred at 20 °C for 16 h. The reaction was cooled to 0 °C and quenched with water (20 mL). The mixture was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with water (10 mL) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 15%) to give compound 10-3. MS m / z (ESI): 280.0, 282.0 [M+H] + .

[0473] Step 3: Synthesis of compound 10-4

[0474] To a solution of compound 10-3 (500 mg, 1.58 mmol) in NMP (3 mL) was added compound K (307 mg, 0.70 mmol), potassium carbonate (221 mg, 1.61 mmol), copper iodide (30 mg, 0.16 mmol) and (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (23 mg, 0.16 mmol). The mixture was stirred at 130 °C for 3 h under nitrogen atmosphere. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with water (5 mL x 2) and saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (dichloromethane / methanol = 3-6%) to give compound 10-4. MS m / z (ESI): 641.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 8.0 Hz, 1H), 7.17 (s, 1H), 7.08 (t, J = 9.6 Hz, 3H), 6.69 (d, J = 3.2 Hz, 1H), 6.30 (s, 1H), 5.33 (d, J = 18.0 Hz, 1H), 4.33 (s, 1H), 3.23 (s, 3H), 3.14 (s, 1H), 2.80 (s, 2H), 2.23 (d, J = 1.6 Hz, 6H), 2.19-2.06 (m, 4H), 2.03-1.93 (m, 2H), 1.88-1.79 (m, 2H), 1.50 (s, 9H), 1.32 (d, J = 6.8 Hz, 3H).

[0475] Step 4: Synthesis of compound 10-5

[0476] To a solution of compound 10-4 (150 mg, 0.23 mmol) in dichloromethane (4 mL) was added hydrochloric acid dioxane (2 mL, 8.0 mmol, 4 M). The mixture was stirred at 20 °C for 2 h. The reaction was concentrated under reduced pressure to give compound 10-5, which was used directly in the next step. MS m / z (ESI): 541.3 [M+H] + .

[0477] Step 5: Synthesis of compound 10

[0478] To a solution of compound G-S (50 mg, 0.12 mmol) in DMF (0.8 mL) was added N,N- diisopropylethylamine (78.5 mg, 0.61 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol- 1-yl)urea hexafluorophosphate (92.4 mg, 0.24 mmol) and compound 10-5 (92 mg, 0.17 mmol). The mixture was stirred at 20 °C for 4 h. The reaction was added dropwise into ice water (20 mL), stirred for 5 min and then filtered, the filter cake was washed with water (5 mL). The crude product was purified by preparative HPLC (ASA-AZZOTA-C18-7μm-30*150mm, A: 0.1% FA / H2O B: ACN, gradient: 65%) to give compound 10. MS m / z (ESI): 934.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 11.30 (d, J = 22.0 Hz, 1H), 7.60 (t, J = 9.6 Hz, 1H), 7.56-7.48 (m, 1H), 7.27 (s, 1H), 7.18-7.12 (m, 3H), 7.08-6.88 (m, 1H), 6.78-6.59 (m, 2H), 6.24-6.22 (m, 1H), 5.81-5.77 (m, 1H), 4.93-4.39 (m, 1H), 4.01-3.75 (m, 2H), 3.71-3.37 (m, 1H), 3.26 (s, 2H), 3.19-3.01 (m, 3H), 2.28 (d, J = 2.0 Hz, 4H), 2.26-2.08 (m, 5H), 2.01-1.75 (m, 7H), 1.66 (d, J = 6.4 Hz, 6H), 1.56 (d, J = 6.4 Hz, 4H), 1.36 (d, J = 4.8 Hz, 3H), 1.29 (d, J = 10.4 Hz, 3H), 1.17-1.11 (m, 3H).

[0479] Example 13: Preparation of compound 11

[0480] Synthetic route:

[0481] Step 1: Synthesis of compound 11-1

[0482] Compound 3-1 (3.0 g, 10.63 mmol) was dissolved in super dry tetrahydrofuran (60 mL) under nitrogen protection, lithium aluminum hydride (1.21 g, 31.90 mmol) was added into above solution in batches at room temperature, the reaction solution was stirred at reflux for 8 hours. The reaction solution was slowly cooled to 0 °C, then quenched with water (1.2 mL), 20% sodium hydroxide aqueous solution (1.2 mL) and water (2.4 mL) in turn, and stirred at room temperature for 1 hour. The mixture was filtered through diatomite, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 10) to obtain compound 11-1. MS m / z (ESI): 268.0, 270.0 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ 6.95 (d, J = 8.0 Hz, 1H), 6.65 (dd, J = 8.0, 1.8 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 5.85 (s, 1H), 3.85-3.77 (m, 2H), 3.53-3.32 (m, 4H), 1.84-1.68 (m, 2H), 1.57-1.44 (m, 2H).

[0483] Step 2: Synthesis of compound 11-2

[0484] Compound 11-1 (500 mg, 1.86 mmol) was dissolved in N,N-dimethylformamide (7 mL) under nitrogen protection at 0 °C, sodium hydride (223 mg, 5.59 mmol) was added into above solution, the reaction solution was stirred at 0 °C for half an hour, then iodomethane (0.30 mL, 3.73 mmol) was added, the reaction solution was stirred at room temperature for 8 hours. The reaction solution was quenched with saturated ammonium chloride aqueous solution (30 mL), extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine, then dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) to obtain compound 11-2. MS m / z (ESI): 282.0, 284.0 [M+H] + . 1HNMR (400 MHz, CD3OD) δ 6.91 (d, J = 7.6 Hz, 1H), 6.75 (dd, J = 7.6, 1.6 Hz, 1H), 6.58 (d, J = 1.6 Hz, 1H), 3.98-3.86 (m, 2H), 3.65-3.55 (m, 2H), 3.35 (s, 2H), 2.75 (s, 3H), 1.96-1.85 (m, 2H), 1.64-1.56 (m, 2H).

[0485] Step 3: Synthesis of compound 11-3

[0486] To a solution of compound 11-2 (125 mg, 0.44 mmol) and compound K (130 mg, 0.29 mmol) in N-methylpyrrolidone (1.5 mL) was added (1S,2S)-(+)-N,N'-dimethyl-1,2-cyclohexanediamine (21 mg, 0.15 mmol), cuprous iodide (28 mg, 0.15 mmol) and potassium carbonate (203 mg, 1.47 mmol), and the reaction was stirred at 90 °C for 3 h under nitrogen. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 1) to give compound 11-3. MS m / z (ESI): 643.3 [M+H] + .

[0487] Step 4: Synthesis of compound 11-4

[0488] Compound 11-3 (98 mg, 0.15 mmol) was dissolved in 1,4-dioxane (1 mL), and hydrochloric acid dioxane (1.0 mL, 4.0 mmol, 4M) was added. The reaction was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure to give compound 11-4, which was used directly in the next step. MS m / z (ESI): 543.4 [M+H] + .

[0489] Step 5: Synthesis of compound 11

[0490] Compound G-S (20 mg, 0.05 mmol) was dissolved in N,N-dimethylformamide solution (1.5 mL), then N,N-diisopropyl ethylamine (31 mg, 0.24 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (14 mg, 0.07 mmol), 1-hydroxybenzotriazole (10 mg, 0.07 mmol) and compound 11-4 (40 mg, 0.07 mmol) were added, the reaction solution was stirred at room temperature for 3 hours under nitrogen protection. The reaction solution was purified by preparative HPLC (Column Waters-Sun Fire-C18-10 μm-19*250 mm; Mobile: phase A: 0.1% TFA / H2O B: ACN; Gradient; 10% to 95%) to obtain compound 11. MS m / z (ESI): 936.4 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.53 (s, 1H), 7.40 (d, J = 8.4 Hz, 1H), 7.31-7.19 (m, 2H), 7.18-7.03 (m, 3H), 6.99-6.43 (m, 4H), 5.55 (d, J = 7.2 Hz, 1H), 4.38 (d, J = 10.8 Hz, 1H), 3.90-3.77 (m, 2H), 3.71 (d, J = 7.2 Hz, 2H), 3.66-3.56 (m, 1H), 3.49 (t, J = 11.2 Hz, 2H), 3.41-3.25 (m, 2H), 3.25-3.12 (m, 1H), 3.09-2.97 (m, 1H), 2.96-2.83 (m, 1H), 2.82-2.55 (m, 4H), 2.22 (s, 6H), 1.90-1.62 (m, 6H), 1.63-1.45 (m, 4H), 1.38 (d, J = 6.0 Hz, 1H), 1.35-1.23 (m, 6H), 1.23-1.11 (m, 5H).

[0491] Example 14: Preparation of compound 12

[0492] Compound 12 was synthesized by a similar method to compound 5 in Example 7.

[0493] Compound 12: MS m / z (ESI): 992.3 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 7.76 (s, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.54-7.46 (m, 2H), 7.32-7.24 (m, 2H), 7.19-7.07 (m, 3H), 7.01-6.87 (m, 1H), 6.80 (d, J = 10.0 Hz, 1H), 5.78-5.43 (m, 2H), 5.34 (t, J = 4.8 Hz, 1H), 5.15 (d, J = 6.4 Hz, 1H), 5.04-5.00 (m, 2H), 4.22-4.14 (m, 2H), 3.94-3.81 (m, 4H), 3.09-2.94 (m, 2H), 2.23 (d, J = 12.4 Hz, 6H), 2.04-2, 00 (m, 1H), 1.87-1.71 (m, 8H), 1.62-1.51 (m, 5H), 1.34 (d, J = 8.4 Hz, 6H), 1.26-1.18 (m, 4H), 1.06 (d, J = 6.0 Hz, 1H), 0.89 (t, J = 5.2 Hz, 1H).

[0494] Example 15: Preparation of compound 13

[0495] Synthetic route:

[0496] Step 1: Synthesis of compound 13-2

[0497] To a solution of trichloroacetaldehyde hydrate (21.0 g, 127 mmol) in water (253 mL) and concentrated hydrochloric acid (22 mL) was added compound 13-1 (11 g, 57.89 mmol), sodium sulfate (156 g, 1.1 mol), hydroxylamine hydrochloride (25.7 g, 370 mmol) at room temperature, the reaction mixture was stirred at 90 degree Celsius for 3 hours. After the reaction solution was cooled to room temperature, it was filtered, the filter cake was washed with water (100 mL), and the filter cake was dried to give the crude compound 13-2. MS m / z (ESI): 260.9, 262.9 [M+H] + .

[0498] Step 2: Synthesis of compound 13-3

[0499] Compound 13-2 (8.8 g, 33.85 mmol) was dissolved in sulfuric acid (90 mL) at room temperature, after stirring at 90 degree Celsius for 3 hours under nitrogen protection, it was cooled to room temperature, the reaction solution was poured into ice water (200 mL), filtered, the filter cake was washed with water (100 mL), and the filter cake was collected and dried to give the crude compound 13-3. 1HNMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.46-7.23 (m, 2H).

[0500] Step 3: Synthesis of compound 13-4

[0501] Compound 13-3 (8.0 g, 32.92 mmol) was added to ethanol (100 mL), the reaction mixture was stirred at 85 degrees Celsius for 0.5 hours, after cooling to room temperature, the filter cake was collected and dried to obtain the crude compound 13-4. The crude product was directly used in the next step. MS m / z (ESI): 257.9, 259.9 [M+H] + .

[0502] Step 4: Synthesis of compound 13-5

[0503] To the solution of compound 13-4 (5.0 g, 19.46 mmol) in ethanol (100 mL) was added potassium tert-butoxide (6.55 g, 58.38 mmol), the mixture was stirred at 85 degrees Celsius for 2 hours. After the reaction solution was cooled to room temperature, water (50 mL) was added, and the pH was adjusted to 2 with 1M dilute hydrochloric acid (50 mL), extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to obtain compound 13-5. MS m / z (ESI): 229.9, 231.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 7.21 (dd, J = 8.0, 6.4 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 3.55 (d, J = 1.2 Hz, 2H).

[0504] Step 5: Synthesis of compound 13-6

[0505] To a solution of compound 13-5 (1.7 g, 7.39 mmol) in tetrahydrofuran (20 mL) was added sodium bis(trimethylsilyl)amide (22 mL, 22.17 mmol, 1 M) at -78 °C. After the reaction mixture was stirred at -78 °C for 1 h, 1-bromo-2-(2-bromoethoxy)ethane (2.06 g, 8.87 mmol) was added. The reaction solution was warmed to room temperature and stirred for 18 h. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 3) and concentrated to give compound 13-6. MS m / z (ESI): 299.9, 301.9 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 11.11 (s, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.26 (dd, J = 8.0, 6.0 Hz, 1H), 4.02 (ddd, J = 12.0, 6.8, 4.8 Hz, 2H), 3.78 (dt, J = 11.2, 5.2 Hz, 2H), 1.78 - 1.71 (m, 4H).

[0506] Step 6: Synthesis of compound 13-7

[0507] To a solution of compound 13-6 (100 mg, 0.33 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (12.0 mg, 0.50 mmol) at 0 °C under nitrogen. After the reaction mixture was stirred at room temperature for 0.5 h, iodomethane (57 mg, 0.40 mmol) was added. After the reaction mixture was stirred at room temperature for 2 h, water (5 mL) was added. The reaction solution was extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 3) and concentrated to give compound 13-7. MS m / z (ESI): 314.1, 316.1 [M+H] + .

[0508] Step 7: Synthesis of compound 13-8

[0509] To a solution of compound 13-7 (80 mg, 0.25 mmol) and compound K (123 mg, 0.28 mmol) in N-methylpyrrolidone (2 mL) was added potassium carbonate (105 mg, 0.76 mmol), cuprous iodide (10.0 mg, 0.05 mmol) and trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (18 mg, 0.13 mmol), the reaction mixture was stirred at 130 degree Celsius for 18 hours under nitrogen protection. After cooling to room temperature, diluted with water (20 mL), extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 13-8. MS m / z (ESI): 675.3 [M+H] + .

[0510] Step 8: Synthesis of compound 13-9

[0511] To compound 13-8 (60 mg, 0.09 mmol) was added hydrochloric acid dioxane (3.0 mL, 4 M, 12 mmol), the reaction mixture was stirred at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give compound 13-9. MS m / z (ESI): 575.3 [M+H] + .

[0512] Step 9: Synthesis of compound 13

[0513] To compound 13-9 (51 mg, 0.09 mmol) and compound G-S (54.78 mg, 0.13 mmol) in N,N-dimethylformamide (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (50.62 mg, 0.13 mmol), N,N-diisopropylethylamine (57.36 mg, 0.44 mmol), the reaction mixture was reacted at room temperature for 18 hours. The reaction was diluted with water (5 mL), extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-7μm-30*150mm A:0.1% TFA / H2O B:ACN 35% A-65%B:Ret 1.49min) to give compound 13. MS m / z (ESI): 968.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 7.52 (d, J = 9.2 Hz, 2H), 7.40 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 1H), 7.16 (t, J = 7.6 Hz, 3H), 7.05 (s, 1H), 6.95 (d, J = 6.8 Hz, 2H), 5.59 - 5.22 (m, 1H), 4.38 (d, J = 13.2 Hz, 1H), 4.07 (t, J = 9.2 Hz, 3H), 3.84 - 3.80 (m, 2H), 3.71 (d, J = 8.8 Hz, 4H), 3.25 (s, 2H), 3.08 - 2.88 (m, 2H), 2.25 (brs, 7H), 1.84 (s, 1H), 1.75 (d, J = 13.6 Hz, 3H), 1.68 (s, 2H), 1.53 (d, J = 13.2 Hz, 2H), 1.41 (s, 1H), 1.25 (d, J = 14.8 Hz, 7H), 1.18 (s, 6H).

[0514] Example 16: Preparation of compound 14

[0515] Synthetic route:

[0516] Step 1: Synthesis of compound 14-1

[0517] To a solution of compound 1-1 (3.00 g, 10.68 mmol) in DMF (30 mL) was added sodium hydride (854 mg, 21.36 mmol) under ice-bath. After the mixture was stirred for 30 min, iodomethane (2.28 g, 16.02 mmol) in DMF (6 mL) was added dropwise. The reaction was stirred at room temperature for 2 h. After the reaction was completed, the reaction was quenched with water (30 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined and washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. After the solvent was removed under reduced pressure, the crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 2 / 1) to give compound 14-1. MS m / z (ESI): 296.0, 298.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.50 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 1.6 Hz, 1H), 7.22 (dd, J = 8.0, 1.6 Hz, 1H), 4.11 - 3.98 (m, 2H), 3.84 - 3.72 (m, 2H), 3.12 (s, 3H), 1.79 - 1.67 (m, 4H).

[0518] Step 2: Synthesis of compound 14-2

[0519] To a solution of compound 14-1 (1.4 g, 4.73 mmol) in DMF (30 mL) was added Selectfluor (2.51 g, 7.09 mmol) under nitrogen protection. The reaction was stirred at 60 °C for 24 h. The reaction was quenched with ice water (90 mL), extracted with ethyl acetate (30 mL x 3), washed with water (20 mL), washed with saturated brine (20 mL x 2), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to give compound 14-2. MS m / z (ESI): 314.0, 316.0 [M+H] + . 1 HNMR (400MHz, DMSO-d6) δ 7.69 (d, J = 8.4 Hz, 1H), 7.38 (d, J = 5.6 Hz, 1H), 4.00-4.06 (m, 2H), 3.76-3.82 (m, 2H), 3.12 (s, 3H), 1.74-1.80 (m, 2H), 1.66-1.72 (m, 2H).

[0520] Step 3: Synthesis of compound 14-3

[0521] To a solution of compound K (200 mg, 0.45 mmol) in N-methyl pyrrolidone (3 mL) was added compound 14-2 (170 mg, 0.54 mmol), potassium carbonate (188 mg, 1.35 mmol), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (32 mg, 0.23 mmol) and cuprous iodide (17 mg, 0.09 mmol). The reaction was stirred at 130 °C for 16 h. To the reaction was added water (5 mL), extracted with ethyl acetate (5 mL x 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 14-3. MS m / z (ESI): 675.4 [M+H] + .

[0522] Step 4: Synthesis of compound 14-4

[0523] To a solution of compound 14-3 (190 mg, 0.28 mmol) in dichloromethane (3 mL) was added 4 M hydrochloric acid in dioxane (1 mL), and the reaction was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure to give compound 14-4. The crude product was used directly in the next step. MS m / z (ESI): 575.3 [M+H] + .

[0524] Step 5: Synthesis of compound 14

[0525] To a solution of compound G-S (15 mg, 0.04 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (33 mg, 0.28 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (42 mg, 0.12 mmol). After the reaction solution was stirred at room temperature for 30 min, compound 14-4 (25 mg, 0.05 mmol) was added, and the reaction solution was stirred at room temperature for 16 h. The reaction solution was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with saturated brine (4 mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC (waters-xbridge-C18-10um-19*250mm, Mobile phase: 0.1% FA / H2O B:CH3CN, Gradient: 50% B-70% B, Ret 12.98 min) to give compound 14. MS m / z (ESI): 968.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 11.75 (br s, 1H), 7.78 (d, J = 9.6 Hz, 1H), 8.15 - 6.86 (m, 9H), 5.73 - 4.91 (m, 1H), 4.41 - 4.03 (m, 2H), 3.89 - 3.78 (m, 2H), 3.71 (d, J = 8.0 Hz, 2H), 3.31 - 3.25 (m, 1H), 3.15 (s, 3H), 3.05 (d, J = 12.4 Hz, 2H), 2.89 (s, 1H), 2.34 - 2.20 (m, 7H), 1.83 - 1.52 (m, 11H), 1.48 - 1.31 (m, 3H), 1.28 - 1.15 (m, 9H).

[0526] Example 17: Preparation of compound 15

[0527] Synthetic route:

[0528] Step 1: Synthesis of compound 15-2

[0529] To a solution of compound 15-1 (7.00 g, 25.18 mmol) in ethanol (70 mL) was added concentrated sulfuric acid (1 mL, 18.66 mmol) dropwise under ice bath. The reaction was stirred at 80 °C for 12 h. The reaction was quenched by adding to ice water (10 mL) and the pH was adjusted to neutral with aqueous sodium carbonate solution. The mixture was extracted with ethyl acetate (100 mL x 3). The organic layers were combined and washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give compound 15-2. MS m / z (ESI): 306.0, 308.0 [M+H] + .

[0530] Step 2: Synthesis of compound 15-3

[0531] To a solution of compound 15-2 (600.0 mg, 1.96 mmol) in N,N-dimethylformamide (10 mL) was added 4,4'-dipyridine (30.6 mg, 0.20 mmol) under ice bath. The mixture was stirred for 2 min before adding tetrahydroxydiboron (527.2 mg, 5.88 mmol). The reaction was stirred at 0 °C for 1 h. The reaction was quenched by adding water (50 mL) and extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed with saturated brine (50 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give compound 15-3. The crude was used directly in the next step. MS m / z (ESI): 276.0, 278.0 [M+H] + .

[0532] Step 3: Synthesis of compound 15-4

[0533] Compound 15-3 (5.00 g, 1.81 mmol) was dissolved in glacial acetic acid (25 mL) and stirred at 100 °C for 3 h. The reaction was quenched by adding water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined and washed with saturated brine (20 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 4 / 1) to give compound 15-4. MS m / z (ESI): 229.9, 231.9 [M+H] + .

[0534] Step 4: Synthesis of compound 15-5

[0535] To a solution of compound 15-4 (400.0 mg, 1.74 mmol) in tetrahydrofuran (5 mL) and water (5 mL) was added sodium hydroxide (290.0 mg, 7.17 mmol) under ice bath. After stirring at room temperature for 30 min, dimethyl sulfate (218.0 mg, 1.74 mmol) was added dropwise. The reaction was stirred at 60 °C for 16 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 10 / 1) to give compound 15-5. MS m / z (ESI): 244.0, 246.0 [M+H] + .

[0536] Step 5: Synthesis of compound 15-6

[0537] To a solution of compound 15-5 (200.0 mg, 0.82 mmol) in N,N-dimethylacetamide (2 mL) was added cesium carbonate (1.07 g, 3.28 mmol) under ice bath. After stirring for 10 min, a solution of l-iodo-2-(2-iodoethoxy)ethane (320.5 mg, 0.98 mmol) in N,N-dimethylacetamide (2 mL) was added dropwise. The reaction was stirred at room temperature for 2 h. The reaction was quenched with water (10 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give compound 15-6. MS m / z (ESI): 314.0, 316.0 [M+H] + .

[0538] Step 6: Synthesis of compound 15-7

[0539] To a solution of compound K (112.4 mg, 0.25 mmol) in N-methylpyrrolidinone (2 mL) was added compound 15-6 (80.0 mg, 0.25 mmol), potassium carbonate (70.4 mg, 0.51 mmol), trans-(lR,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (18.1 mg, 0.13 mmol) and copper(I) iodide (9.7 mg, 0.05 mmol). The reaction was stirred at 130 °C for 3 h. To the reaction was added water (4 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and the solution was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 10 / 1) to give compound 15-7. MS m / z (ESI): 675.4 [M+H]+ .

[0540] Step 7: Synthesis of compound 15-8

[0541] To a solution of compound 15-7 (150.0 mg, 0.22 mmol) in dichloromethane (3 mL) was added 4 M hydrochloric acid in dioxane (1 mL), and the reaction was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure to give compound 15-8. The crude product was used directly in the next step. MS m / z (ESI): 575.2 [M+H] + .

[0542] Step 8: Synthesis of compound 15 To a solution of compound G-S (21.5 mg, 0.05 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (13.5 mg, 0.10 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (23.8 mg, 0.05 mmol). After the reaction was stirred at room temperature for 30 min, compound 15-8 (30.0 mg, 0.05 mmol) was added, and the reaction was stirred at room temperature for 16 h. The reaction was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with saturated brine (4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (waters-xbridge-C18-10um-19*250mm, Mobile phase: 0.1% TFA / H2O B:CH3CN, Gradient: 50% B-70% B, Ret 12.58 min) to give compound 15. MS m / z (ESI): 968.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.56-7.23 (m, 3H), 7.22-7.02 (m, 4H), 6.96-6.57 (m, 3H), 5.76-5.38 (m, 1H), 4.51-4.48 (m, 1H), 4.29-4.23 (m, 2H), 3.86-3.78 (m, 4H), 3.68-3.54 (m, 2H), 3.21 (s, 2H), 3.13-2.93 (m, 4H), 2.25-2.17 (m, 8H), 1.82-1.48 (m, 10H), 1.38-1.28 (m, 5H), 1.27-1.18 (m, 4H), 1.07-1.06 (m, 1H).

[0543] Example 18: Preparation of compound H

[0544] Compound H was synthesized by a similar method as for compounds G-S in Example 1.

[0545] Compound H: MS m / z (ESI): 384.2 [M+H] + .

[0546] Example 19: Preparation of compound 16

[0547] Synthetic route:

[0548] Step 1: Synthesis of compound 16

[0549] To compound 13-9 (34 mg, 0.06 mmol) and compound H (22.69 mg, 0.06 mmol) in N,N-dimethylformamide (2 mL) was added O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (34.22 mg, 0.09 mmol), N,N- diisopropylethylamine (38.78 mg, 0.30 mmol), the reaction mixture was stirred at room temperature for 18 hours. The reaction was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-7 μm-30*150 mm A: 0.1% TFA / H2O B: ACN 35% A-65% B: Ret 1.49 min) to give compound 16. MS m / z (ESI): 940.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.52 (d, J = 9.6 Hz, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.15 (t, J = 7.2 Hz, 3H), 7.05 (s, 1H), 6.96 (s, 2H), 5.56 (d, J = 6.8 Hz, 1H), 4.38 (d, J = 11.2 Hz, 1H), 4.10 - 3.79 (m, 8H), 3.33 (d, J = 2.8 Hz, 3H), 3.18 (s, 1H), 2.93 - 2.79 (m, 3H), 2.30 - 2.20 (m, 8H), 1.82 (d, J = 8.8 Hz, 2H), 1.77 (s, 2H), 1.64 (d, J = 8.0 Hz, 2H), 1.42 (d, J = 6.4 Hz, 3H), 1.31 (s, 2H), 1.24 (s, 1H), 1.17 (d, J = 6.0 Hz, 3H).

[0550] Example 20: Preparation of compound 17

[0551] Compound 17 was synthesized by a similar method to compound 16 in Example 19.

[0552] Compound 17: MS m / z (ESI): 940.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.61 - 6.50 (m, 10 H), 5.82 - 5.31 (m, 1 H), 4.54 - 3.46 (m, 10 H), 3.24 - 2.82 (m, 6 H), 2.26 (d, J = 13.6 Hz, 6 H), 1.86 - 1.06 (m, 17 H).

[0553] Example 21: Preparation of compound 18

[0554] Compound 18 was synthesized by a similar method to compound 10 in Example 12.

[0555] Compound 18: MS m / z (ESI): 951.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1 H), 8.57 (s, 1 H), 7.88 (s, 1 H), 7.62 - 7.51 (m, 2 H), 7.46 - 7.32 (m, 2 H), 7.26 (d, J = 8.4 Hz, 1 H), 7.18 (d, J = 6.0 Hz, 2 H), 6.96 (s, 1 H), 5.57 (d, J = 7.2 Hz, 1 H), 4.40 (d, J = 13.2 Hz, 1 H), 4.01 (d, J = 6.4 Hz, 2 H), 3.86 - 3.82 (m, 2 H), 3.75 - 3.58 (m, 4 H), 3.18 - 3.12 (m, 3 H), 3.04 - 3.01 (m, 1 H), 2.89 - 2.86 (m, 1 H), 2.25 - 2.15 (m, 8 H), 1.83 - 1.78 (m, 2 H), 1.76 - 1.60 (m, 4 H), 1.51 (d, J = 12.0 Hz, 2 H), 1.36 (d, J = 6.4 Hz, 2 H), 1.27 (d, J = 6.0 Hz, 6 H), 1.24 (d, J = 3.6 Hz, 2 H), 1.18 - 1.11 (m, 3 H).

[0556] Example 22: Preparation of compound 19

[0557] Compound 19 was synthesized by a similar procedure as for compound 10 in Example 12.

[0558] Compound 19: MS m / z (ESI): 951.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.50-8.36 (m, 2H), 7.70 (s, 1H), 7.49 (t, J = 11.2 Hz, 2H), 7.29-7.24 (m, 1H), 7.23-7.19 (m, 1H), 7.16 (d, J = 6.0 Hz, 1H), 7.08 (d, J = 6.0 Hz, 1H), 6.89-6.84 (m, 1H), 4.68-4.41 (m, 2H), 4.21-4.15 (m, 2H), 4.09-4.04 (m, 2H), 3.88-3.80 (m, 2H), 3.28-3.24 (m, 3H), 3.10-3.06 (m, 2H), 2.99-2.94 (m, 1H), 2.27-2.23 (m, 6H), 1.94-1.88 (m, 2H), 1.85-1.82 (m, 2H), 1.77-1.75 (m, 2H), 1.64-1.60 (m, 2H), 1.53-1.50 (m, 2H), 1.37-1.32 (m, 6H), 1.31-1.27 (m, 2H), 1.27-1.22 (m, 3H), 1.21-1.18 (m, 2H), 1.10-1.05 (m, 1H).

[0559] Example 23: Preparation of compound 20

[0560] Compound 20 was synthesized by a similar procedure as for compound 10 in Example 12.

[0561] Compound 20: MS m / z (ESI): 951.4 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.04 - 7.92 (m, 2H), 7.64 (d, J = 3.2 Hz, 1H), 7.55 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.21 (br s, 1H), 7.15 (br s, 1H), 6.89 (br s, 1H), 6.77 (br s, 1H), 5.78 - 5.27 (m, 1H), 4.50 (d, J = 17.2 Hz, 1H), 4.17 - 4.10 (m, 2H), 3.95 - 3.91 (m, 2H), 3.85 - 3.79 (m, 2H), 3.72 - 3.66 (m, 2H), 3.30 - 3.26 (m, 3H), 3.06 - 3.02 (m, 2H), 2.23 (d, J = 7.6 Hz, 6H), 1.98 - 1.54 (m, 8H), 1.49 (d, J = 6.4 Hz, 3H), 1.36 (s, 3H), 1.32 - 1.11 (m, 9H).

[0562] Example 24: Preparation of compound J

[0563] Compound J was synthesized by a similar method as compound G-S in Example 1.

[0564] Compound J: SFC separation method: SFC separation column: ChiralPak AD 250 x 25 mm I.D., 5 μm mobile phase: A for CO2 and B for Isopropanol [0.1% NH3(7M in MeOH)], 25%, 3.5 min, flow rate: 100 mL / min, column temperature: 40 °C, ABPR: 2000 psi. Retention time: 3.139 min (second peak). MS m / z (ESI): 354.2 [M+H] + .

[0565] Example 25: Preparation of compound 21

[0566] Compound 21 was synthesized by a similar method as compound 16 in Example 19 (replace compound 13-9 with compound 3-4, and replace compound H with compound J).

[0567] Compound 21: MS m / z (ESI): 936.4 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 7.65-7.43 (m, 3H), 7.32-7.06 (m, 5H), 6.91-6.54 (m, 3H), 4.63-4.56 (m, 2H), 4.25-4.13 (m, 2H), 3.98-3.78 (m, 4H), 3.28-2.96 (m, 6H), 2.28-2.21 (m, 5H), 1.87-1.71 (m, 7H), 1.69-1.56 (m, 3H), 1.49-1.44 (m, 1H), 1.43-1.15 (m, 12H).

[0568] Example 26: Preparation of compound 22

[0569] Compound 22 was synthesized by a similar procedure as for compound 16 in Example 19 (with compound 3-4 replacing compound 13-9).

[0570] Compound 22: MS m / z (ESI): 922.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.58 (s, 1H), 7.50 (d, J = 7.6 Hz, 2H), 7.29 (d, J = 7.2 Hz, 2H), 7.14 (d, J = 7.2 Hz, 2H), 7.07 (d, J = 6.0 Hz, 1H), 6.95 (d, J = 3.6 Hz, 1H), 6.87-6.78 (m, 2H), 5.76 (d, J = 6.8 Hz, 1H), 5.42-5.32 (m, 1H), 4.48 (dd, J = 14.0, 5.2 Hz, 1H), 4.18 (q, J = 5.6 Hz, 3H), 4.04 (d, J = 11.2 Hz, 3H), 3.92 (dd, J = 11.6, 5.6 Hz, 2H), 3.57 (d, J = 3.2 Hz, 2H), 3.22 (s, 3H), 2.25 (s, 6H), 1.83 (d, J = 6.4 Hz, 4H), 1.61 (d, J = 6.8 Hz, 2H), 1.52 (d, J = 6.8 Hz, 2H), 1.31 (dd, J = 12.2, 4.0 Hz, 5H), 1.19 (d, J = 5.6 Hz, 2H), 1.06 (d, J = 6.0 Hz, 2H), 0.93-0.86 (m, 1H).

[0571] Example 27: Preparation of compound 23

[0572] Synthetic route:

[0573] Step 1: Synthesis of compound 23-2

[0574] To a mixture solution of compound 23-1 (10 g, 52.63 mmol) in hydrochloric acid (50 mL) and water (50 mL) was added sodium nitrite (5.45 g, 78.94 mmol) slowly under ice-bath, after stirring at 0 °C for 1 h, stannous chloride dihydrate (29.9 g, 157.88 mmol) was added, the reaction mixture was stirred at room temperature for 18 h. The mixture was filtered and the solid was washed with water (50 mL), the filter cake was dried to give compound 23-2. MS m / z (ESI): 205.1, 207.1 [M+H] + .

[0575] Step 2: Synthesis of compound 23-3

[0576] To a solution of compound 23-2 (7.1 g, 34.63 mmol) in ethanol (100 mL) was added ethyl pyruvate (5.23 g, 45.02 mmol) slowly at room temperature, after stirring at 60 °C for 2 h, the reaction mixture was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 3 / 1) to give compound 23-3. MS m / z (ESI): 303.0, 305.0 [M+H] + .

[0577] Step 3: Synthesis of compound 23-4

[0578] To a solution of compound 23-3 (8.0 g, 26.39 mmol) in toluene (100 mL) was added Eaton’s reagent (12.6 g, 53 mmol) at room temperature, after stirring at 100 °C for 2 h, the reaction mixture was poured into ice water (40 mL), extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 3) to give compound 23-4. MS m / z (ESI): 286.1, 288.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 12.66 (s, 1H), 7.75 (d, J = 1.6 Hz, 1H), 7.35 (dd, J = 10.8, 1.6 Hz, 1H), 7.21 (dd, J = 3.2, 2.0 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 1.34 (t, J = 7.2 Hz, 3H).

[0579] Step 4: Synthesis of compound 23-5

[0580] To a mixture of compound 23-4 (0.5 g, 1.75 mmol) and 3,6-dihydro-2H-pyran-4- boronic acid pinacol ester (0.55 g, 2.62 mmol) in dioxane (10 mL) and water (2.5 mL) was added potassium carbonate (0.48 g, 3.5 mmol) and l,l'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (0.26 g, 0.35 mmol), and the reaction mixture was purged with nitrogen three times and stirred at 100 °C for 18 h. After the reaction was completed, the reaction mixture was cooled to room temperature, diluted with water (10 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 1) to give compound 23-5. MS m / z (ESI): 290.1 [M+H] + .

[0581] Step 5: Synthesis of compound 23-6

[0582] To a mixture of compound 23-5 (410 mg, 1.42 mmol) in methanol (3 mL) and ethyl acetate (3 mL) was added 10% palladium-carbon (100 mg), and the reaction mixture was purged with hydrogen three times and stirred at room temperature for 18 h. The reaction mixture was filtered through celite, and the filtrate was washed with dichloromethane (5 mL x 3), and the filtrate was concentrated under reduced pressure to give compound 23-6. MS m / z (ESI): 292.1 [M+H] + .

[0583] Step 6: Synthesis of compound 23-7

[0584] To a solution of compound 23-6 (410 mg, 1.41 mmol) in N,N-dimethylformamide (5 mL) was added sodium hydride (70 mg, 2.81 mmol) at 0 °C under nitrogen. After the reaction mixture was stirred at room temperature for 0.5 h, bromoacetonitrile (340 mg, 2.81 mmol) was added slowly, and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with saturated ammonium chloride solution (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 3 / 1) to give compound 23-7. MS m / z (ESI): 331.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.42 (dd, J = 16.0, 1.6 Hz, 2H), 7.25 (dd, J = 14.4, 1.2 Hz, 1H), 5.73 (s, 2H), 4.37 (q, J = 7.2 Hz, 2H), 4.00 - 3.91 (m, 2H), 3.44 (td, J = 11.2, 3.2 Hz, 2H), 2.87 (tt, J = 10.0, 4.4 Hz, 1H), 1.78 - 1.66 (m, 4H), 1.36 (t, J = 7.2 Hz, 3H).

[0585] Step 7: Synthesis of compound 23-8

[0586] To the solution of compound 23-7 (320 mg, 0.97 mmol) in N,N-dimethyl acrylamide (5 mL) was added compound G-S-10 (803 mg, 5.81 mmol) under ice-bath, the reaction mixture was stirred at room temperature for 10 min, then lithium bis(trimethylsilyl)amide (9.7 mL, 9.7 mmol, 1 M) was added slowly, the reaction mixture was stirred at room temperature for 18 h, then diluted with saturated ammonium chloride solution (5 mL), extracted with ethyl acetate (10 mL x 3), the combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated, the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 3 / 1) to give compound 23-8. MS m / z (ESI): 371.1 [M+H] + .

[0587] Step 8: Synthesis of compound 23-9

[0588] To the mixture of compound 23-8 (50 mg, 0.13 mmol) in methanol (2 mL) and water (0.5 mL) was added sodium hydroxide (26 mg, 0.65 mmol), the reaction mixture was stirred at 50 °C for 2 h, then adjusted to pH 2 with 2 M hydrochloric acid under ice-bath, extracted with dichloromethane (10 mL x 3), the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated to give compound 23-9. MS m / z (ESI): 343.2 [M+H] + .

[0589] Step 9: Synthesis of compound 23-10

[0590] To a solution of compound 23-9 (46 mg, 0.13 mmol) in N,N-dimethylformamide (4 mL) was added compound 3-4 (75 mg, 0.13 mmol), O-(7-azabenzotriazol-l-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (74 mg, 0.20 mmol), N,N-diisopropylethylamine (84 mg, 0.65 mmol), the reaction mixture was stirred at room temperature for 18 h. The reaction was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 5) to give compound 23-10. MS m / z (ESI): 881.4 [M+H] + .

[0591] Step 10: Synthesis of compound 23-11

[0592] To a solution of compound 23-10 (118 mg, 0.13 mmol) in ethanol (5 mL) was added hydroxylamine hydrochloride (42 mg, 0.60 mmol), N,N-diisopropylethylamine (78 mg, 0.60 mmol), the reaction mixture was stirred at 60 degree Celsius for 1 h. The reaction was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated to give compound 23-11. MS m / z (ESI): 914.4 [M+H] + .

[0593] Step 11: Synthesis of compound 23

[0594] To a solution of compound 23-11 (94 mg, 0.10 mmol) in dimethyl sulfoxide (4 mL) was added N,N'-carbonyldiimidazole (42 mg, 0.26 mmol), 1,8-diazabicycloundec-7-ene (39 mg, 0.26 mmol), the reaction mixture was stirred at room temperature for 1 h. The reaction was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated to give crude which was purified by preparative HPLC (Waters-Xbridge-C18-7 pm-30*150mm A:0.1% TFA / H20 B:ACN 35% A-65%B:Ret 1.40 min) to give compound 23. MS m / z (ESI): 940.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.90 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.37-7.33 (m, 4H), 7.16 (d, J = 6.4 Hz, 2H), 7.08 (d, J = 13.6 Hz, 2H), 6.98 (s, 1H), 5.52 (d, J = 6.8 Hz, 1H), 4.38 (s, 1H), 4.08-4.03 (m, 2H), 3.96 (d, J = 10.4 Hz, 2H), 3.86-3.81 (m, 2H), 3.15 (s, 3H), 2.88 (d, J = 16.0 Hz, 2H), 2.34-2.32 (m, 1H), 2.21 (d, J = 6.4 Hz, 6H), 1.78-1.62 (m, 8H), 1.56 (d, J = 22.4 Hz, 2H), 1.36 (d, J = 6.8 Hz, 2H), 1.27-1.22 (m, 4H), 1.16 (d, J = 6.0 Hz, 3H), 1.10-1.02 (m, 1H).

[0595] Example 28: Preparation of compound 24

[0596] Synthetic route:

[0597] Step 1: Synthesis of compound 24-1

[0598] To a solution of compound 23-1 (10 g, 52.63 mmol) in ethanol (100 mL) was added silver sulfate (16.41 g, 52.63 mmol) and iodine (24.04 g, 94.73 mmol) at room temperature. After the addition was completed, the mixture was stirred at room temperature for 3 hours. The reaction solution was quenched with saturated sodium sulfite (100 mL), diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 2) to obtain compound 24-1. MS m / z (ESI): 315.8, 317.8 [M+H] + .

[0599] Step 2: Synthesis of compound 24-2

[0600] To a solution of compound 24-2 (1.84 g, 7.13 mmol) and N-methylaniline (1.15 g, 10.70 mmol) in N,N-dimethylacetamide (35 mL) was added N-methylimidazole (3.51 g, 42.78 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (2.40 g, 8.56 mmol) at room temperature. The reaction was stirred at room temperature for 1 h. To the reaction was added sodium hydroxide (2 M, 100 mL) solution and stirred for 6 h. Yellow solid was precipitated and filtered. The filter cake was washed with water for 3 times and concentrated under reduced pressure to give compound 24-3. MS m / z (ESI): 347.0, 349.0 [M+H] + .

[0601] Step 3: Synthesis of compound 24-3

[0602] To a solution of compound 24-2 (1.84 g, 7.13 mmol) and N-methylaniline (1.15 g, 10.70 mmol) in N,N-dimethylacetamide (35 mL) was added N-methylimidazole (3.51 g, 42.78 mmol) and N,N,N',N'-tetramethylchloroformamidinium hexafluorophosphate (2.40 g, 8.56 mmol) at room temperature. The reaction was stirred at room temperature for 1 h. To the reaction was added sodium hydroxide (2 M, 100 mL) solution and stirred for 6 h. Yellow solid was precipitated and filtered. The filter cake was washed with water for 3 times and concentrated under reduced pressure to give compound 24-3. MS m / z (ESI): 347.0, 349.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 12.03 (s, 1H), 7.46 - 7.33 (m, 6H), 7.19 - 7.16 (m, 1H), 5.55 (d, J = 3.2 Hz, 1H), 3.40 (s, 3H).

[0603] Step 4: Synthesis of compound 24-4

[0604] To a mixture solution of compound 24-3 (1.66 g, 4.78 mmol) and compound G-S-3A (1.14 g, 4.78 mmol) in dioxane (25 mL) and water (5 mL) was added potassium carbonate (1.32 g, 9.56 mmol) and 1,1'-bis(diphenylphosphino)ferrocene palladium(II) dichloride (0.35 g, 0.48 mmol), and the reaction was protected by nitrogen for three times. The reaction was stirred at 100 °C for 2 h. After the reaction was cooled to room temperature, the reaction was diluted with water (100 mL) and extracted with ethyl acetate (100 mL x 2). The organic phase was washed with saturated brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 1) to give compound 24-4. MS m / z (ESI): 379.1 [M+H] + .

[0605] Step 5: Synthesis of compound 24-5

[0606] To a solution of compound 24-4 (1.3 g, 3.44 mmol) in methanol (50 mL) was added 10% palladium-carbon (1.0 g), and the reaction was protected by hydrogen for three times. The reaction was stirred at room temperature for 18 h. The reaction was filtered through celite, and the filtrate was washed with dichloromethane for three times. The filtrate was concentrated under reduced pressure to give compound 24-5. MS m / z (ESI): 381.2 [M+H] + .

[0607] Step 6: Synthesis of compound 24-6

[0608] To a solution of compound 24-5 (900 mg, 2.37 mmol) and potassium tert-butoxide (796.32 mg, 7.10 mmol) in N,N-dimethylacetamide (10 mL) was added bromoacetonitrile (567.50 mg, 4.73 mmol), and the reaction was protected by nitrogen for three times. The reaction was stirred at 90 °C for 3 h. After the reaction was cooled to room temperature, the reaction was diluted with water (100 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (100 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 4) to give compound 24-6. MS m / z (ESI): 420.1 [M+H] + .

[0609] Step 7: Synthesis of compound 24-7

[0610] To a solution of compound 24-6 (540 mg, 1.29 mmol) and compound G-S-10 (533.46 mg, 3.86 mmol) in N,N-dimethyl acrylamide (15 mL) was added lithium bis(trimethylsilyl)amide (1.0 M, 11.59 mL, 11.59 mmol) dropwise under nitrogen protection with ice bath. After the addition was completed, the mixture was stirred in ice bath for 1 hour. The reaction solution was quenched with saturated ammonium chloride (50 mL), diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 2) to give compound 24-7. MS m / z (ESI): 460.2 [M+H] + .

[0611] Step 8: Synthesis of compound 24-8

[0612] To a solution of compound 24-7 (590 mg, 1.28 mmol) and hydroxylamine hydrochloride (446.06 mg, 6.42 mmol) in ethanol (16 mL) was added N,N-diisopropylethylamine (829.66 mg, 6.42 mmol), and the reaction solution was stirred at 60 °C for 4 hours under nitrogen protection. After the reaction solution was cooled to room temperature, water (50 mL) was added for dilution and extraction with ethyl acetate (50 mL x 2). The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give compound 24-8. MS m / z (ESI): 493.2 [M+H] + .

[0613] Step 9: Synthesis of compound 24-9

[0614] To a solution of compound 24-8 (5.0 g, 10.5 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (590 mg, 1.20 mmol) in dimethyl sulfoxide (6 mL) was added N,N'-carbonyldiimidazole (388.42 mg, 2.40 mmol) at room temperature. The reaction solution was stirred at room temperature for 1 hour. Water (5 mL) was added for dilution and extraction with ethyl acetate (5 mL x 2). The organic phase was washed with saturated brine (5 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 24-9. MS m / z (ESI): 519.2 [M+H] + .

[0615] Step 10: Synthesis of compounds 24-10 and 24-10A

[0616] Compound 24-9 (400 mg, 0.77 mmol) was separated by SFC (Separation column: ChiralPak AD 250 x 25 mm I.D., 5 μm, Mobile phase: A for CO2 and B for Ethanol [0.1% NH3(7M in MeOH)], Flow rate: 80 mL / min, Column temperature: 35 °C, ABPR: 100 psi) to give the first peak as compound 24-10 (retention time: 2.458 min) and the second peak as compound 24-10A (retention time: 2.724 min).

[0617] Step 11: Synthesis of compound 24-11

[0618] To a solution of compound 24-10A (85 mg, 0.16 mmol) in ethylene glycol methyl ether (0.4 mL) was added potassium hydroxide (91.97 mg, 1.64 mmol) and the reaction was stirred at 120 °C for 18 h. After the reaction was cooled to room temperature, ice water was added to dilute the reaction, 1M diluted hydrochloric acid was added dropwise to adjust the pH to about 3, and ethyl acetate (20 mL x 2) was added to extract the organic phase. The organic phase was dried over anhydrous sodium sulfate and concentrated. The residue was washed with acetonitrile, filtered, and the filtrate was concentrated to give compound 24-11. MS m / z (ESI): 430.2 [M+H] + .

[0619] Step 12: Synthesis of compound 24

[0620] To a solution of compound 24-11 (35 mg, 0.08 mmol) and compound 3-4 (45.37 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (31.60 mg, 0.24 mmol), 2-(7-azobenzotriazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (46.48 mg, 0.12 mmol), and the reaction was stirred at room temperature for 1 h. The reaction was filtered, and the filtrate was purified by reverse phase HPLC preparation (Waters-SunFire-C18-10 μm-19*250 mm; Mobile: phase A: 0.1% FA / H2O B: ACN; Gradient; 0% to 95%) to give compound 24. MS m / z (ESI): 968.4 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 7.65-7.44 (m, 1H), 7.38-7.32 (m, 2H), 7.27-7.10 (m, 3H), 7.05-6.94 (m, 2H), 6.89-6.57 (m, 2H), 5.78-5.36 (m, 1H), 4.61-4.48 (m, 1H), 4.25-4.21 (m, 2H), 3.98-3.51 (m, 5H), 3.26-2.97 (m, 6H), 2.30-2.20 (m, 6H), 1.89-1.54 (m, 12H), 1.38-1.21 (m, 10H), 1.09 (d, J = 5.6 Hz, 1H).

[0621] Example 29: Preparation of compound 25

[0622] Synthetic route:

[0623] Step 1: Synthesis of compound 25-2

[0624] To a solution of compound 25-1 (20 g, 132.45 mmol) in hydrochloric acid (80 mL) and water (80 mL) was added sodium nitrite (10.0 g, 145 mmol) under ice bath. After the reaction solution was stirred under ice bath for 1 h, stannous chloride dihydrate (5.14 g, 23.60 mmol) in hydrochloric acid (80 mL) and water (80 mL) was added. The reaction solution was stirred under ice bath for 2 h. After quenched with water (200 mL), the pH was adjusted to 8 with 50% NaOH aqueous solution, filtered, and the filtrate was extracted with ethyl acetate (200 mL x 3). The organic layer was combined, washed with saturated brine (500 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave compound 25-2. MS m / z (ESI): 167.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 6.84 (dd, J = 10.0, 8.8 Hz, 1H), 6.56-6.50 (m, 1H), 6.43 (s, 1H), 6.35 (dd, J = 6.8, 2.8 Hz, 1H), 3.87 (s, 2H), 2.00-1.90 (m, 1H), 0.94-0.87 (m, 2H), 0.66-0.61 (m, 2H).

[0625] Step 2: Synthesis of compound 25-3

[0626] To a solution of compound 25-2 (16 g, 96.39 mmol) in ethanol (200 mL) was added compound D-3 (22.9 g, 96.39 mmol) and pyridine hydrochloride (2.22 g, 19.28 mmol). The reaction was refluxed at 90 degree Celsius for 16 hours. The reaction was diluted with water (200 mL) and extracted with ethyl acetate (200 mL x 3). The organic layers were combined and washed with saturated brine (500 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 25-3. MS m / z (ESI): 387.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.19-7.14 (m, 1H), 7.04-6.95 (m, 2H), 5.04 (d, J = 70.2 Hz, 1H), 4.41-4.10 (m, 1H), 3.50 (s, 1H), 2.59 (s, 2H), 2.09-1.99 (m, 1H), 1.42 (s, 9H), 1.27 (d, J = 6.4 Hz, 3H), 0.98-0.91 (m, 2H), 0.73-0.66 (m, 2H).

[0627] Step 3: Synthesis of compound 25-4

[0628] To a solution of aminoacetaldehyde dimethyl acetal (28.6 g, 272.02 mmol) in tetrahydrofuran (300 mL) was added N,N-diisopropylethylamine (30.0 g, 233 mmol) and p-nitrophenyl chloroformate (39.0 g, 194 mmol) at ice bath. The reaction was stirred at room temperature for 3 hours. The reaction was concentrated under reduced pressure. To the residue was added a solution of compound 25-3 (15 g, 38.86 mmol) in pyridine (150 mL). The reaction was stirred at 40 degree Celsius for 16 hours. To the reaction was added water (250 mL) and extracted with ethyl acetate (200 mL x 3). The organic layers were washed with water (300 mL) and saturated brine (500 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 25-4. MS m / z (ESI): 518.3 [M+H] + . 1H NMR (400 MHz, CDC13) δ 7.19 (dd, J = 7.2, 4.0 Hz, 1H), 7.04 - 6.94 (m, 2H), 5.15 (s, 1H), 4.50 - 4.17 (m, 2H), 3.33 (d, J = 3.6 Hz, 6H), 3.13 (d, J = 12.0 Hz, 2H), 2.71 (s, 2H), 2.12 - 2.05 (m, 1H), 1.93 - 1.73 (m, 1H), 1.61 - 1.26 (m, 12H), 1.04 - 0.89 (m, 2H), 0.79 - 0.65 (m, 2H).

[0629] Step 4: Synthesis of compound 25-5

[0630] To a solution of compound 25-4 (15 g, 29.01 mmol) in tetrahydrofuran (200 mL) was added methylsulfonic acid (2.51 g, 26.11 mmol). The reaction was stirred at 60 °C for 4 hours. After the reaction was cooled to room temperature, triethylamine (5.86 g, 58.02 mmol) and di-tert-butyl dicarbonate (1.58 g, 7.25 mmol) were added and the reaction mixture was stirred at room temperature for 16 hours. After the reaction was completed, water (150 mL) was added for dilution, extracted with ethyl acetate (150 mL x 3), washed with saturated brine (300 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 3 / 1) to give compound 25-5. MS m / z (ESI): 454.2 [M+H] + . 1 H NMR (400 MHz, CDC13) δ 7.19 (dd, J = 7.2, 4.0 Hz, 1H), 7.04 - 6.94 (m, 2H), 5.15 (s, 1H), 4.50 - 4.17 (m, 2H), 3.33 (d, J = 3.6 Hz, 6H), 3.13 (d, J = 12.0 Hz, 2H), 2.71 (s, 2H), 2.12 - 2.05 (m, 1H), 1.93 - 1.73 (m, 1H), 1.61 - 1.26 (m, 12H), 1.04 - 0.89 (m, 2H), 0.79 - 0.65 (m, 2H).

[0631] Step 5: Synthesis of compound 25-6

[0632] To a solution of compound 14-1 (3 g, 6.62 mmol) in N-methylpyrrolidine (40 mL) was added compound 25-5 (2.15 g, 7.28 mmol), potassium carbonate (2.74 g, 19.9 mmol), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (470 mg, 3.31 mmol) and cuprous iodide (252 mg, 1.32 mmol). The reaction was stirred at 130 °C for 4 h. To the reaction was added water (50 mL) and extracted with ethyl acetate (50 mL x 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to give compound 25-6. MS m / z (ESI): 669.4 [M+H] + .

[0633] Step 6: Synthesis of compound 25-7

[0634] To a solution of compound 25-6 (60 mg, 0.09 mmol) in dichloromethane (2 mL) was added 4 M hydrochloric acid in dioxane (1 mL) and the reaction was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure to give compound 25-7. The crude product was used directly in the next step. MS m / z (ESI): 569.3 [M+H] + .

[0635] Step 7: Synthesis of compound 25

[0636] To a solution of compound G-S (30 mg, 0.07 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (66 mg, 0.49 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (83 mg, 0.21 mmol). After the reaction was stirred at room temperature for 30 min, compound 25-7 (50 mg, 0.08 mmol) was added and the reaction was stirred at room temperature for 16 h. The reaction was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with saturated brine (3 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC (waters-xbridge-C18-10um-19*250mm, Mobile phase: 0.1% FA / H2O B:CH3CN, Gradient: 50% B-70% B, Ret 11.51 min) to give compound 25. MS m / z (ESI): 962.4 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 8.39 - 6.50 (m, 12 H), 5.94 - 5.13 (m, 1 H), 4.57 - 4.16 (m, 2 H), 3.98 - 3.42 (m, 5 H), 3.25 - 2.64 (m, 7 H), 2.21 - 1.60 (m, 12 H), 1.59 - 1.47 (m, 3 H), 1.30 (d, J = 39.6 Hz, 6 H), 1.23 - 0.93 (m, 5 H), 0.62 (d, J = 28.4 Hz, 2 H).

[0637] Example 30: Preparation of compound 26

[0638] Compound 26 was synthesized by a similar method to compound 25 in Example 29.

[0639] Compound 26: MS m / z (ESI): 936.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.65 - 7.54 (m, 1 H), 7.50 (d, J = 8.0 Hz, 2 H), 7.38 (s, 1 H), 7.33 - 7.24 (m, 3 H), 7.20 - 7.07 (m, 2 H), 6.99 - 6.55 (m, 3 H), 5.82 - 5.28 (m, 1 H), 4.22 - 4.17 (m, 2 H), 4.00 - 3.72 (m, 4 H), 3.65 - 3.50 (m, 2 H), 3.23 (s, 3 H), 3.10 - 2.90 (m, 3 H), 2.27 (d, J = 12.8 Hz, 3 H), 1.89 - 1.49 (m, 11 H), 1.38 - 1.16 (m, 11 H), 1.12 - 1.02 (m, 1 H).

[0640] Example 31: Preparation of compound 27

[0641] Compound 27 was synthesized by a similar method to compound 25 in Example 29.

[0642] Compound 27: MS m / z (ESI): 990.2 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.78-7.56 (m, 3H), 7.55-7.43 (m, 2H), 7.42-7.29 (m, 3H), 7.28-7.11 (m, 2H), 6.96 (s, 1H), 5.90-5.44 (m, 1H), 4.41 (d, J = 12.8 Hz, 1H), 4.11-4.00 (m, 2H), 3.89-3.77 (m, 2H), 3.74-3.45 (m, 3H), 3.18-3.14 (m, 3H), 3.09-2.75 (m, 3H), 1.88-1.47 (m, 11H), 1.38 (d, J = 6.4 Hz, 2H), 1.33-1.22 (m, 5H), 1.19-1.15 (m, 5H).

[0643] Example 32: Preparation of compound 28

[0644] Compound 28 was synthesized by a similar method to that of compound 10 in Example 12.

[0645] Compound 28: MS m / z (ESI): 948.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.78-7.56 (m, 3H), 7.55-7.43 (m, 2H), 7.42-7.29 (m, 3H), 7.28-7.11 (m, 2H), 6.96 (s, 1H), 5.90-5.44 (m, 1H), 4.41 (d, J = 12.8 Hz, 1H), 4.11-4.00 (m, 2H), 3.89-3.77 (m, 2H), 3.74-3.45 (m, 3H), 3.18-3.14 (m, 3H), 3.09-2.75 (m, 3H), 1.88-1.47 (m, 11H), 1.38 (d, J = 6.4 Hz, 2H), 1.33-1.22 (m, 5H), 1.19-1.15 (m, 5H).

[0646] Example 33: Preparation of compound 29

[0647] Compound 29 was synthesized by a similar method to that of compound 29-P1 in Example 34 (compound 29-2 replaced compound 29-P1-3 in step 3).

[0648] Compound 29: MS m / z (ESI): 936.4 [M+H]+ . 1 H NMR (400 MHz, CD3OD) δ 7.54-7.42 (m, 3H), 7.31-7.26 (m, 2H), 7.16-7.12 (m, 2H), 7.08 (d, J = 5.6 Hz, 1H), 6.96-6.55 (m, 3H), 5.77-5.38 (m, 1H), 4.58-3.44 (m, 10H), 3.25-2.94 (m, 6H), 2.44-2.22 (m, 1H), 2.26-2.17 (m, 6H), 1.83-1.51 (m, 10H), 1.35-1.20 (m, 7H), 1.07 (d, J = 5.6 Hz, 1H).

[0649] Example 34: Preparation of compound 29-P1

[0650] Synthetic route:

[0651] Step 1: Synthesis of compound 29-2

[0652] To a solution of compound 29-1 (1 g, 4.42 mmol) in DMF (20 mL) was added sodium hydride (106 mg, 4.42 mmol) under nitrogen protection at 0 °C, the reaction solution was stirred at the same temperature for 0.5 h, then 2-chloroethyl chloromethyl ether (0.57 g, 4.42 mmol) and sodium iodide (66.3 mg, 4.42 mmol) were added dropwise into the above reaction solution, then the temperature was raised to 80 °C and stirred for 18 h. Saturated NH4Cl (100 mL) was added to the above reaction at 0 °C, then extracted with ethyl acetate (100 mL x 3), the combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 29-2. MS m / z (ESI): 282.0, 284.0 [M+H] + .

[0653] Step 2: Synthesis of compounds 29-P1-3 and 29-P2-3

[0654] Compound 29-2 (400 mg, 1.42 mmol) was separated by SFC (separation column: ChiralPak IG, 250 x 30 mm I.D., 5 μm, mobile phase: A for CO2 and B for Methanol [0.1% NH3(7M in MeOH)], flow rate: 80 mL / min, column temperature: 35 °C, ABPR: 2000 psi) to give the first peak as compound 29-P1-3 (retention time: 2.302 min) and the second peak as compound 29-P2-3 (retention time: 2.530 min).

[0655] Step 3: Synthesis of compound 29-P1-4

[0656] To a solution of compound 29-P1-3 (60 mg, 0.21 mmol) and compound K (85.36 mg, 0.19 mmol) in N-methylpyrrolidine (1 mL) was added potassium carbonate (80 mg, 0.58 mmol), cuprous iodide (7.4 mg, 0.04 mmol) and trans-(1S,2S)-N,N-dimethylcyclohexanediamine (13.8 mg, 0.10 mmol). The reaction was stirred at 130 °C for 2 h. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 2). The organic phase was washed with saturated brine (20 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 2) to give compound 29-P1-4. MS m / z (ESI): 643.3 [M+H] + .

[0657] Step 4: Synthesis of compound 29-P1-5

[0658] The solution of compound 29-P1-4 (82 mg, 0.13 mmol) in dioxane hydrochloride (1 mL, 4M) was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure to give crude compound 29-P1-5. The crude was used directly in the next step. MS m / z (ESI): 543.2 [M+H] + .

[0659] Step 5: Synthesis of compound 29-P1

[0660] To a solution of compound 29-P1-5 (30 mg, 0.06 mmol) and compound G-S (23 mg, 0.06 mmol) in N,N-dimethylformamide (1.5 mL) was added N,N- diisopropylethylamine (21 mg, 0.17 mmol) and 2-(7-azabenzotriazol-1- yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (31.5 mg, 0.08 mmol) at room temperature. The reaction was stirred at room temperature for 1 h. After the reaction was completed, the reaction was filtered, and the filtrate was purified by reverse phase HPLC preparation (waters-xbridge-C18-10um-19*250mm, Mobile phase: 0.1% FA / H2O B:CH3CN, Gradient: 50% B-70% B, Ret 10.71 min) to give compound 29-P1. MS m / z (ESI): 936.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 11.78 (s, 1H), 7.50-7.27 (m, 6H), 7.19-7.13 (m, 4H), 7.01 (br s, 1H), 5.60-5.49 (m, 1H), 4.13-4.01 (m, 2H), 3.86-3.80 (m, 2H), 3.73-3.69 (m, 2H), 3.18 (s, 3H), 3.10-3.01 (m, 3H), 2.20-2.16 (m, 8H), 1.73-1.50 (m, 7H), 1.47-1.24 (m, 9H), 1.20-1.16 (m, 5H).

[0661] Example 35: Preparation of compound 29-P2

[0662] Compound 29-P2 was synthesized by a similar method as compound 29-P1 in Example 34, taking compound 29-P2-3 as raw material.

[0663] Compound 29-P2: MS m / z (ESI): 936.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 7.50-7.27 (m, 5H), 7.19-7.13 (m, 4H), 7.02-6.92 (m, 2H), 5.60-5.49 (m, 1H), 4.13-4.01 (m, 2H), 3.86-3.80 (m, 2H), 3.73-3.69 (m, 2H), 3.18 (s, 3H), 3.10-3.01 (m, 3H), 2.22-2.02 (m, 8H), 1.73-1.50 (m, 8H), 1.47-1.24 (m, 8H), 1.20-1.16 (m, 5H).

[0664] Example 36: Preparation of compound 30

[0665] Synthetic route:

[0666] Step 1: Synthesis of compound 30-2

[0667] To a solution of compound 30-1 (50 g, 182 mmol) in toluene (500 mL) was added paraformaldehyde (16.4 g, 547 mmol), potassium carbonate (75.6 g, 547 mol), tetrabutylammonium iodide (2.7 g, 7.30 mmol) at room temperature. The reaction mixture was stirred at 80 degree Celsius for 16 hours. The reaction solution was added water (1000 mL), extracted with ethyl acetate (500 mL x 3), the combined organic phase was washed with saturated brine (1000 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 10 / 1) and concentrated to give compound 30-2. 1 H NMR (400 MHz, DMSO-d6) δ 8.31 (d, J = 2.0 Hz, 1H), 8.03 (dd, J = 8.4, 2.0 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 6.50 (s, 1H), 6.15 (s, 1H), 3.65 (s, 3H).

[0668] Step 2: Synthesis of compound 30-3

[0669] To a solution of compound 30-2 (33 g, 115 mmol) in mesitylene (300 mL) was added 2-trimethylsiloxy-1,3-butadiene (16.4 g, 115 mmol), the mixture was heated to 130 degree Celsius and stirred for 10 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure to give compound 30-3. 1H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 2.4 Hz, 1H), 7.89 (dd, J = 8.8, 2.4 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 4.88 (s, 1H), 3.57 (s, 3H), 2.20 - 2.12 (m, 2H), 2.11 - 2.02 (m, 2H), 1.99 - 1.84 (m, 2H), 0.20 (s, 9H).

[0670] Step 3: Synthesis of compound 30-4

[0671] To a solution of compound 30-3 (6 g, 14.01 mmol) in ethyl acetate (60 mL) was added hydrogen chloride ethyl acetate (10 mL, 2M), the reaction was stirred at room temperature for 10 hours, the mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 10 / 1) to give compound 30-4. MS m / z (ESI): 356.2, 358.2 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 2.4 Hz, 1H), 7.89 (dd, J = 8.8, 2.4 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 4.88 (s, 1H), 3.57 (s, 3H), 2.20 - 2.12 (m, 2H), 2.11 - 2.02 (m, 2H), 1.99 - 1.84 (m, 2H), 0.20 (s, 9H).

[0672] Step 4: Synthesis of compound 30-5

[0673] To a solution of compound 30-4 (12 g, 33.69 mmol) in acetic acid (100 mL) was added iron powder (15 g, 269 mmol), the mixture was raised to 100 degrees Celsius and stirred for 10 hours. After the mixture was cooled to room temperature, it was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 10 / 1) to give compound 30-5. MS m / z (ESI): 294.0, 296.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.15 (d, J = 2.4 Hz, 1H), 7.89 (dd, J = 8.8, 2.4 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 4.88 (s, 1H), 3.57 (s, 3H), 2.20 - 2.12 (m, 2H), 2.11 - 2.02 (m, 2H), 1.99 - 1.84 (m, 2H), 0.20 (s, 9H).

[0674] Step 5: Synthesis of compound 30-6

[0675] To a solution of compound 30-5 (2 g, 6.80 mmol) in toluene (20 mL) was added sodium hydride (0.24 g, 10.2 mmol), the mixture was stirred at room temperature for 1 h, then iodomethane (1.21 g, 8.50 mmol) was added. The mixture was stirred at 60 °C for 1 h, the mixture was cooled to room temperature, then water (50 mL) was added, the mixture was extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to give compound 30-6. MS m / z (ESI): 308.0, 310.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 7.47 (d, J = 8.0 Hz, 1H), 7.31 (d, J = 2.0 Hz, 1H), 7.23 (dd, J = 8.0, 1.6 Hz, 1H), 3.16 (s, 3H), 2.85 (ddd, J = 15.6, 10.2, 6.0 Hz, 2H), 2.40 (dt, J = 15.2, 5.6 Hz, 2H), 2.15 (ddd, J = 13.6, 10.2, 5.2 Hz, 2H), 2.05 - 1.91 (m, 2H).

[0676] Step 6: synthesis of compound 30-7

[0677] To a solution of compound 30-6 (100 mg, 0.23 mmol) in N-methylpyrrolidine (1 mL) was added compound K (84 mg, 0.27 mmol), potassium carbonate (94 mg, 0.68 mmol), cuprous iodide (8.6 mg, 0.05 mmol) and trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (16 mg, 0.11 mmol), the mixture was stirred at 130 °C for 18 h under nitrogen protection. The mixture was cooled to room temperature, then diluted with water (5 mL), extracted with ethyl acetate (5 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 1) to give compound 30-7. MS m / z (ESI): 669.2 [M+H] + .

[0678] Step 7: synthesis of compound 30-8

[0679] To compound 30-7 (20 mg, 0.03 mmol) was added hydrochloric acid dioxane (3.0 mL, 4 M), the reaction mixture was stirred at room temperature for 1 h, the mixture was concentrated to give crude compound 30-8, which was used directly in the next step. MS m / z (ESI): 569.4 [M+H] + .

[0680] Step 8: Synthesis of compound 30

[0681] To compound 30-8 (20 mg, 0.04 mmol) and compound G-S (10 mg, 0.02 mmol) in N,N-dimethylformamide (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (11 mg, 0.03 mmol), N,N-diisopropylethylamine (4.7 mg, 0.04 mmol), the reaction mixture was stirred at room temperature for 18 h. The reaction was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-7μm-30*150mm A:0.1% TFA / H2O B:ACN 30% A-70%B:Ret 1.459 min) to give compound 30. MS m / z (ESI): 962.3 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.58-7.46 (m, 3H), 7.36-7.24 (m, 3H), 7.18-7.07 (m, 3H), 6.93-6.76 (m, 2H), 3.92-3.68 (m, 3H), 3.28-3.21 (m, 3H), 3.14-2.91 (m, 6H), 2.57-2.47 (m, 1H), 2.28-2.22 (m, 8H), 1.80-1.70 (m, 5H), 1.64-1.58 (m, 3H), 1.55-1.51 (m, 2H), 1.36-1.33 (m, 4H), 1.29-1.25 (m, 4H), 1.24-1.18 (m, 3H), 1.08-1.05 (m, 1H), 0.93-0.87 (m, 1H).

[0682] Example 37: Preparation of compound 31

[0683] Synthetic route:

[0684] Step 1: Synthesis of compound 31-2

[0685] To a solution of compound 31-1 (10.0 g, 48.54 mmol) in ethanol (120 mL) was added sodium borohydride (7.35 g, 194 mmol) under ice bath. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with water (100 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were combined and washed with saturated brine (200 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give compound 31-2. The crude product was used directly in the next step. 1 H NMR (400 MHz, CDCl3) δ 3.74-3.66 (m, 4H), 2.70 (t, J = 5.6 Hz, 4H), 2.01 (s, 2H).

[0686] Step 2: Synthesis of compound 31-3

[0687] To a solution of compound 31-2 (1.10 g, 9.02 mmol) in tetrahydrofuran (20 mL) was added phosphorus tribromide (2.43 g, 9.02 mmol) under ice bath. The reaction mixture was stirred at room temperature for 16 hours. After completion of the reaction, the reaction mixture was quenched with saturated aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined and washed with saturated brine (30 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give compound 31-3. 1 H NMR (400 MHz, CDCl3) δ 3.74-3.66 (m, 4H), 2.70 (t, J = 5.6 Hz, 4H), 2.01 (s, 2H).

[0688] Step 3: Synthesis of compound 31-4

[0689] To a solution of 6-bromo-1-methyldihydro-2-one (265 mg, 1.18 mmol) in DMF (3 mL) was added sodium hydride (94 mg, 2.36 mmol) under ice bath. After stirring at room temperature for 30 minutes, a solution of compound 31-3 (348 mg, 1.42 mmol) in DMF (1 mL) was added dropwise. The reaction mixture was stirred at 50 °C for 1 hour. After completion of the reaction, the reaction mixture was quenched with water (5 mL) and extracted with ethyl acetate (5 mL x 3). The organic layers were combined and washed with saturated brine (10 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure and the residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 10 / 1) to give compound 31-4. MS m / z (ESI): 312.0, 314.0 [M+H] + . 1H NMR (400 MHz, CDC13) δ 7.17 - 7.07 (m, 2H), 6.92 (d, J = 1.6 Hz, 1H), 3.28 - 3.17 (m, 2H), 3.10 (s, 3H), 2.65 - 2.53 (m, 2H), 2.03 - 1.93 (m, 2H), 1.93 - 1.82 (m, 2H).

[0690] Step 4: Synthesis of compound 31-5

[0691] To a solution of compound 31-4 (200 mg, 0.64 mmol) in dichloromethane (4 mL) was added m-chloroperoxybenzoic acid (276 mg, 1.60 mmol) at ice-bath temperature. The reaction was stirred at room temperature for 3 hours. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (5 mL x 3). The combined organic layers were washed with saturated brine solution (10 mL) and dried over anhydrous sodium sulfate. The solution was concentrated under reduced pressure to give compound 31-5. The crude product was used directly for the next step. MS m / z (ESI): 344.0, 346.0 [M+H] + . 1 H NMR (400 MHz, CDC13) δ 7.17 - 7.07 (m, 2H), 6.92 (d, J = 1.6 Hz, 1H), 3.28 - 3.17 (m, 2H), 3.10 (s, 3H), 2.65 - 2.53 (m, 2H), 2.03 - 1.93 (m, 2H), 1.93 - 1.82 (m, 2H).

[0692] Step 5: Synthesis of compound 31-6

[0693] To a solution of compound K (160 mg, 0.36 mmol) in N-methylpyrrolidone (2 mL) was added compound 31-5 (155 mg, 0.45 mmol), potassium carbonate (150 mg, 1.08 mmol), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (26 mg, 0.18 mmol) and copper iodide (14 mg, 0.07 mmol). The reaction was stirred at 130 °C for 3 hours. To the reaction was added water (4 mL) and extracted with ethyl acetate (3 mL x 3). The combined organic layers were washed with saturated brine solution (8 mL), dried over anhydrous sodium sulfate and the solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 31-6. MS m / z (ESI): 705.4 [M+H] + . 1H NMR (400 MHz, CDC13) δ 7.28 (s, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.06-6.97 (m, 3H), 6.63 (d, J = 3.2 Hz, 1H), 6.26 (d, J = 2.8 Hz, 1H), 5.33-5.21 (m, 1H), 4.03-3.94 (m, 2H), 3.18 (s, 3H), 3.11-2.50 (m, 8H), 2.15 (d, J = 1.6 Hz, 6H), 2.04-1.98 (m, 2H), 1.43 (s, 9H), 1.24 (d, J = 6.8 Hz, 3H).

[0694] Step 6: Synthesis of compound 31-7

[0695] To a solution of compound 31-6 (160 mg, 0.23 mmol) in dichloromethane (3 mL) was added 4 M hydrochloric acid in dioxane (1 mL), and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure to give compound 31-7. The crude product was used directly in the next step. MS m / z (ESI): 605.2 [M+H] + .

[0696] Step 7: Synthesis of compound 31

[0697] To a solution of compound G-S (20 mg, 0.05 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (50 mg, 0.40 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (55 mg, 0.15 mmol). After the reaction was stirred at room temperature for 30 minutes, compound 31-7 (35 mg, 0.06 mmol) was added, and the reaction was stirred at room temperature for 16 hours. The reaction was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with saturated brine (4 mL), dried over anhydrous sodium sulfate, and filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC (waters-xbridge-C18-10um-19*250mm, Mobile phase: 0.1% TFA / H20 B:CH3CN, Gradient: 50% B-70% B, Ret 8.82 min) to give compound 31. MS m / z (ESI): 998.4 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 7.56 - 6.54 (m, 11H), 5.75 - 5.37 (m, 1H), 4.53 - 3.50 (m, 6H), 3.19 - 2.99 (m, 8H), 2.65 - 2.04 (m, 10H), 1.84 - 1.64 (m, 4H), 1.59 - 1.04 (m, 15H).

[0698] Example 38: Preparation of compound 32

[0699] Compound 32 was synthesized by a similar method to that of compound 10 in Example 12.

[0700] Compound 32: MS m / z (ESI): 962.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.70 (brs, 1H), 7.59 - 6.81 (m, 11H), 5.57 - 5.53 (m, 1H), 4.72 (d, J = 35.6 Hz, 4H), 3.78 - 3.70 (m, 2H), 3.15 - 2.88 (m, 5H), 2.82 - 2.55 (m, 6H), 2.33 - 2.16 (m, 7H), 1.69 - 1.37 (m, 7H), 1.35 - 1.04 (m, 12H).

[0701] Example 39: Preparation of compound 33

[0702] Synthetic route:

[0703] Step 1: Synthesis of compound 33-1

[0704] To a solution of compound 29-1 (100.0 mg, 0.44 mmol) in N,N- dimethylformamide (1 mL) was added sodium hydride (26.5 mg, 1.11 mmol) at 0 °C under nitrogen protection. After completion, stirring was continued for 1 hour, then a solution of tert-butyl N,N-bis(2-chloroethyl)carbamate (128.5 mg, 0.53 mmol) in N,N-dimethylformamide (1 mL) was added. The mixture was stirred at 60 °C for 2 hours. The reaction solution was cooled to 0 °C and quenched with saturated ammonium chloride (10 mL), diluted with water (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was washed with water (10 mL), saturated brine (10 mL), and dried over anhydrous sodium sulfate. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 25%) to give compound 33-1. MS m / z (ESI): 339.0, 341.0 [M+H-56] +. 1 H NMR (400 MHz, CDC13) δ 7.13 (dd, J = 8.0, 1.6 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 1.6 Hz, 1H), 3.82-3.63 (m, 4H), 3.11 (s, 3H), 1.77-1.72 (m, 2H), 1.68-1.63 (m, 2H), 1.40 (s, 9H).

[0705] Step 2: Synthesis of compound 33-2

[0706] To a solution of compound 33-1 (80 mg, 0.20 mmol) in dichloromethane (2.0 mL) was added hydrochloric acid dioxane solution (0.25 mL, 1.00 mmol) at room temperature, and the mixture was stirred at 25 °C for 2 h. The reaction was directly concentrated to give compound 33-2, which was used directly in the next step. MS m / z (ESI): 295.0, 297.0 [M+H] + .

[0707] Step 3: Synthesis of compound 33-3

[0708] To a solution of compound 33-2 (60 mg, 0.20 mmol) in dichloromethane (1 mL) was added N,N-diisopropylethylamine (103 mg, 0.80 mmol). The mixture was added acetyl chloride (23 mg, 0.30 mmol) dropwise at 0 °C, and then stirred for 2 h. The reaction was diluted with water (10 mL) and extracted with dichloromethane (10 mL x 3). The organic phase was washed with water (10 mL), saturated brine (10 mL), and dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 50%) to give compound 33-3. MS m / z (ESI): 337.0, 339.0 [M+H] + .

[0709] Step 4: Synthesis of compound 33-4

[0710] To a solution of compound 33-3 (50 mg, 0.15 mmol) in N-methylpyrrolidine (1 mL) was added compound K (68 mg, 0.15 mmol), potassium carbonate (43 mg, 0.31 mmol), cuprous iodide (6.0 mg, 0.03 mmol), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (11 mg, 0.08 mmol). The mixture was stirred at 120 °C for 3 h under nitrogen. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with water (5 mL x 2), saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated. The crude product was purified by column chromatography on silica gel (dichloromethane / methanol = 3-6%) to give compound 33-4. MS m / z (ESI): 698.4 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 7.21-7.19 (m, 1H), 7.06 (d, J = 8.0 Hz, 1H), 6.96 (d, J = 1.6 Hz, 1H), 3.97 (td, J = 14.0, 3.2 Hz, 2H), 3.14 (s, 3H), 2.88 (dd, J = 14.8, 3.2 Hz, 2H), 2.64-2.52 (m, 2H), 1.99 (d, J = 15.2 Hz, 2H).

[0711] Step 5: Synthesis of compound 33-5

[0712] To a solution of compound 33-4 (50 mg, 0.07 mmol) in dichloromethane (2 mL) was added hydrochloric acid dioxane (2 mL, 4 M). The mixture was stirred at 20 °C for 2 h. The reaction was directly concentrated to give compound 33-5, which was used directly in the next step. MS m / z (ESI): 598.4 [M+H] + .

[0713] Step 6: Synthesis of compound 33

[0714] To a solution of compound 33-5 (29 mg, 0.05 mmol) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (13 mg, 0.10 mmol), N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)urea hexafluorophosphate (22 mg, 0.06 mmol), compound G-S (20 mg, 0.05 mmol). The mixture was stirred at 20 °C for 4 h. The reaction was dropped into water (5 mL), extracted with ethyl acetate (10 mL x 3), the organic phase was washed with water (5 mL x 2), saturated brine (10 mL), dried over anhydrous sodium sulfate. The crude product was purified by prep-HPLC (ASA-AZZOTA-C18-7μm-30*150mm, A: 0.1% TFA / H2O B: ACN, gradient: 70%) to give compound 33. MS m / z (ESI): 991.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.56-7.34 (m, 3H), 7.32-7.24 (m, 2H), 7.18-7.02 (m, 3H), 7.00-6.54 (m, 3H), 5.77-5.39 (m, 1H), 4.51-4.48 (m, 1H), 4.06-4.00 (m, 2H), 3.90-3.76 (m, 4H), 3.72-3.43 (m, 2H), 3.24 (s, 3H), 3.09-2.93 (m, 3H), 2.26-2.22 (m, 6H), 2.18 (s, 3H), 1.89-1.74 (m, 8H), 1.65-1.51 (m, 5H), 1.36-1.34 (m, 3H), 1.29-1.17 (m, 5H), 1.07 (d, J = 5.6 Hz, 1H).

[0715] Example 40: Preparation of compound 34

[0716] Synthetic route:

[0717] Step 1: Synthesis of compound 34-1

[0718] To a solution of compound K (10 g, 41.97 mmol) in dichloromethane (60 mL) was added trifluoroacetic acid (25 mL, 65.34 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 3 h, then concentrated under reduced pressure to give compound 34-1. The crude product was used directly in the next step. MS m / z (ESI): 342.1 [M+H] + .

[0719] Step 2: Synthesis of compound 34-2

[0720] Compound 34-1 (8.0 g, 57.90 mmol) was dissolved in tetrahydrofuran (100 mL), triethylamine (24 mL, 173.7 mmol) was added, benzyl chloroformate (11.8 g, 69.48 mmol) was added under nitrogen protection at zero degrees Celsius, the resulting mixture was stirred at room temperature for 18 hours, the reaction liquid was poured into ice water (100 mL), and extracted with ethyl acetate (300 mL x 2), the organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to obtain compound 34-2. MS m / z (ESI): 476.1 [M+H] + .

[0721] Step 3: Synthesis of compound 34-3

[0722] To a solution of compound 33-1 (60 mg, 0.15 mmol) in N-methylpyrrolidone (5 mL) was added compound 34-2 (71 mg, 0.15 mmol), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (10 mg, 0.07 mmol), potassium carbonate (62 mg, 0.45 mmol) and cuprous iodide (14 mg, 0.07 mmol), the reaction liquid was warmed to 130°C and stirred for 16 hours. The reaction liquid was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 2 / 1) to obtain compound 34-3. MS m / z (ESI): 790.4 [M+H] + .

[0723] Step 4: Synthesis of compound 34-4

[0724] To a solution of compound 34-3 (70 mg, 0.09 mmol) in isopropanol (5 mL) was added 10% palladium-carbon (10 mg), and stirred at room temperature for 1 hour. The reaction liquid was filtered through diatomite, and the filtrate was concentrated to obtain compound 34-4, which was used directly in the next step. MS m / z (ESI): 656.4 [M+H] + .

[0725] Step 5: Synthesis of compound 34-5

[0726] To a solution of compound G-S (16 mg, 0.04 mmol) in N,N-dimethylformamide (2 mL) was added triethylamine (20 mg, 0.2 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)urea hexafluorophosphate (30 mg, 0.08 mmol). After the reaction solution was stirred at room temperature for 30 min, compound 34-4 (40 mg, 0.06 mmol) was added, and the reaction solution was stirred at room temperature for 16 h. The reaction solution was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with saturated brine (6 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 34-5. MS m / z (ESI): 949.4 [M+H-100] + .

[0727] Step 6: Synthesis of compound 34

[0728] To a solution of compound 34-5 (20 mg, 0.02 mmol) in dichloromethane (2 mL) was added 4 M hydrogen chloride dioxane solution (1 mL), and the reaction solution was stirred at room temperature for 2 h. The reaction solution was concentrated under reduced pressure, and the crude product was purified by preparative HPLC (waters-xbridge-C18-10 um-19*250 mm, Mobile phase: 0.1% TFA / H2O B:CH3CN, Ret 6.54 min) to give compound 34. MS m / z (ESI): 949.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.57-7.43 (m, 3H), 7.37-7.24 (m, 3H), 7.17-7.05 (m, 3H), 6.98-6.79 (m, 2H), 5.84-5.19 (m, 2H), 4.50 (d, J = 13.6 Hz, 1H), 3.87-3.75 (m, 3H), 3.25 (s, 2H), 3.19-2.96 (m, 3H), 2.26-2.20 (m, 6H), 2.08-1.91 (m, 3H), 1.87-1.71 (m, 5H), 1.66-1.50 (m, 6H), 1.36-1.25 (m, 9H), 1.21-1.07 (m, 3H), 0.97-0.81 (m, 1H).

[0729] Example 41: Preparation of compound 35

[0730] Compound 35 was synthesized by a similar method to that of compound 10 in Example 12.

[0731] Compound 35: MS m / z (ESI): 982.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.55 - 6.57 (m, 15H), 5.78 - 5.40 (m, 1H), 4.82 - 3.44 (m, 6H), 3.29 - 2.86 (m, 8H), 2.23 (d, J = 12.0 Hz, 6H), 1.87 - 1.51 (m, 7H), 1.51 - 1.04 (m, 12H).

[0732] Example 42: Preparation of compound 36

[0733] Synthetic route:

[0734] Step 1: Synthesis of compound 36-1

[0735] To a solution of compound 30-7 (100 mg, 0.15 mmol) in tetrahydrofuran (1 mL) was added sodium borohydride (5.66 g, 0.15 mmol) at room temperature, and the reaction mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 3), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (dichloromethane / methanol = 10 / 1) to give compound 36-1. MS m / z (ESI): 671.4 [M+H] + .

[0736] Step 2: Synthesis of compound 36-2

[0737] To a solution of compound 36-1 (35 mg, 0.05 mmol) in tetrahydrofuran (1 mL) was added sodium hydride (2.3 mg, 0.06 mmol), and the mixture was stirred at room temperature for 10 minutes, and then iodomethane (22 mg, 0.08 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was diluted with water (10 mL) and extracted with ethyl acetate (5 mL x 3), and the combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to give compound 36-2. MS m / z (ESI): 685.4 [M+H] + .

[0738] Step 3: Synthesis of compound 36-3

[0739] To compound 36-2 (30 mg, 0.04 mmol) was added hydrochloric acid dioxane (3.0 mL, 4 M, 12 mmol), the reaction mixture was stirred at room temperature for 1 hour. The reaction was concentrated under reduced pressure to give compound 36-3, which was used directly in the next step. MS m / z (ESI): 585.3 [M+H] + .

[0740] Step 4: Synthesis of compound 36

[0741] To compound 36-3 (11 mg, 0.02 mmol) and compound G-S (10 mg, 0.02 mmol) in N,N-dimethylformamide (2 mL) was added O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (11 mg, 0.03 mmol), N,N-diisopropylethylamine (4.7 mg, 0.04 mmol), the reaction mixture was stirred at room temperature for 18 hours. The reaction was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-7 μm-30*150mm A:0.1% TFA / H2O B:ACN 30% A-70%B:Ret 1.58 min) to give compound 36. MS m / z (ESI): 978.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.58-7.45 (m, 3H), 7.34-7.20 (m, 3H), 7.18-7.05 (m, 3H), 6.95-6.88 (m, 1H), 6.84-6.77 (m, 1H), 5.78-5.40 (m, 1H), 3.88-3.78 (m, 2H), 3.66-3.45 (m, 2H), 3.40 (s, 3H), 3.21 (s, 3H), 3.14-3.03 (m, 2H), 3.02-2.95 (m, 2H), 2.27-2.22 (m, 6H), 2.14-2.06 (m, 2H), 2.01-1.90 (m, 4H), 1.79-1.69 (m, 4H), 1.65-1.56 (m, 4H), 1.54-1.50 (m, 2H), 1.36-1.33 (m, 4H), 1.33-1.26 (m, 3H), 1.26-1.22 (m, 3H), 1.21-1.19 (m, 1H).

[0742] Example 43: Preparation of compound 37

[0743] Synthesis route:

[0744] Step 1: Synthesis of compound 37-1

[0745] To a solution of compound 30-6 (100 mg, 0.32 mmol) in dichloromethane (1 mL) was added diethylamine trifluoride (52 mg, 0.32 mmol) under nitrogen protection. The reaction mixture was stirred at room temperature for 0.5 h. It was diluted with saturated aqueous sodium bicarbonate solution (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 4) and concentrated to give compound 37-1. MS m / z (ESI): 330.0, 332.0 [M+H] + .

[0746] Step 2: Synthesis of compound 37-2

[0747] To a solution of compound 37-1 (100 mg, 0.30 mmol) in N-methylpyrrolidine (2 mL) was added compound K (134 mg, 0.30 mmol), potassium carbonate (42 mg, 0.30 mmol), copper(I) iodide (58 mg, 0.30 mmol) and trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (43 mg, 0.30 mmol). The reaction mixture was stirred at 130 °C for 18 h under nitrogen protection. After cooling to room temperature, it was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 1) to give compound 37-2. MS m / z (ESI): 691.4 [M+H] + .

[0748] Step 3: Synthesis of compound 37-3

[0749] To compound 37-2 (20 mg, 0.03 mmol) was added hydrochloric acid-dioxane (3.0 mL, 12 mmol, 4 M). The reaction mixture was stirred at room temperature for 1 h. The mixture was concentrated to give crude compound 37-3. The crude was used directly in the next step. MS m / z (ESI): 591.2 [M+H] + .

[0750] Step 4: Synthesis of compound 37

[0751] To compound 37-3 (20 mg, 0.04 mmol) and compound G-S (10 mg, 0.02 mmol) in N,N-dimethylformamide (2 mL) was added O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (11 mg, 0.03 mmol), N,N-diisopropylethylamine (4.7 mg, 0.04 mmol), the reaction mixture was stirred at room temperature for 18 hours. The reaction was diluted with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-7 pm-30*150 mm A: 0.1% TFA / H20 B: ACN 20% A-80% B: Ret 1.554 min) to give compound 37. MS m / z (ESI): 984.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) d 7.56-7.43 (m, 3H), 7.32-7.20 (m, 3H), 7.17-7.11 (m, 2H), 7.09-7.05 (m, 1H), 6.96-6.88 (m, 1H), 6.84-6.77 (m, 1H), 3.89-3.78 (m, 2H), 3.72-3.51 (m, 1H), 3.23 (s, 3H), 3.14-3.03 (m, 2H), 3.03-3.01 (m, 1H), 3.00-2.93 (m, 1H), 2.60-2.48 (m, 2H), 2.26-2.22 (m, 6H), 2.13-1.97 (m, 4H), 1.95-1.88 (m, 2H), 1.87-1.79 (m, 2H), 1.77-1.65 (m, 4H), 1.63-1.59 (m, 2H), 1.54-1.50 (m, 2H), 1.36-1.33 (m, 4H), 1.28-1.22 (m, 4H), 1.22-1.16 (m, 2H).

[0752] Example 44: Preparation of compound 38

[0753] Synthetic route:

[0754] Step 1: Synthesis of compound 38-1

[0755] To a solution of compound 30-6 (1.0 g, 3.24 mmol) in tetrahydrofuran (10 mL) was added potassium tert-butoxide (546 mg, 4.87 mmol) and methyl triphenylphosphonium iodide (1.96 g, 4.87 mmol) under nitrogen protection. The reaction mixture was stirred at room temperature for 16 hours. The reaction solution was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 4) and concentrated to give compound 38-1. MS m / z (ESI): 306.1, 308.1 [M+H] + .

[0756] Step 2: Synthesis of compounds 38-2A, 38-2B and 38-2C

[0757] To a solution of diiodomethane (2.10 g, 7.84 mmol) in dichloromethane (20 mL) was added diethylzinc (4.0 mL, 4.0 mmol, 1 M) under nitrogen protection at -40 °C. The reaction mixture was stirred at -40 °C for 1 hour, trifluoroacetic acid (0.30 mL, 3.92 mmol) was added, and the reaction mixture was stirred at -15 °C for 1 hour. Compound 38-1 (0.30 mL, 3.92 mmol) was added, and the reaction mixture was stirred at 60 °C for 10 hours. The reaction solution was diluted with saturated aqueous sodium bicarbonate solution (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 10) and concentrated to give compounds 38-2A, 38-2B and 38-2C.

[0758] Compound 38-2A: MS m / z (ESI): 320.0, 322.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.45 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 2.0 Hz, 1H), 7.21 (dd, J = 8.0, 2.0 Hz, 1H), 3.13 (s, 3H), 1.76 (d, J = 8.8 Hz, 2H), 1.58 (s, 6H), 0.34 (p, J = 2.8 Hz, 4H).

[0759] Compound 38-2B: MS m / z (ESI): 320.0, 322.0 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 7.32 - 7.18 (m, 3H), 3.11 (s, 3H), 1.91 - 1.69 (m, 4H), 1.50 (td, J = 13.2, 5.2 Hz, 1H), 1.23 - 1.18 (m, 4H), 0.86 (tdd, J = 8.4, 4.8, 2.79 Hz, 1H), 0.58 (dd, J = 8.8, 4.4 Hz, 1H), 0.31 (t, J = 4.8 Hz, 1H).

[0760] Compound 38-2C: MS m / z (ESI): 320.0, 322.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.29 (d, J = 1.6 Hz, 1H), 7.19 (dd, J = 8.0, 2.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 5.55 - 5.47 (m, 1H), 3.14 (s, 3H), 2.42 (dq, J = 17.6, 2.4 Hz, 1H), 2.24 - 2.13 (m, 2H), 2.07 (dd, J = 96, 5.6 Hz, 2H), 1.93 - 1.78 (m, 2H), 1.52 - 1.42 (m, 1H), 1.05 (t, J = 7.6 Hz, 3H).

[0761] Step 3: Synthesis of compound 38-3

[0762] To a solution of compound 38-2B (50 mg, 0.16 mmol) in N-methylpyrrolidone (1 mL) was added compound K (69 mg, 0.16 mmol), potassium carbonate (64 mg, 0.47 mmol), cuprous iodide (6.0 mg, 0.20 mmol) and trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (11 mg, 0.08 mmol), the reaction mixture was stirred at 130 degree Celsius for 3 hours under nitrogen protection. After cooling to room temperature, diluted with water (5 mL), extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (20 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated. The residue was purified by silica gel column chromatography (ethyl acetate / petroleum ether = 1 / 1) to give compound 38-3. MS m / z (ESI): 681.4 [M+H] + .

[0763] Step 4: Synthesis of compound 38-4

[0764] To a solution of compound 38-3 (35 mg, 0.05 mmol) in dichloromethane (2 mL) was added trifluoroacetic acid (0.5 mL), the reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure to give crude compound 38-4, which was used directly in the next step. MS m / z (ESI): 581.4 [M+H] + .

[0765] Step 5: Synthesis of compound 38

[0766] To a solution of compound 38-4 (25 mg, 0.04 mmol) and compound G-S (21.26 mg, 0.05 mmol) in N,N-dimethylformamide (2 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (25 mg, 0.06 mmol), N,N-diisopropylethylamine (17 mg, 0.13 mmol), the reaction mixture was stirred at room temperature for 2 hours. The reaction was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated. The crude product was purified by preparative HPLC (Waters-SunFire-C18-5 μm-19*250mm A:0.1% TFA / H2O B:ACN 15% A-85%B:Ret 1.69 min) to give compound 38. MS m / z (ESI): 974.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 7.57-7.49 (m, 1H), 7.42-7.39 (m, 2H), 7.35-7.25 (m, 4H), 7.22-7.07 (m, 3H), 7.03-6.96 (m, 1H), 4.45-4.32 (m, 1H), 3.78-3.61 (m, 1H), 3.15 (s, 3H), 3.10-2.95 (m, 2H), 2.94-2.85 (m, 1H), 2.28-2.19 (m, 6H), 1.98-1.62 (m, 10H), 1.58-1.46 (m, 4H), 1.44-1.36 (m, 3H), 1.28 (s, 3H), 1.26-1.23 (m, 6H), 1.19 (s, 3H), 1.17-1.14 (m, 2H), 0.90-0.84 (m, 1H), 0.63-0.57 (m, 1H), 0.37-0.30 (m, 1H).

[0767] Example 45: Preparation of compound 39

[0768] Compound 39 was synthesized by a similar procedure as for compound 38 in Example 44.

[0769] Compound 39: MS m / z (ESI): 974.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.75 (br s, 1H), 7.71 - 7.49 (m, 1H), 7.44 - 7.29 (m, 4H), 7.25 - 7.15 (m, 3H), 7.08 - 6.52 (m, 3H), 5.60 - 5.51 (m, 1H), 4.38 (d, J = 13.2 Hz, 1H), 3.82 - 3.60 (m, 3H), 3.17 (s, 3H), 3.08 - 2.80 (m, 2H), 2.24 - 2.18 (m, 6H), 2.10 - 2.00 (m, 3H), 1.90 - 1.82 (m, 3H), 1.72 - 1.60 (m, 4H), 1.53 - 1.49 (m, 3H), 1.40 - 1.11 (d, J = 5.6 Hz, 15H), 1.08 - 1.06 (m, 3H), 0.85 (t, J = 6.4 Hz, 1H).

[0770] Example 46: Preparation of compound 40

[0771] Compound 40 was synthesized by a similar procedure as for compound 38 in Example 44.

[0772] Compound 40: MS m / z (ESI): 974.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.71 (br s, 1H), 7.57 - 7.04 (m, 9H), 6.71 - 6.62 (m, 2H), 5.58 - 5.30 (m, 1H), 3.72 - 3.69 (m, 4H), 3.22 - 3.15 (m, 2H), 3.11 - 2.99 (m, 2H), 2.25 - 2.17 (m, 3H), 2.03 - 1.96 (m, 6H), 1.58 - 1.37 (m, 9H), 1.34 - 1.25 (m, 14H), 1.12 - 1.00 (m, 2H), 0.88 - 0.83 (m, 5H).

[0773] Example 47: Preparation of compound 41

[0774] Synthesis route:

[0775] Step 1: Synthesis of compound 41-1 H NMR (400 MHz, DMSO-d6) δ 11.71 (br s, 1H), 7.57 - 7.04 (m, 9H), 6.71 - 6.62 (m, 2H), 5.58 - 5.30 (m, 1H), 3.72 - 3.69 (m, 4H), 3.22 - 3.15 (m, 2H), 3.11 - 2.99 (m, 2H), 2.25 - 2.17 (m, 3H), 2.03 - 1.96 (m, 6H), 1.58 - 1.37 (m, 9H), 1.34 - 1.25 (m, 14H), 1.12 - 1.00 (m, 2H), 0.88 - 0.83 (m, 5H).

[0776] To a solution of compound 29-1 (300 mg, 1.33 mmol) in tetrahydrofuran (6 mL) was added N-chlorosuccinimide (443 mg, 3.32 mmol) and 1,8-diazabicyclo[5,4,0]undec-7-ene (606 mg, 3.98 mmol) under ice-bath. The reaction was stirred for 2 h under ice-bath. After the reaction was completed, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 41-1. The crude product was used directly in the next step. MS m / z (ESI): 312.9 [M+H+NH3] + .

[0777] Step 2: Synthesis of compound 41-2

[0778] To a solution of compound 41-1 (390 mg, 1.32 mmol) and catechol (145.35 mg, 1.32 mmol) in acetonitrile (8 mL) was added potassium carbonate (547 mg, 3.96 mmol) at room temperature. The reaction was stirred for 3 h at 80 °C. The reaction was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 3) to give compound 41-2. MS m / z (ESI): 331.9, 333.9 [M+H] + .

[0779] Step 3: Synthesis of compound 41-3

[0780] To a solution of compound 41-2 (92 mg, 0.28 mmol) and compound K (122 mg, 0.28 mmol) in N-methylpyrrolidone (2 mL) was added potassium carbonate (1143 mg, 0.83 mmol), cuprous iodide (11 mg, 0.06 mmol) and trans-(1S,2S)-N,N-dimethylcyclohexane-1,2-diamine (20 mg, 0.14 mmol). The reaction was stirred for 2 h at 130 °C. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 2) to give compound 41-3. MS m / z (ESI): 693.2 [M+H] + .

[0781] Step 4: Synthesis of compound 41-4

[0782] A solution of compound 41-3 (50 mg, 0.07 mmol) in hydrogen chloride in dioxane (3 mL, 4 M, 12 mmol) was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure to give compound 41-4, which was used directly in the next step. MS m / z (ESI): 593.2 [M+H] + .

[0783] Step 5: Synthesis of compound 41

[0784] To a solution of compound 41-4 (42 mg, 0.07 mmol) and compound G-S (29 mg, 0.07 mmol) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (27 mg, 0.21 mmol) and 2-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (40 mg, 0.10 mmol) at room temperature. The reaction was stirred at room temperature for 1 h. The reaction was filtered, and the filtrate was purified by reverse phase HPLC preparation (Phenomenex-Luna-C18-10um-25*250mm; Mobile: phase A: 0.1% FA / H2O B: ACN; Gradient; 0% to 95%) to give compound 41. MS m / z (ESI): 986.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) d 7.55-7.39 (m, 4H), 7.27-7.06 (m, 5H), 6.92 (s, 4H), 6.83-6.64 (m, 2H), 5.78-5.33 (m, 1H), 3.89-3.48 (m, 3H), 3.17-2.93 (m, 6H), 2.25-2.17 (m, 6H), 1.81-1.65 (m, 4H), 1.62-1.43 (m, 6H), 1.40-1.18 (m, 9H), 1.06 (d, J = 6.0 Hz, 1H).

[0785] Example 48: Preparation of compound 42

[0786] Compound 42 was synthesized by a similar method to compound 33 in Example 39.

[0787] Compound 42: MS m / z (ESI): 1045.4 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 7.56-7.45 (m, 3H), 7.32-7.25 (m, 2H), 7.21-6.99 (m, 4H), 6.96-6.77 (m, 2H), 5.78-5.32 (m, 2H), 4.53-4.44 (m, 1H), 4.21-4.12 (m, 2H), 3.98-3.80 (m, 4H), 3.24 (d, J = 2.0 Hz, 2H), 3.09-2.96 (m, 3H), 2.24 (d, J = 13.2 Hz, 6H), 2.05-1.94 (m, 3H), 1.78-1.73 (m, 2H), 1.63-1.51 (m, 6H), 1.33 (d, J = 3.6 Hz, 6H), 1.29 (s, 6H), 0.89 (t, J = 7.2 Hz, 1H).

[0788] Example 49: Preparation of compound 43

[0789] Compound 43 was synthesized by a similar method to compound 33 in Example 39.

[0790] Compound 43: MS m / z (ESI): 963.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.56-7.45 (m, 3H), 7.32-7.25 (m, 2H), 7.21-6.99 (m, 4H), 6.96-6.77 (m, 2H), 5.78-5.32 (m, 2H), 4.53-4.44 (m, 1H), 4.21-4.12 (m, 2H), 3.98-3.80 (m, 4H), 3.24 (d, J = 2.0 Hz, 2H), 3.09-2.96 (m, 3H), 2.24 (d, J = 13.2 Hz, 6H), 2.05-1.94 (m, 3H), 1.78-1.73 (m, 2H), 1.63-1.51 (m, 6H), 1.33 (d, J = 3.6 Hz, 6H), 1.29 (s, 6H), 0.89 (t, J = 7.2 Hz, 1H).

[0791] Example 50: Preparation of compound 44

[0792] Compound 44 was synthesized by a similar method to compound 33 in Example 39.

[0793] Compound 44: MS m / z (ESI): 1027.4 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 7.55-7.45 (m, 3H), 7.35-7.24 (m, 3H), 7.17-7.06 (m, 3H), 6.96-6.78 (m, 2H), 5.85-5.27 (m, 2H), 4.49 (dd, J = 9.6 Hz, 1H), 3.90-3.79 (m, 2H), 3.70-3.64 (m, 2H), 3.60-3.55 (d, J = 7.6 Hz, 2H), 3.22 (s, 2H), 2.93 (d, J = 4.4 Hz, 3H), 2.24 (d, J = 12.4 Hz, 6H), 2.01-1.89 (m, 3H), 1.81-1.72 (m, 3H), 1.62-1.50 (m, 5H), 1.35 (d, J = 5.6 Hz, 3H), 1.33-1.28 (m, 6H), 1.27-1.18 (m, 5H), 1.06 (d, J = 5.2 Hz, 1H), 0.90 (t, J = 6.8 Hz, 1H).

[0794] Example 51: Preparation of compound 45

[0795] Compound 45 was synthesized by a similar method to that of compound 33 in Example 39.

[0796] Compound 45: MS m / z (ESI): 1002.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.58-7.54 (m, 3H), 7.36 (d, J = 7.6 Hz, 1H), 7.28 (d, J = 8.4 Hz, 1H), 7.18-7.04 (m, 4H), 6.99-6.81 (m, 2H), 5.83-5.68 (m, 1H), 5.37-5.30 (m, 1H), 4.51 (dd, J = 9.6 Hz, 1H), 3.95-3.80 (m, 4H), 3.67-3.58 (m, 4H), 3.25 (s, 2H), 3.13-3.04 (m, 4H), 2.24 (d, J = 13.6 Hz, 6H), 2.03 (d, J = 5.6 Hz, 1H), 1.84-1.73 (m, 4H), 1.64-1.57 (m, 3H), 1.51 (d, J = 6.4 Hz, 2H), 1.36 (s, 3H), 1.34 (d, J = 4.4 Hz, 3H), 1.29 (d, J = 4.0 Hz, 3H), 1.25 (d, J = 8.4 Hz, 3H), 1.20 (d, J = 5.2 Hz, 2H), 0.92-0.87 (m, 1H).

[0797] Example 52: Preparation of compound 46

[0798] Compound 46 was synthesized by a similar method to compound 33 in Example 39.

[0799] Compound 46: MS m / z (ESI): 1021.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) d 7.55 (s, 1H), 7.52-7.46 (m, 2H), 7.34-7.22 (m, 3H), 7.17-7.12 (m, 2H), 7.10-7.06 (m, 1H), 6.96-6.88 (m, 1H), 6.84-6.77 (m, 1H), 5.77-5.73 (m, 1H), 5.34 (t, J = 4.80 Hz, 1H), 4.68-4.63 (m, 1H), 4.58-4.42 (m, 1H), 4.07-3.97 (m, 2H), 3.92-3.78 (m, 4H), 3.27-3.22 (m, 3H), 3.11-2.93 (m, 4H), 2.24-2.17 (m, 9H), 2.05-2.01 (m, 2H), 1.85-1.81 (m, 2H), 1.78-1.71 (m, 4H), 1.66-1.58 (m, 4H), 1.54-1.50 (m, 2H), 1.36-1.34 (m, 4H), 1.26-1.20 (m, 4H).

[0800] Example 53: Preparation of compound 47

[0801] Compound 47 was synthesized by a similar method to compound 33 in Example 39.

[0802] Compound 47: MS m / z (ESI): 988.4 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 7.59-7.46 (m, 3H), 7.32-7.26 (m, 2H), 7.17-6.77 (m, 6H), 5.81-5.31 (m, 1H), 4.50 (d, J = 13.2 Hz, 1H), 3.90-3.79 (m, 2H), 3.23 (s, 2H), 3.14-2.94 (m, 6H), 2.26-2.21 (m, 6H), 2.05-1.95 (m, 3H), 1.89-1.72 (m, 6H), 1.63-1.51 (m, 5H), 1.35 (d, J = 6.4 Hz, 6H), 1.29-1.25 (m, 6H), 1.07 (d, J = 5.6 Hz, 1H), 0.89 (t, J = 7.2 Hz, 1H).

[0803] Example 54: Preparation of compound 48

[0804] Compound 48 was synthesized by a similar method to compound 33 in Example 39.

[0805] Compound 48: MS m / z (ESI): 1031.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.59-7.46 (m, 3H), 7.32-7.26 (m, 2H), 7.17-6.77 (m, 6H), 5.81-5.31 (m, 1H), 4.50 (d, J = 13.2 Hz, 1H), 3.90-3.79 (m, 2H), 3.23 (s, 2H), 3.14-2.94 (m, 6H), 2.26-2.21 (m, 6H), 2.05-1.95 (m, 3H), 1.89-1.72 (m, 6H), 1.63-1.51 (m, 5H), 1.35 (d, J = 6.4 Hz, 6H), 1.29-1.25 (m, 6H), 1.07 (d, J = 5.6 Hz, 1H), 0.89 (t, J = 7.2 Hz, 1H).

[0806] Example 55: Preparation of compound 49

[0807] Synthetic route:

[0808] Step 1: Synthesis of compound 49-2

[0809] To a solution of compound 49-1 (28.0 g, 94.3 mmol) in tetrahydrofuran (200 mL) was added dropwise n-butyllithium (41 mL, 102.5 mmol, 2.5 M) at -78 °C. After the reaction solution was stirred for 30 minutes under a nitrogen atmosphere, a solution of 3-oxetanone (6.80 g, 94.3 mmol) in tetrahydrofuran (70 mL) was added dropwise to the above solution. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was quenched by dropwise addition of saturated aqueous ammonium chloride solution (100 mL) and extracted with ethyl acetate (500 mL x 3). The organic layers were combined and washed with saturated brine solution (20 mL) and dried over anhydrous sodium sulfate. Concentration under reduced pressure and purification of the residue by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 2) gave compound 49-2. MS m / z (ESI): 225.0, 227.0 [M+H-H2O] + .

[0810] Step 2: Synthesis of compound 49-3

[0811] To a solution of compound 49-2 (5.0 g, 20.57 mmol), lithium bistrifluoromethanesulfonimide (1.26 g, 4.39 mmol) and tetrabutylammonium hexafluorophosphate (800 mg, 2.06 mmol) in toluene (40 mL) was added dropwise a solution of 2-methylfuran (5.1 g, 61.70 mmol) in tetrahydrofuran (50 mL). The reaction solution was stirred at 60 °C for 18 hours. The reaction solution was quenched by addition of water (20 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with saturated brine solution (20 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give compound 49-3. MS m / z (ESI): 307.0, 309.2 [M+H] + .

[0812] Step 3: Synthesis of compound 49-4

[0813] To a solution of compound 49-3 (2.0 g, 6.51 mmol) and sodium periodate (9.75 g, 45.57 mmol) in a mixture of ethyl acetate (50 mL), n-hexane (50 mL) and water (100 mL) was added ruthenium chloride trihydrate (0.1 g, 0.33 mmol). The reaction solution was stirred at 25 °C for 18 hours. The reaction solution was quenched by addition of water (20 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with saturated brine solution (20 mL) and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 49-4. MS m / z (ESI): 270.9, 272.9 [M+H] + .

[0814] Step 4: Synthesis of compound 49-5

[0815] To a solution of compound 49-4 (1.5 g, 5.53 mmol) and potassium carbonate (3.1 g, 22.13 mmol) in acetonitrile (20 mL), iodomethane (1.35 mL, 16.60 mmol) was added dropwise, and stirred at room temperature for 18 hours. After the reaction was completed, it was concentrated under reduced pressure, the residue was diluted with water (50 mL) and extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 20 / 1) to give compound 49-5. 1 H NMR (400 MHz, CDC13) δ 7.27 (dd, J = 8.4, 2.0 Hz, 1H), 7.23 (d, J = 2.0 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 5.10 (d, J = 6.0 Hz, 2H), 4.99 (d, J = 6.0 Hz, 2H), 3.67 (s, 3H), 2.00 (s, 3H).

[0816] Step 5: Synthesis of compound 49-6

[0817] To a solution of compound 49-5 (100 mg, 0.35 mmol) and N-bromosuccinimide (75 mg, 0.42 mmol) in carbon tetrachloride (3 mL), azobisisobutyronitrile (11.5 mg, 0.07 mmol) was added, and stirred at 50°C for 3 hours under nitrogen atmosphere. After the reaction was completed, it was diluted with water (10 mL) and extracted with dichloromethane (20 mL x 3). The organic layers were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave compound 49-6, which was used directly in the next step. MS m / z (ESI): 365.5 [M+H] + .

[0818] Step 6: Synthesis of compound 49-7

[0819] To a solution of compound 49-6 (100.0 g, 0.27 mmol) and methylamine hydrochloride (56 mg, 0.82 mmol) in acetonitrile (5 mL), N,N-diisopropylethylamine (177 mg, 1.37 mmol) was added dropwise, and the reaction was stirred at 50°C for 2 hours. The reaction was concentrated under reduced pressure, the residue was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure, the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 49-7. MS m / z (ESI): 282.0, 284.0 [M+H] + .

[0820] Step 7: Synthesis of compound 49-8

[0821] To a solution of compound K (47 mg, 0.11 mmol) in N-methylpyrrolidone (1 mL) was added compound 49-7 (30.0 mg, 0.11 mmol), potassium carbonate (29 mg, 0.21 mmol), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (7.6 mg, 0.05 mmol) and cuprous iodide (4.0 mg, 0.02 mmol). The reaction was stirred at 130 degree Celsius for 3 hours. To the reaction was added water (4 mL) and extracted with ethyl acetate (5 mL x 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 49-8. MS m / z (ESI): 643.4 [M+H] + .

[0822] Step 8: Synthesis of compound 49-9

[0823] To a solution of compound 49-8 (30.0 mg, 0.05 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL) and the reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure to give compound 49-9, which was used directly in the next step. MS m / z (ESI): 543.2 [M+H] + .

[0824] Step 9: Synthesis of compound 49

[0825] To a solution of compound G-S (19 mg, 0.05 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (12 mg, 0.09 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (21 mg, 0.06 mmol). After the reaction was stirred at room temperature for 30 minutes, compound 49-9 (25 mg, 0.05 mmol) was added and the reaction was stirred at room temperature for 16 hours. The reaction was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with saturated brine (4 mL), dried over anhydrous sodium sulfate and filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC (waters-xbridge-C18-10um-19*250mm, Mobile phase: 0.1% TFA / H2O B:CH3CN, Gradient: 50% B-70% B, Ret 12.58 min) to give compound 49. MS m / z (ESI): 936.4 [M+H]+ . 1 H NMR (400 MHz, CD3OD) δ 8.08-7.82 (m, 1H), 7.74-7.31 (m, 4H), 7.30-7.12 (m, 3H), 7.08-6.57 (m, 3H), 5.77-5.33 (m, 1H), 5.32-5.26 (m, 2H), 4.68 (d, J = 5.6 Hz, 1H), 4.60-4.46 (m, 3H), 3.90-3.78 (m, 2H), 3.71-3.54 (m, 1H), 3.14-3.07 (m, 3H), 3.09-2.94 (m, 2H), 2.29-2.20 (m, 6H), 1.86-1.65 (m, 5H), 1.64-1.48 (m, 5H), 1.37-1.19 (m, 11H).

[0826] Example 56: Preparation of compound 50

[0827] Synthetic route:

[0828] Step 1: Synthesis of compound 50-2

[0829] To a solution of methyl tetrahydropyran-4-carboxylate (300 mg, 2.08 mmol) in tetrahydrofuran (6 mL) was added lithium diisopropylamide in tetrahydrofuran (2.7 mL, 2.7 mmol, 1.0 M) at -78 °C, and the reaction was stirred at -78 °C for 0.5 h. Then a solution of compound 50-1 (821 mg, 2.50 mmol) in tetrahydrofuran (2 mL) was added to the reaction, which was stirred at room temperature for 1.5 h. After completion of the reaction, the reaction was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 4) to give compound 50-2. MS m / z (ESI): 393.0 [M+H] + .

[0830] Step 2: Synthesis of compound 50-3

[0831] To a solution of compound 50-2 (200 mg, 0.51 mmol) in methanol (2 mL) and water (2 mL) was added sodium hydroxide (61 mg, 1.53 mmol) at room temperature. The reaction was stirred at room temperature for 1 h. The reaction was adjusted to pH 3 with 1M diluted hydrochloric acid, and then extracted with ethyl acetate (20 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give crude compound 50-3. The crude was used directly in the next step. MS m / z (ESI): 376.9 [M-H] - .

[0832] Step 3: Synthesis of compound 50-4

[0833] To a solution of compound 50-3 (190 mg, 0.79 mmol) in N,N-dimethylformamide (5 mL) was added N,N-diisopropylethylamine (195 mg, 1.51 mmol), 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (287 mg, 0.75 mmol) and ammonium chloride (134 mg, 2.51 mmol), and the reaction was stirred at room temperature for 1 h. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 4) to give compound 50-4. MS m / z (ESI): 378.0 [M+H] + .

[0834] Step 4: Synthesis of compound 50-5

[0835] To a solution of compound 50-4 (74 mg, 0.20 mmol) in dimethyl sulfoxide (2 mL) was added cuprous iodide (3.7 mg, 0.02 mmol), cesium carbonate (64 mg, 0.20 mmol) and 1,10-phenanthroline (7.0 mg, 0.04 mmol), and the reaction was stirred at 110 °C under microwave heating for 1 h. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 2) to give compound 50-5. MS m / z (ESI): 296.0, 298.0 [M+H] + . 1H NMR (400 MHz, CD3OD) δ 7.14-7.09 (m, 2H), 7.01 (d, J = 1.6 Hz, 1H), 3.85-3.80 (m, 2H), 3.76-3.70 (m, 2H), 2.92 (s, 2H), 1.95-1.89 (m, 2H), 1.46-1.39 (m, 2H).

[0836] Step 5: Synthesis of compound 50-6

[0837] To a solution of compound 50-5 (43 mg, 0.15 mmol) in N,N-dimethylformamide (1 mL) was added sodium hydride (7.0 mg, 0.17 mmol) under ice-bath. The reaction was stirred at ice-bath for 10 min under nitrogen. Then iodomethane (31 mg, 0.22 mmol) was added to the reaction, which was stirred at room temperature for 50 min. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 2), the combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure to give compound 50-6. MS m / z (ESI): 310.0, 312.0 [M+H] + .

[0838] Step 6: Synthesis of compound 50-7

[0839] To a solution of compound 50-6 (43 mg, 0.14 mmol) and compound K (61 mg, 0.14 mmol) in N-methylpyrrolidone (1 mL) was added potassium carbonate (57 mg, 0.42 mmol), copper iodide (5.28 mg, 0.03 mmol) and trans-(1S,2S)-N,N-dimethylcyclohexanediamine (10 mg, 0.07 mmol), the reaction was stirred at 130 °C for 2 h. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2), the combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (methanol / dichloromethane = 1 / 10) to give compound 50-7. MS m / z (ESI): 671.3 [M+H] + .

[0840] Step 7: Synthesis of compound 50-8

[0841] A solution of compound 50-7 (33 mg, 0.05 mmol) in hydrogen chloride / dioxane (2 mL, 4 M) was stirred at room temperature for 1 h, the reaction was concentrated under reduced pressure to give crude compound 50-8. The crude was used directly in the next step. MS m / z (ESI): 571.3 [M+H]+ .

[0842] Step 8: Synthesis of compound 50

[0843] To a solution of compound 50-8 (28 mg, 0.05 mmol) and compound G-S (20 mg, 0.05 mmol) in N,N-dimethylformamide (1 mL) was added N,N-diisopropyl ethylamine (19 mg, 0.15 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (28 mg, 0.07 mmol) at room temperature. The reaction was stirred at room temperature for 1 h. The reaction was filtered, and the filtrate was purified by preparative HPLC (Waters-SunFire-C18-10 μm-19*250 mm; Mobile: phase A: 0.1% FA / H2O B: ACN; Gradient; 0% to 95%) to give compound 50. MS m / z (ESI): 964.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) d 8.45 (s, 1H), 7.54-7.46 (m, 2H), 7.35 (d, J = 5.6 Hz, 1H), 7.27-7.23 (m, 2H), 7.16-7.12 (m, 2H), 7.06 (d, J = 6.0 Hz, 1H), 6.95-6.88 (m, 1H), 6.83-6.76 (m, 1H), 6.61-6.52 (m, 1H), 5.75-5.34 (m, 1H), 4.51-4.47 (m, 1H), 3.87-3.72 (m, 7H), 3.37 (s, 1H), 3.14-2.90 (m, 6H), 2.24 (d, J = 13.2 Hz, 6H), 1.93-1.83 (m, 6H), 1.65-1.50 (m, 5H), 1.37-1.19 (m, 12H), 1.07-1.04 (m, 1H).

[0844] Example 57: Preparation of compound 51

[0845] Synthetic route:

[0846] Step 1: Synthesis of compound 51-2

[0847] To a solution of 3-hydroxyoxetane-3-carboxylic acid (1.00 g, 8.47 mmol) in N,N- dimethylformamide (20 mL) was added sodium hydride (0.85 g, 21.17 mmol) under ice bath. After 30 min, a solution of compound 51-1 (1.86 g, 8.47 mmol) in N,N-dimethylformamide (10 mL) was added dropwise to the above solution under ice bath. The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, saturated aqueous ammonium chloride solution (10 mL) was added dropwise to quench the reaction, and the pH value was adjusted to 3 with dilute hydrochloric acid solution. The mixture was extracted with ethyl acetate (50 mL x 3). The organic layers were combined and washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 51-2. MS m / z (ESI): 317.9, 319.9 [M+H] + .

[0848] Step 2: Synthesis of compound 51-3

[0849] To a mixture of compound 51-2 (300 mg, 0.94 mmol) in ethanol (4 mL) and water (1 mL) was added ammonium chloride (151 mg, 0.20 mmol) and iron powder (527 mg, 5.88 mmol). The reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL x 3). The organic layers were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 51-3. MS m / z (ESI): 269.9, 271.9 [M+H] + .

[0850] Step 3: Synthesis of compound 51-4

[0851] To a solution of compound 51-3 (150 mg, 0.56 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (44 mg, 60%, 1.11 mmol) under ice bath. After 30 min, iodomethane (157 mg, 1.11 mmol) in N,N-dimethylformamide (1 mL) was added dropwise to the above solution under ice bath. The reaction mixture was stirred at room temperature for 3 h. After completion of the reaction, saturated aqueous ammonium chloride solution (10 mL) was added dropwise to quench the reaction, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with saturated brine (20 mL), and dried over anhydrous sodium sulfate. Concentration under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 51-4. MS m / z (ESI): 284.0, 286.0 [M+H] + . 1H NMR (400 MHz, CDC13) δ 7.08 (dd, J = 8.4, 2.0 Hz, 1H), 7.00 (d, J = 2.0 Hz, 1H), 6.93 (d, J = 8.4 Hz, 1H), 5.00 (dd, J = 7.2, 1.2 Hz, 2H), 4.66 (dd, J = 7.2, 1.2 Hz, 2H), 3.30 (s, 3H).

[0852] Step 4: Synthesis of compound 51-5

[0853] To a solution of compound K (112 mg, 0.25 mmol) in N-methylpyrrolidone (2 mL) was added compound 51-4 (60 mg, 0.21 mmol), potassium carbonate (58 mg, 0.42 mmol), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (15 mg, 0.11 mmol) and cuprous iodide (8.0 mg, 0.20 mmol). The reaction was stirred at 130 degree Celsius for 3 hours. Water (4 mL) was added to the reaction, extracted with ethyl acetate (3 mL x 3), washed with saturated brine (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 51-5. MS m / z (ESI): 645.4 [M+H] + .

[0854] Step 5: Synthesis of compound 51-6

[0855] To a solution of compound 51-5 (10.0 mg, 0.02 mmol) in dichloromethane (1 mL) was added trifluoroacetic acid (0.2 mL), the reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure to give compound 51-6, which was used directly in the next step. MS m / z (ESI): 545.2 [M+H] + .

[0856] Step 6: Synthesis of compound 51

[0857] To a solution of compound G-S (11 mg, 0.02 mmol) in N,N-dimethylformamide (0.5 mL) was added N,N-diisopropylethylamine (5.0 mg, 0.04 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (9.0 mg, 0.02 mmol). After the reaction solution was stirred at room temperature for 30 min, compound 51-6 (8.0 mg, 0.02 mmol) was added, and the reaction solution was stirred at room temperature for 16 h. The reaction solution was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with saturated brine (4 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (waters-xbridge-C18-10um-19*250mm, Mobile phase: 0.1% TFA / H20 B:CH3CN, Gradient: 50% B-70% B, Ret 12.58 min) to give compound 51. MS m / z (ESI): 938.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), 7.55-7.36 (m, 2H), 7.26-7.23 (m, 2H), 7.19-7.01 (m, 3H), 6.97-6.50 (m, 3H), 5.75-5.32 (m, 1H), 5.05-4.94 (m, 2H), 4.76-4.55 (m, 4H), 3.90-3.81 (m, 2H), 3.11-2.93 (m, 3H), 2.25-2.17 (m, 6H), 1.85-1.50 (m, 9H), 1.41-1.23 (m, 13H).

[0858] Example 58: Preparation of compound 52

[0859] Compound 52 was synthesized by a similar method to compound 51 in Example 57.

[0860] Compound 52: MS m / z (ESI): 951.3 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 7.53 (s, 1H), 7.39 (d, J = 7.6 Hz, 1H), 7.29-7.26 (m, 3H), 7.16-7.09 (m, 3H), 7.02-6.86 (m, 3H), 5.55 (d, J = 6.8 Hz, 1H), 4.92-4.80 (m, 5H), 4.44-4.36 (m, 1H), 3.73-3.61 (m, 2H), 3.18-3.14 (m, 4H), 3.03-2.85 (m, 2H), 2.25-2.15 (m, 7H), 1.78-1.52 (m, 7H), 1.41-1.35 (m, 2H), 1.30-1.22 (m, 6H), 1.21-1.11 (m, 6H).

[0861] Example 59: Preparation of compound 53

[0862] Compound 53 was synthesized by a similar method to compound 50 in Example 56.

[0863] Compound 53: MS m / z (ESI): 970.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 7.53-7.49 (m, 1H), 7.42-7.38 (m, 4H), 7.26 (d, J = 9.2 Hz, 1H), 7.16 (d, J = 6.0 Hz, 2H), 7.10-6.94 (m, 2H), 6.86-6.83 (m, 1H), 5.54 (s, 1H), 4.38 (d, J = 13.6 Hz, 1H), 3.73-3.62 (m, 3H), 3.17-2.86 (m, 7H), 2.44-2.42 (m, 2H), 2.20 (d, J = 11.2 Hz, 6H), 1.77-1.52 (m, 8H), 1.39-1.24 (m, 8H), 1.18-1.00 (m, 6H).

[0864] Example 60: Preparation of compound 54

[0865] Compound 54 was synthesized by a similar method to compound 50 in Example 56.

[0866] Compound 54: MS m / z (ESI): 936.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 7.55-7.51 (m, 1H), 7.43-7.34 (m, 4H), 7.26-7.10 (m, 4H), 7.04-6.90 (m, 2H), 5.60-5.52 (m, 1H), 4.75 (d, J = 6.0 Hz, 2H), 4.39-4.30 (m, 3H), 3.73-3.69 (m, 2H), 3.39-3.37 (m, 1H), 3.09-3.00 (m, 2H), 2.90-2.85 (m, 1H), 2.21-2.18 (m, 6H), 1.67-1.61 (m, 3H), 1.52-1.33 (m, 10H), 1.27-1.24 (m, 5H), 1.18-1.02 (m, 6H).

[0867] Example 61: Preparation of compound 55

[0868] Compound 55 was synthesized by a similar method to that of compound 5 in Example 7.

[0869] Compound 55: MS m / z (ESI): 925.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.64-7.53 (m, 3H), 7.34-7.31 (m, 2H), 7.21-7.17 (m, 2H), 7.12-7.10 (m, 1H), 7.01-6.79 (m, 3H), 5.86-5.33 (m, 1H), 4.58-4.46 (m, 1H), 4.24-4.19 (m, 2H), 4.11-4.05 (m, 2H), 3.98-3.93 (m, 2H), 3.78-3.66 (m, 1H), 3.64-3.58 (m, 3H), 3.30-3.21 (m, 1H), 3.01-2.91 (m, 2H), 2.29-2.25 (m, 6H), 1.88-1.85 (m, 4H), 1.83-1.80 (m, 4H), 1.66-1.62 (m, 2H), 1.57-1.52 (m, 3H), 1.47-1.29 (m, 2H), 1.10 (d, J = 5.6 Hz, 1H).

[0870] Example 62: Preparation of compound 56

[0871] Compound 56 was synthesized by a similar method to that of compound 25 in Example 29.

[0872] Compound 56: MS m / z (ESI): 922.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.65-7.50 (m, 4H), 7.48-7.39 (m, 1H), 7.37-7.21 (m, 5H), 7.19-7.09 (m, 1H), 7.01-6.91 (m, 1H), 6.87-6.80 (m, 1H), 5.85-5.34 (m, 1H), 4.58-4.47 (m, 1H), 4.28-4.15 (m, 2H), 3.98-3.78 (m, 5H), 3.26 (s, 3H), 3.18-2.97 (m, 5H), 1.90-1.83 (m, 3H), 1.81-1.73 (m, 4H), 1.67-1.52 (m, 4H), 1.40-1.36 (m, 3H), 1.34-1.31 (m, 2H), 1.30-1.26 (m, 3H), 1.24-1.20 (m, 2H).

[0873] Example 63: Preparation of compound 57

[0874] Compound 57 was synthesized by a similar method to that of compound 25 in Example 29.

[0875] Compound 57: MS m / z (ESI): 958.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.74 (s, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.55 (s, 1H), 7.49-7.35 (m, 6H), 7.28 (d, J = 8.4 Hz, 1H), 7.13 (s, 1H), 6.97 (s, 1H), 5.61 (d, J = 7.6 Hz, 1H), 4.42 (d, J = 13.2 Hz, 1H), 4.09-4.05 (m, 2H), 3.87-3.83 (m, 2H), 3.74-3.72 (m, 2H), 3.18 (s, 3H), 3.06-3.02 (m, 2H), 2.98-2.92 (m, 1H), 2.04-1.99 (m, 1H), 1.77-1.46 (m, 8H), 1.40-1.37 (m, 2H), 1.30-1.27 (m, 2H), 1.28 (d, J = 8.4 Hz, 6H), 1.20 (s, 3H), 1.17-1.15 (m, 2H).

[0876] Example 64: Preparation of compound 58

[0877] Synthesis route:

[0878] Step 1: Synthesis of compound 58-2

[0879] To a solution of compound 58-1 (1.00 g, 4.5 mmol) in sulfuric acid (5 mL) was added nitric acid (5 mL), and the mixture was stirred at 25 °C for 10 h. The reaction solution was diluted with water (50 mL) and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated brine (100 mL) and dried over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 10) to give compound 58-2. 1 H NMR (400 MHz, CDCl3) δ 8.71 (dd, J = 5.6, 2.8 Hz, 1H), 8.45 (dt, J = 9.2, 3.2 Hz, 1H), 7.44 (t, J = 9.6 Hz, 1H).

[0880] Step 2: Synthesis of compound 58-3

[0881] To a solution of compound 58-2 (20 mg, 0.075 mmol) in methanol (1 mL) was added 10% wet palladium carbon (5 mg), and the mixture was replaced with hydrogen three times. The reaction mixture was stirred at 25 °C for 3 h under the protection of hydrogen balloon. The reaction solution was filtered and the filter cake was washed with methanol (3 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate / petroleum ether = 1 / 4) to give compound 58-3. MS m / z (ESI): 238.0 [M+H] + .

[0882] Step 3: Synthesis of compound 58-4

[0883] To a solution of compound 58-3 (800 mg, 3.37 mmol) in hydrochloric acid (10 mL) was added sodium nitrite (5012 mg, 72.65 mmol) under ice bath. After the reaction solution was stirred at ice bath for 1 h, a solution of stannous chloride dihydrate (2.76 g, 14.53 mmol) in hydrochloric acid (40 mL) and water (40 mL) was added. The reaction solution was stirred at ice bath for 2 h. After the reaction was quenched with water (100 mL), the pH was adjusted to 8 with 50% NaOH aqueous solution. The mixture was filtered and the filtrate was extracted with ethyl acetate (100 mL x 3). The organic layers were combined, washed with saturated brine (200 mL), and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure. The residue was purified by prep-HPLC (waters-xbridge-C18-10um-19*250mm, Mobile phase: 0.1% FA / H2O B:CH3CN, Gradient: 50% B-70% B, Ret 11.51 min) to give compound 58-4. MS m / z (ESI): 253.2 [M+H] + .

[0884] Step 4: Synthesis of compound 58-5

[0885] To a solution of compound 58-4 (150 mg, 0.59 mmol) in ethanol (2 mL) was added compound D-3 (286 mg, 1.20 mmol), pyridine hydrochloride (13.9 mg, 0.12 mmol). The reaction solution was stirred at 90 °C for 2 h. The reaction was diluted with water (20 mL) and extracted with ethyl acetate (20 mL x 3). The organic layers were combined, washed with saturated brine (50 mL), and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 2) to give compound 58-5. MS m / z (ESI): 473.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.07 (dd, J = 6.2, 2.4 Hz, 1H), 7.97 (ddd, J = 9.2, 4.0, 2.4 Hz, 1H), 7.67 (dd, J = 11.6, 9.2 Hz, 1H), 5.44 (s, 2H), 5.21 - 5.01 (m, 1H), 4.27 - 4.07 (m, 1H), 3.13 - 2.96 (m, 2H), 2.36 - 2.27 (m, 1H), 1.46 - 1.37 (m, 12H).

[0886] Step 5: Synthesis of compound 58-6

[0887] To a solution of compound 58-6 (100 mg, 0.0.17 mmol) in tetrahydrofuran (1 mL) was added methylsulfonic acid (20 mg, 0.21 mmol). The reaction mixture was stirred at 60 °C for 2 h. After the reaction mixture was cooled to room temperature, triethylamine (586 mg, 5.80 mmol) and di-tert-butyl dicarbonate (158 mg, 0.73 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 2) to give compound 58-7. MS m / z (ESI): 540.4 [M+H] + .

[0888] Step 6: Synthesis of compound 58-7

[0889] To a solution of compound 58-6 (100 mg, 0.0.17 mmol) in tetrahydrofuran (1 mL) was added methylsulfonic acid (20 mg, 0.21 mmol). The reaction mixture was stirred at 60 °C for 2 h. After the reaction mixture was cooled to room temperature, triethylamine (586 mg, 5.80 mmol) and di-tert-butyl dicarbonate (158 mg, 0.73 mmol) were added. The reaction mixture was stirred at room temperature for 16 h. After the reaction was completed, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 3). The combined organic phase was washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 2) to give compound 58-7. MS m / z (ESI): 540.4 [M+H] + .

[0890] Step 7: Synthesis of compound 58-8

[0891] To a solution of compound 14-1 (57 mg, 0.19 mmol) in N-methylpyrrolidone (1 mL) was added compound 58-7 (80 mg, 0.19 mmol), potassium carbonate (80 mg, 0.58 mmol), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (14 mg, 0.10 mmol) and cuprous iodide (7.4 mg, 0.04 mmol). The reaction mixture was stirred at 130 °C for 2 h. To the reaction mixture was added water (50 mL), extracted with ethyl acetate (50 mL x 3), washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (petroleum ether / ethyl acetate = 1 / 1) to give compound 58-8. MS m / z (ESI): 755.2 [M+H] + .

[0892] Step 8: Synthesis of compound 58-9

[0893] To a solution of compound 58-8 (50 mg, 0.08 mmol) in dichloromethane (2 mL) was added 4 M hydrochloric acid in dioxane (1 mL), and the reaction was stirred at room temperature for 1 h. The reaction was concentrated under reduced pressure to give compound 58-9. The crude product was used directly in the next step. MS m / z (ESI): 655.2 [M+H] + .

[0894] Step 9: Synthesis of compound 58

[0895] To a solution of compound G-S (31.2 mg, 0.08 mmol) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (9.8 mg, 0.08 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)uronium hexafluorophosphate (28.8 mg, 0.08 mmol). After the reaction was stirred at room temperature for 30 min, compound 58-9 (40 mg, 0.08 mmol) was added, and the reaction was stirred at room temperature for 2 h. The reaction was diluted with water (5 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with saturated brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (Waters-Xbridge-C18-7 pm-30*150 mm A: 0.1% TFA / H20 B: ACN 20% A-80% B: Ret 1.554 min) to give compound 58. MS m / z (ESI): 1048.3 [M+H] + . 1 H NMR (400 MHz, CD3OD) d 7.98 (d, J = 5.6 Hz, 1H), 7.88 (s, 1H), 7.69-7.62 (m, 1H), 7.61-7.49 (m, 4H), 7.35-7.27 (m, 3H), 6.98-6.84 (m, 2H), 5.81-5.40 (m, 1H), 4.55 (d, J = 14.4 Hz, 1H), 4.26-4.19 (m, 2H), 3.98-3.84 (m, 4H), 3.78-3.55 (m, 1H), 3.26 (s, 3H), 3.34-3.00 (m, 4H), 1.90-1.72 (m, 8H), 1.67-1.55 (m, 4H), 1.39 (s, 4H), 1.35-1.29 (m, 2H), 1.27-1.21 (m, 4H).

[0896] Example 65: Preparation of compound 59

[0897] Synthetic route:

[0898] Step 1: Synthesis of compound 59-3

[0899] To a solution of compound 3-1 (200 mg, 0.71 mmol) in N,N-dimethylformamide (3 mL) was added sodium hydride (25.5 mg, 1.06 mmol) at ice bath. The mixture was stirred for 30 min, and then a solution of iodomethane (205.5 mg, 1.42 mmol) in N,N-dimethylformamide (1 mL) was added dropwise. The reaction was stirred at room temperature for 2 h. The reaction was quenched with saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (30 mL x 3). The organic layers were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give compound 59-3. MS m / z (ESI): 299.0, 301.0 [M+H] + .

[0900] Step 2: Synthesis of compound 59-1

[0901] To a solution of compound 34-2 (500 mg, 1.05 mmol) in deuterated dimethyl sulfoxide (0.5 mL) was added potassium tert-butoxide (1180 mg, 10.51 mmol) at room temperature. The reaction was stirred at 70 °C for 5 h. The reaction was diluted with water (0.5 mL) and filtered. The filtrate was purified by prep-HPLC (waters-xbridge-C18-10um-19*250mm, Mobile phase: 0.1% FA / H2O B:CH3CN, Gradient: 50% B-70% B, Ret 8.27 min) to give compound 59-1. MS m / z (ESI): 348.0 [M+H] + .

[0902] Step 3: Synthesis of compound 59-2

[0903] To a solution of compound 59-1 (70 mg, 0.21 mmol) and compound H (81 mg, 0.21 mmol) in N,N-dimethylformamide (1 mL) was added N,N-diisopropyl ethylamine (82 mg, 0.18 mmol) and 2-(7-azobenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (34 mg, 0.09 mmol) at room temperature. The reaction was stirred at room temperature for 1 h. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 2). The combined organic phase was washed with saturated brine (30 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 10 / 1) to give compound 59-2. MS m / z (ESI): 713.4 [M+H] + .

[0904] Step 4: Synthesis of compound 59

[0905] To a solution of compound 59-2 (86 mg, 0.12 mmol) and compound 59-3 (36 mg, 0.12 mmol) in N-methyl pyrrolidone (2 mL) was added potassium carbonate (50 mg, 0.36 mmol), cuprous iodide (4.6 mg, 0.02 mmol) and trans-(1S,2S)-N,N-dimethylcyclohexane diamine (8.6 mg, 0.06 mmol). The reaction was stirred at 80 °C for 2 h. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2). The organic phase was washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters-SunFire-C18-10 µm-19*250 mm; Mobile: phase A: 0.1% FA / H2O B: ACN; Gradient; 0% to 95%) to give compound 59. MS m / z (ESI): 931.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.53-7.25 (m, 5H), 7.19-7.03 (m, 4H), 6.85-6.55 (m, 1H), 5.68-5.59 (m, 1H), 4.82-4.40 (m, 1H), 4.09-3.97 (m, 4H), 4.58 (br s, 2H), 3.48-3.45 (m, 2H), 2.88-2.84 (m, 2H), 1.75-1.53 (m, 12H), 1.39-1.07 (m, 7H).

[0906] Example 66: Preparation of compound 60

[0907] Compound 60 was synthesized by a similar method to compound 49 in Example 55.

[0908] Compound 60: MS m / z (ESI): 964.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.69-7.50 (m, 4H), 7.34-7.28 (m, 1H), 7.24-7.07 (m, 3H), 6.98-6.58 (m, 3H), 5.84-5.30 (m, 1H), 4.72-4.65 (m, 1H), 4.57-4.49 (m, 1H), 4.16-4.02 (m, 2H), 3.95-3.78 (m, 4H), 3.14-3.08 (m, 3H), 2.61-2.35 (m, 6H), 2.18-1.96 (m, 5H), 1.90-1.72 (m, 5H), 1.71-1.62 (m, 3H), 1.61-1.51 (m, 3H), 1.42-1.36 (m, 4H), 1.35-1.28 (m, 6H), 1.27-1.22 (m, 2H).

[0909] Example 67: Preparation of compound 61

[0910] Compound 61 was synthesized by a similar method to compound 51 in Example 57.

[0911] Compound 61: MS m / z (ESI): 979.4 [M+H] + . 1 H NMR (400 MHz, CD3OD) δ 7.61-7.45 (m, 2H), 7.36-6.49 (m, 9H), 5.78-5.37 (m, 1H), 3.89-3.76 (m, 5H), 3.62-3.33 (m, 3H), 3.17-3.02 (m, 3H), 2.98-2.83 (m, 3H), 2.29-2.26 (m, 5H), 2.06 (s, 1H), 1.85-1.49 (m, 13H), 1.39-1.03 (m, 13H).

[0912] Example 68: Preparation of compound L

[0913] Compound L was synthesized by a similar method to compound 50-6 in Example 56.

[0914] Compound L: MS m / z (ESI): 282.0, 284.0 [M+H] + .

[0915] Example 69: Preparation of compound 62

[0916] Synthetic route:

[0917] Step 1: Synthesis of compound 62-1

[0918] To a solution of compound L (400 mg, 1.42 mmol) in carbon tetrachloride (5 mL) was added N-bromosuccinimide (757 mg, 4.25 mmol) and azobisisobutyronitrile (35 mg, 0.21 mmol). The reaction was stirred at 70 degrees Celsius for 3 hours. After the reaction was naturally cooled to room temperature, it was blown dry, the mixture was added into acetonitrile (4 mL) and triethylamine trifluoride acid salt (704 mg, 4.36 mmol), the reaction was stirred at 80 degrees Celsius for 18 hours. The reaction was concentrated under reduced pressure. The crude product was purified by preparative HPLC (waters-xbridge-C18-10um-19*250mm, Mobile phase: 0.1% FA / H2O B:CH3CN, Gradient: 33% B-95% B, Ret 1.17 min) to give compound 62-1. MS m / z (ESI): 318.0, 320.0 [M+H] + .

[0919] Step 2: Synthesis of compound 62-2

[0920] To a solution of compound 62-1 (70 mg, 0.22 mmol) in N-methylpyrrolidone (1 mL) was added compound K (97 mg, 0.22 mmol), potassium carbonate (91 mg, 0.66 mmol), trans-(1R,2R)-N,N'-dimethyl 1,2-cyclohexanediamine (15.7 mg, 0.11 mmol) and cuprous iodide (8.4 mg, 0.04 mmol). The reaction was stirred at 130 degrees Celsius for 2 hours. To the reaction was added water (30 mL), extracted with ethyl acetate (30 mL x 3), the combined organic phase was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give compound 62-2. MS m / z (ESI): 679.4 [M+H] + .

[0921] Step 3: Synthesis of compound 62-3

[0922] To a solution of compound 62-2 (50 mg, 0.07 mmol) in dichloromethane (4 mL) was added trifluoroacetic acid (2 mL), the reaction was stirred at room temperature for 2 hours. The reaction was concentrated under reduced pressure to give compound 62-3. The crude was used directly in the next step. MS m / z (ESI): 579.2 [M+H] + .

[0923] Step 4: Synthesis of compound 62

[0924] To a solution of compound G-S (42.7 mg, 0.09 mmol) in N,N-dimethylformamide (2 mL) was added N,N-diisopropylethylamine (33.5 mg, 0.26 mmol) and N,N,N',N'-tetramethyl-O-(7-azabenzotriazol-l-yl)urea hexafluorophosphate (49.3 mg, 0.13 mmol). The reaction was stirred at room temperature for 30 minutes, then compound 62-3 (50 mg, 0.09 mmol) was added, the reaction was stirred at room temperature for 2 hours. The reaction was diluted with water (2 mL) and extracted with ethyl acetate (2 mL x 3). The combined organic phase was washed with saturated brine (3 mL), dried over anhydrous sodium sulfate and filtered, the filtrate was concentrated under reduced pressure. The crude was purified by preparative HPLC (waters-xbridge-C18-10um-19*250mm, Mobile phase: A: 0.1% FA / H2O B: ACN, Gradient: 13% B-23% B, Ret 1.61 min) to give compound 62. MS m / z (ESI): 972.3 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 11.73 (s, 1H), 8.34-8.05 (m, 1H), 7.91-7.65 (m, 2H), 7.61-7.49 (m, 1H), 7.48-7.29 (m, 2H), 7.26-7.08 (m, 4H), 6.87-6.42 (m, 1H), 5.68-5.13 (m, 1H), 4.87-4.75 (m, 2H), 4.74-4.57 (m, 2H), 4.55-4.17 (m, 1H), 3.78-3.67 (m, 2H), 3.63-3.36 (m, 6H), 3.16-2.63 (m, 4H), 2.26-2.14 (m, 5H), 2.10-1.44 (m, 7H), 1.43-1.02 (m, 10H).

[0925] Example 70: Preparation of compound 63

[0926] Synthetic route:

[0927] Step 1: Synthesis of compounds 63-1 and 63-2

[0928] To a solution of compound 50-6 (150 mg, 0.48 mmol) in N,N- dimethylformamide (3 mL) was added Selectfluor (171 mg, 0.48 mmol) and the reaction was stirred at 110 °C for 24 h. After the reaction was cooled to room temperature, it was filtered and the filtrate was purified by preparative HPLC (Waters-SunFire-C18-10 μm-19*250 mm; Mobile: phase A: 0.1% FA / H2O B: ACN; Gradient; 30% to 60%) to give compounds 63-1 and 63-2.

[0929] Compound 63-1: MS m / z (ESI): 328.0, 330.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.41 - 7.35 (m, 2H), 3.73 - 3.55 (m, 4H), 3.28 (s, 3H), 2.97 (s, 2H), 1.81 - 1.74 (m, 2H), 1.34 - 1.24 (m, 2H).

[0930] Compound 63-2: MS m / z (ESI): 328.0, 330.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 7.40 (dd, J = 8.0, 6.4 Hz, 1H), 7.10 (d, J = 8.0 Hz, 1H), 3.74 - 3.55 (m, 4H), 3.28 (s, 3H), 2.97 (s, 2H), 1.80 - 1.69 (m, 2H), 1.33 - 1.23 (m, 2H).

[0931] Step 2: Synthesis of compound 63-3

[0932] To a solution of compound 63-1 (12 mg, 0.04 mmol) and compound K (16 mg, 0.04 mmol) in N-methylpyrrolidone (2 mL) was added potassium carbonate (15 mg, 0.11 mmol), cuprous iodide (1.4 mg, 0.01 mmol) and trans-(1S,2S)-N,N-dimethylcyclohexanediamine (2.6 mg, 0.02 mmol), the reaction was stirred at 130 Celsius for 2 hours. The reaction was diluted with water (30 mL) and extracted with ethyl acetate (30 mL x 2), the combined organic phase was washed with saturated brine (30 mL x 3), the organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (methanol / dichloromethane = 1 / 10) to give compound 63-3. MS m / z (ESI): 688.8 [M+H] + .

[0933] Step 3: Synthesis of compound 63-4

[0934] To compound 63-3 (12 mg, 0.02 mmol) was added hydrogen chloride in dioxane (4.0 M, 2 mL), the reaction was stirred at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give compound 63-4. The crude product was used directly in the next step. MS m / z (ESI): 589.4 [M+H] + .

[0935] Step 4: Synthesis of compound 63

[0936] To a solution of compound 63-4 (9.0 mg, 0.02 mmol) and compound G-S (7.6 mg, 0.02 mmol) in N,N-dimethylformamide (1 mL) was added N,N-diisopropylethylamine (5.9 mg, 0.05 mmol) and 2-(7-azobenzo-triazol)-N,N,N',N'-tetramethyluronium hexafluorophosphate (8.7 mg, 0.02 mmol) at room temperature, the reaction was stirred at room temperature for 2 hours. The reaction was filtered, the filtrate was purified by preparative HPLC (Waters-SunFire-C18-10 μm-19*250 mm; Mobile: phase A: 0.1% FA / H2O B: ACN; Gradient; 0% to 95%) to give compound 63. MS m / z (ESI): 982.4 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 8.26 - 8.18 (m, 1H), 7.53 - 7.30 (m, 3H), 7.27 - 7.25 (m, 1H), 7.22 - 7.01 (m, 3H), 7.00 - 6.44 (m, 2H), 5.81 - 5.22 (m, 1H), 3.80 - 3.57 (m, 5H), 3.52 - 3.32 (m, 5H), 3.24 - 3.17 (m, 1H), 3.07 - 2.95 (m, 3H), 2.26 - 2.19 (m, 4H), 2.06 - 1.97 (m, 1H), 1.85 - 1.77 (m, 1H), 1.76 - 1.61 (m, 3H), 1.60 - 1.46 (m, 2H), 1.33 - 1.28 (m, 4H), 1.27 - 1.24 (m, 4H), 1.22 - 1.10 (m, 12H).

[0937] Example 71: Preparation of compound 64

[0938] Compound 64 was synthesized by a similar method to compound 63 in Example 70.

[0939] Compound 64: MS m / z (ESI): 982.4 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.26 - 8.18 (m, 1H), 7.53 - 7.30 (m, 3H), 7.27 - 7.25 (m, 1H), 7.22 - 7.01 (m, 3H), 7.00 - 6.44 (m, 2H), 5.81 - 5.22 (m, 1H), 3.80 - 3.57 (m, 5H), 3.52 - 3.32 (m, 5H), 3.24 - 3.17 (m, 1H), 3.07 - 2.95 (m, 3H), 2.26 - 2.19 (m, 4H), 2.06 - 1.97 (m, 1H), 1.85 - 1.77 (m, 1H), 1.76 - 1.61 (m, 3H), 1.60 - 1.46 (m, 2H), 1.33 - 1.28 (m, 4H), 1.27 - 1.24 (m, 4H), 1.22 - 1.10 (m, 12H).

[0940] Example 72: Preparation of compound 65

[0941] Compound 65 was synthesized by a similar method to compound 62 in Example 69.

[0942] Compound 65: MS m / z (ESI): 1000.6 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 11.79 (s, 1H), 7.78-7.75 (m, 1H), 7.69-7.64 (m, 1H), 7.61-7.46 (m, 2H), 7.46-7.34 (m, 2H), 7.32-7.24 (m, 1H), 7.20-6.83 (m, 4H), 5.79-5.17 (m, 1H), 4.88-4.31 (m, 1H), 3.91-3.55 (m, 7H), 3.39 (s, 3H), 3.26-3.00 (m, 2H), 2.99-2.86 (m, 1H), 2.84-2.55 (m, 1H), 2.34-2.12 (m, 6H), 1.89-1.76 (m, 3H), 1.74-1.49 (m, 8H), 1.45-1.36 (m, 2H), 1.34-1.23 (m, 5H), 1.23-1.04 (m, 4H).

[0943] Experimental Example 1: Determination of the ability of compounds to stimulate the production of cAMP by human GLP-1 receptor stable cell line

[0944] The aim of this test example is to test the ability of compounds to activate the human GLP-1 receptor at the cell surface. The EC50 value for the stimulation of cAMP production after agonism was determined. 50 The compounds were characterized for their ability to activate the human GLP-1 receptor.

[0945] Cell culture: The cell line stably expressing human GLP-1R (H_GLP-1R CHO-K1 Cell Line, purchased from GenScript, GM-C35369) was used in the assay. Cells were maintained in F12K medium (ATCC-30-2004) supplemented with 10% fetal bovine serum (Corning-35-081-CV) and 4 pg / mL puromycin (Gibco-A1113803).

[0946] cAMP assay: When the cell density was close to 80%, the culture medium was removed and the flasks were gently rinsed with PBS. Non-enzymatic cell lysis solution (Sigma-C5914) was added and the cells were incubated for 5-10 minutes at 37°C and 5% CO2 to detach the cells. The cell suspension was centrifuged at 1000 rpm for 5 minutes to remove the supernatant. The cell pellet was resuspended in assay buffer (containing 0.1% BSA and 0.5 mM IBMX (Sigma-I-6504) in PBS) and the cell suspension was transferred to a 96-well plate (Corning-3596) at a final concentration of 50,000 cells / well.

[0947] Cells were resuspended and adjusted to a cell density of 750 cells / 10 pL / well in white Proxiplate-384 plates (PerkinElmer-6007290) containing serial dilutions of the test compound (max. concentration 25 pM, 5-fold serial dilution, 12 points). After centrifugation at 1000 rpm for 1 min, the plates were shaken and incubated for 30 min at 37°C in a 5% CO2 incubator. Detection was performed using the Cisbio cAMP-Gs Dynamic kit (Revvity-62AM4PEB) by adding cAMP-d2 (5 pL, 1 x) and Anti-cAMP-Cryptate (5 pL, 1 x) and incubating for 1 h at room temperature. HTRF signal readout was performed using an Envision plate reader with an excitation wavelength of 320 nm and emission wavelengths of 620 nm and 665 nm.

[0948] The signal ratio (665 nm / 620 nm * 10,000) was calculated and the signal ratio was non-linearly fitted with the sample concentration using a four-parameter equation in GraphPad Prism to obtain the EC 50 values. The results are shown in Table 1 for the control compound LY3502970.

[0949] Table 1 EC50values of compounds in the in vitro cAMP signal activation assay 50

[0950] The results of the experiments show that the compounds of the present application significantly increase the accumulation of cAMP in hGLP-1R CHO-K1 cells.

[0951] Experimental Example 2: Liver microsomal stability (LMS) test

[0952] Pre-heat empty "incubation" plates T60 and NCF60 for 10 minutes. Dilute liver microsomes to 0.56 mg / mL in 100 mM phosphate buffer. Transfer 445 uL of microsomal working solution (0.56 mg / mL) to pre-heated "incubation" plates T60 and NCF60, then incubate the "incubation" plates T60 and NCF60 at 37 °C for 10 minutes with constant shaking. Transfer 54 uL of liver microsomes to a blank plate, then add 6 uL of NADPH cofactor to the blank plate, then add 180 uL of quenching solution to the blank plate. Add 5 uL of compound working solution (100 uM) to the "incubation" plates containing microsomes (T60 and NCF60) and mix thoroughly 3 times. For NCF60 plates, add 50 uL of buffer and mix thoroughly 3 times. Start timing, the plates will be incubated at 37 °C for 60 minutes with shaking. In the "quench" plate T0, add 180 uL of quenching solution and 6 uL of NADPH cofactor. Make sure the plates are cooled to prevent evaporation. For T60 plates, mix thoroughly 3 times and immediately take 54 uL of the mixture to the "quench" plate at the 0 minute time point. Then add 44 uL of NADPH cofactor to the incubation plate (T60). Start timing, the plates will be incubated at 37 °C for 60 minutes with shaking. At 5, 15, 30, 45, and 60 min, add 180 uL of quenching solution to the "quench" plate, mix once, and take 60 uL of sample from the T60 plate to the "quench" plate at each time point. For NCF60: mix once and at the 60 minute time point, take 60 uL of sample from the NCF60 incubation to the "quench" plate containing the quenching solution. All sampling plates are shaken for 10 minutes and then centrifuged at 4000 rpm for 20 minutes at 4 °C. Transfer 80 uL of supernatant to 240 uL of HPLC water, shake plate mix for 10 minutes. Each bioanalysis plate is sealed and shaken for 10 minutes, then analyzed by LC-MS / MS.

[0953] Table 2 Half-life of compounds in liver microsomal stability test 1 / 2

[0954] The experimental results show that the compounds of the present application have excellent human liver microsomal metabolic stability, which is superior to that of the control compounds.

[0955] Experimental Example 3: CYP 2C8 & 2C9 inhibition test

[0956] The test compound was prepared into a 10 mM stock solution, then diluted to 0.005, 0.015, 0.05, 0.15, 0.5, 1.5 and 5 mM, and the final test concentration of the test compound was 0.05, 0.15, 0.5, 1.5, 5.0, 15 and 50 μM; the inhibitor substrate was prepared into a 10 mM stock solution with DMSO, then diluted to 20, 100 μM, and the final test concentration of the inhibitor substrate was 2, 10 μM, and the incubation time was 10 min; 100 mM NADPH (MCE, Cat. No. HYF003 / CS-4998) was diluted to 10 mM with phosphate buffer, and the final test concentration was 1 mM. 2 μL of each concentration of compound and inhibitor solution was taken and added to a 96 deep well plate, 20 μL of diluted substrate solution was added, 158 μL of liver microsomal solution was added, 1000 rpm was mixed for 10 s, 37°C water bath pre-incubation for 10 min, then 20 μL of 10 mM NADPH solution was added, and then incubation was continued for 10 min, 400 μL of ice acetonitrile containing internal standard (500 nM tolbutamide, 10 nM terfenadine) was added to terminate the reaction, 1000 rpm was mixed for 1 min, then centrifuged at 4000 rpm for 20 min. 200 μL of supernatant was taken and added to 100 μL of pure water, mixed for 10 min, then mixed and subjected to LC-MS / MS analysis.

[0957] Table 3 IC of compounds in CYP 2C8 & 2C9 inhibition test 50

[0958] The experimental results show that the inhibition activity of the compound of the present application on CYP 2C8 and CYP 2C9 is poor, and compared with the control compound, it is obviously improved, which can reduce the risk of drug-drug interaction (DDI).

[0959] Experimental Example 4: Rat pharmacokinetic test

[0960] The test animals of the present study were SD male rats (6-9 weeks old, Beijing Vital River Laboratory Animal Technology Co., Ltd.), and LC-MS / MS method was used to quantitatively determine the drug concentration in the plasma of rats at different time points after intravenous injection or oral administration of the test compound, so as to evaluate the pharmacokinetic characteristics of the compound in rats. The clear solution of the test compound was injected into the tail vein of SD rats (without fasting, solvent: 10% DMSO / 10% Cremophor EL / 15% PEG400 / 65% 100mM Glycine-NaOH), and was orally administered to SD rats (food was given after fasting for 4h, free drinking water, solvent: 10% DMSO / 10% Cremophor EL / 15% PEG400 / 65% 100mM Glycine-NaOH). After intravenous injection, blood was collected from the carotid vein at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration, and was placed in an EDTA-K2 anticoagulant tube, mixed, and centrifuged at 6800g for 6 minutes at 2-8°C to obtain plasma; after oral administration, blood was collected from the carotid vein at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24h, and was placed in an EDTA-K2 anticoagulant tube, mixed, and centrifuged at 6800g for 6 minutes at 2-8°C to obtain plasma. The blood drug concentration was determined by LC-MS / MS method, and the pharmacokinetic software Phoenix WinNonlin TM Version 7.0 (Pharsight, USA) was used to calculate the relevant pharmacokinetic parameters by linear logarithmic trapezoidal method.

[0961] Table 4 Relevant pharmacokinetic parameters of the compound in rat pharmacokinetic test

[0962] The experimental results show that the compound of the present application has excellent pharmacokinetic properties, and the bioavailability and exposure amount are significantly improved compared with the control compound.

[0963] Experimental Example 5: Mouse pharmacokinetic test

[0964] The test animals of the present study were CD1 male mice (6-8 weeks old, Beijing Vital River Laboratory Animal Technology Co., Ltd.), and LC-MS / MS method was used to quantitatively determine the drug concentration in the plasma of the mice at different time points after intravenous injection or oral administration of the test compound, so as to evaluate the pharmacokinetic characteristics of the compound in the mice. The clear solution of the test compound was injected into the mice through the tail vein (without fasting, solvent: 10% DMSO / 10% Cremophor EL / 15% PEG400 / 65% 100mM Glycine-NaOH), and was orally administered to the mice (food was given after fasting for 4h, free drinking water, solvent: 10% DMSO / 10% Cremophor EL / 15% PEG400 / 65% 100mM Glycine-NaOH). The intravenous injection was administered at 0.033, 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours after administration, and the blood was collected from the jugular vein, placed in an EDTA-K2 anticoagulant tube, mixed, and centrifuged at 4℃, 4000g for 5 minutes to obtain the plasma; the oral administration was administered at 0.083, 0.25, 0.5, 1, 2, 4, 6, 8 and 24h after administration, and the blood was collected from the jugular vein, placed in an EDTA-K2 anticoagulant tube, mixed, and centrifuged at 4℃, 4000g for 5 minutes to obtain the plasma. The blood drug concentration was determined by LC-MS / MS method, and the Phoenix WinNonlin TM Version 7.0 (Pharsight, USA) pharmacokinetic software was used to calculate the relevant pharmacokinetic parameters by non-compartment model linear logarithmic trapezoidal method.

[0965] Table 5. Relevant pharmacokinetic parameters of the compounds in the pharmacokinetic test of mice

[0966] The experimental results show that the compound of the present application has excellent pharmacokinetic properties, and the bioavailability and exposure amount are significantly improved compared with the control compound.

Claims

A GLP-1R agonist, which is a compound of formula (I), its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates or solvates thereof: in, R 1 Selected from C 6-10 Aryl or substituted C 6-10 Aryl, the substituted C 6-10 Aryl groups include C 6-10 One or more hydrogens on the aryl group are each independently selected from halogens, SF5, C 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-6 Substituents of cycloalkyl groups; R 3 R 4 R 5 R 7 R 8 R 9 R 6 Each is independently selected from hydrogen, deuterium, halogen, or C. 1-6 alkyl; R a and R b Each is independently selected from hydrogen, deuterium, halogen, or C. 1-6 Alkyl; or R a and R b Together with the carbon atoms they are attached to, they form C 3～10 cycloalkyl; optionally, the C 3～10 cycloalkyl groups are formed by 1 to 3 independent C atoms. 1-6 Alkyl groups are substituted; R 10 It is selected from 6-membered heterocyclic groups or 6-membered heteroaryl groups, wherein the 6-membered heterocyclic group or 6-membered heteroaryl group is optionally selected by one or more (preferably one to three) independently from deuterium, halogen, C 1-6 Alkyl, C 1-6 Alkoxy, -NR N1 R N2 The substituents are substituted, and optionally, the two Cs are substituents on the 6-membered heterocyclic group or the 6-membered heteroaryl group. 1-6 Alkyl groups, together with the carbon atoms they are attached to, can form C14 groups. 3-8 cycloalkyl or 4-8 membered heterocyclic groups, R N1 and R N2 Independently selected from H and C 1-6 alkyl; R 2 Selected from optionally substituted 13-18 membered heterocyclic groups, optionally substituted C 13-18 Aryl groups, or optionally substituted 13-18 heteroaryl groups. The GLP-1R agonist according to claim 1, characterized in that, The 13-18 membered heterocyclic group, C 13-18 The heteroatoms in the aryl and 13-18 membered heteroaryl groups are selected from N, O, S, and P, and the 13-18 membered heterocyclic groups and C 13-18 The number of heteroatoms in aryl and 13- to 18-membered heteroaryl groups is one or more, and when two or more heteroatoms are included, they may be the same, partially the same or completely different. The GLP-1R agonist according to claim 1, characterized in that, R 2 Selected from 13-18 membered heterocyclic groups, C 13-18 aryl, 13-18 membered heteroaryl, wherein optionally the 13-18 membered heterocyclic group, C 13-18 The aryl group and the 13-18 membered heteroaryl group are optionally substituted by one or more substituents, each independently selected from the following: a) Deuterium, b) Oxo (=O), c) Halogens, d)OH, e) Cyano group f) Among them, R 0 Selected from H, C 1-6 alkyl, g)-NR N3 R N4 , where R N3 and R N4 Each is independently selected from H and C. 1-6 Alkyl and (C 1-6 alkyl)carbonyl, wherein C 1-6 The alkyl group may be optionally selected independently from one or more deuterium, halogen, hydroxyl, C 1-6 Substitution of alkoxy groups, h)-C(=O)R C1 , where R C1 Selected from C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkylene i)C 1-6 Alkyl, wherein C 1-6 The alkyl group may optionally be substituted with one or more substituents independently selected from deuterium, halogen, hydroxyl, cyano, C1-6 alkoxy, and 3- to 12-membered heterocyclic groups, wherein the 3- to 12-membered heterocyclic groups may optionally be substituted with one or more substituents independently selected from C1-6 alkoxy, halogen, hydroxyl, cyano, C1-6 alkoxy, and 3- to 12-membered heterocyclic groups. 1-6 Alkyl substituents, j)C 1-6 Alkoxy, where C 1-6 The alkoxy group may optionally be independently selected from halogen, hydroxyl, C. 1-6 Alkyl or C 1-6 Substitution of alkoxy groups, k) 3 to 12-membered heterocyclic groups, wherein the 3 to 12-membered heterocyclic groups are optionally selected independently by one or more of deuterium, halogen, hydroxyl, NH2, CN, C 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Substitution of alkyl group 2; l) 5 to 10 heteroaryl groups, wherein the 5 to 10 heteroaryl groups are optionally selected independently by one or more deuterium, halogen, hydroxyl, CN, C 1-6 Alkyl, C 1-6 Alkoxy, -NR N5 R N6 Substituents of R, wherein R N5 and R N6 Independently selected from H and C 1-6 alkyl; m)C 3-10 cycloalkyl, wherein C 3-10 The cycloalkyl group is optionally selected independently from one or more of deuterium, halogen, hydroxyl, NH2, CN, C. 1-6 Alkyl, C 1-6 Alkyl groups, -NH(C 1-6 alkyl), -N(C) 1-6 Substitution of alkyl group 2; n)-S(O)2-R S1 , where R S1 Selected from C 1-6 Alkyl, C 1-6 Haloalkyl, C 3-6 cycloalkyl; and o) Where R e R f Each is independently selected from H, deuterium, or halogen. The GLP-1R agonist according to claim 3 is characterized in that, R 2 Selected from 13-18 membered heterocyclic groups, C 13-18 aryl, 13-18 membered heteroaryl, wherein optionally the 13-18 membered heterocyclic group, C 13-18 The aryl group and the 13-18 membered heteroaryl group are optionally replaced by one or more (preferably one to five) substituents, each independently selected from the following: deuterium; halogen; -C 1～6 alkyl; ＝O； -(CH2)n-OH; -(CH2)n-CN; -(CH2)nO-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CX3, -(CH2)n-CH2X; -C 3-10 cycloalkyl groups, 3-10 membered heterocyclic groups; -NH2; =NH; -CO-NH2; -CO-(CH2)n-CH3, -CO-CH(CH3)OH; -CO-(CH2)n-CX3; -SO2-(CH2)n-CH3; =CF2, =CHF; Where n is 0 to 6; X is F, Cl, Br, or I; The 13-18 membered heterocyclic group, C 13-18 The heteroatoms in the aryl and 13-18 membered heteroaryl groups are selected from N, O, S, and P, and the 13-18 membered heterocyclic groups and C 13-18 The number of heteroatoms in aryl and 13- to 18-membered heteroaryl groups is one or more, and when two or more heteroatoms are included, they may be the same, partially the same or completely different; Preferably, R 2 Selected from 13-18 membered heterocyclic groups, C 13-18 Aryl, 13-18 membered heteroaryl, wherein the 13-18 membered heterocyclic group, C 13-18 The aryl group and the 13-18 membered heteroaryl group are optionally replaced by one or more (preferably one to five) substituents, each independently selected from the following: deuterium; Halogens (e.g., F, Cl); -C 1～4 Alkyl groups (e.g., methyl, ethyl, isopropyl, or tert-butyl); ＝O； -(CH2)n-OH (e.g., -(CH2)2-OH); -(CH2)n-CN (e.g., -CH2-CN or -(CH2)2-CN); -(CH2)nO-(CH2)n-CH3 (e.g., -(CH2)2-OCH3); -O-(CH2)n-CH3 (e.g., -O-CH3); -(CH2)n-CX3 (e.g., -CH2-CF3), -(CH2)n-CH2X; -C 3-6 Cycloalkyl (e.g., cyclopropane) or 4-7 membered heterocyclic groups (e.g., oxobutane); -NH2; =NH; -CO-NH2; -CO-(CH2)n-CH3 (e.g., -CO-CH3), -CO-CH(CH3)OH; -CO-(CH2)n-CX3 (e.g., -CO-CF3); -SO2-(CH2)n-CH3 (e.g., -SO2-CH3); =CF2, =CHF; Where n is 0 to 6; X is F, Cl, Br, or I; The 13-18 membered heterocyclic group, C 13-18 The heteroatoms in the aryl and 13-18 membered heteroaryl groups are selected from N, O, S, and P, and the 13-18 membered heterocyclic groups and C 13-18 The number of heteroatoms in aryl and 13- to 18-membered heteroaryl groups is one or more, and when two or more heteroatoms are included, they may be the same, partially the same or completely different. The GLP-1R agonist according to claim 1, characterized in that, The R 1 Selected from phenyl, optionally including one or more (preferably 1 to 5) hydrogen atoms on the phenyl group, each independently selected from halogens, SF5, C. 1-6 Alkyl, C 1-6 Deuterated alkyl, C 3-6 Substituents of cycloalkyl groups; preferably, R 1 for The GLP-1R agonist according to claim 1, characterized in that, R 3 R 4 R 5 Each is independently selected from hydrogen, deuterium, or C. 1-6 Alkyl; R 7 R 8 R 9 R 6 Each is independently selected from hydrogen, deuterium, or halogen; Preferably, R 3 R 4 For hydrogen, R 5 CH3, R 7 For hydrogen, R 8 For hydrogen, F, R 9 For hydrogen, R 6 It is hydrogen. The GLP-1R agonist according to claim 1, characterized in that, R a and R b Each is independently selected from hydrogen, deuterium, halogen, or C. 1-6 Alkyl; or R a and R b Together with the carbon atoms to which they are attached, they form C3 cycloalkyl groups; optionally, the C3 cycloalkyl groups are independently C3-carbon atoms. 1-6 Alkyl groups are substituted; Preferably, R a and R b Each is independently selected from hydrogen, deuterium, halogen, or C. 1-6 Alkyl; or R a and R b Together with the carbon atoms they are attached to, they form cyclopropyl, 2-methylcyclopropyl (e.g.) )。 The GLP-1R agonist according to claim 1, characterized in that, R 10 It is selected from 6-membered heterocyclic groups and 6-membered heteroaryl groups, wherein the 6-membered heterocyclic group and 6-membered heteroaryl group are optionally selected independently by one or more (preferably one to three) deuterium, halogen, C 1-3 Alkyl, C 1-3 alkoxy or -NR N1 R N2 The substituents are substituted, and optionally, the two Cs are substituents on the 6-membered heterocyclic group or the 6-membered heteroaryl group. 1-3 Alkyl groups, together with the carbon atoms they are attached to, form C14 groups. 3-6 Cycloalkyl (e.g., cyclopropane) or 4-7 membered heterocyclic groups; R N1 and R N2 Independently selected from H and C 1-3 alkyl; Preferably, R 10 It is 3,3-dimethyl-cyclo-4-oxo-hexane (e.g., )or The GLP-1R agonist according to claim 1, characterized in that, The R 2 Selected from: Wherein, Q1 is selected from N or CR 13 Q2 is selected from N or CR. 15 Q3 is selected from N or CR. 14 ; R 13 ,R 14 ,R 15 ,R 30 Each is independently selected from H, deuterium, and C. 1-6 Alkyl or halogen; M1, M2, M3, M4, M5, M6, M7, M8, M9, M 10 M 11 M 12 M 13 M 14 M 15 M 16 M 17 M 18 M 19 M 20 M 21 M 22 M 23 Each is independently selected from C, N, O, P, or S. M 24 M 25 Each is independently selected from CH, N, CH2, NH, O, or S; M 26 Selected from CH, N, O, or S; Between M1 and M2, between M2 and M3, between M4 and M5, between M5 and M6, between M6 and M7, M 10 and M 11 Between, M 11 and M 12 Between, M 11 and M 16 Between, M 12 and M 13 Between, M 13 and M 14 Between, M 14 and M 15 Between, M 15 and M 16 Between, M 17 and M 18 Between, M 18 and M 19 Between, M 19 and M 20 Between, M 19 and M 23 Between, M 20 and M 21 Between, M 21 and M 22 Between, M 22 and M 23 Between, M 24 and M 25 M 25 and M 26 Each is an independent single bond or a double bond, wherein the two adjacent chemical bonds are not both double bonds at the same time; The R 11 ,R 12 ,R 21 ,R 22 ,R 31 ,R 32， R 41 ,R 42 ,R 51 ,R 52 ,R 61 ,R 62 ,R 71 ,R 72 R 16 ,R 17 ,R 18 ,R 19 ,R 23 ,R 24 ,R 81 ,R 82 ,R 91 ,R 92 ,R 101 ,R 102 ,R 121 ,R 131 ,R 141 ,R 211 ,R 221 ,R 261 Each is independently selected from: non-existent, hydrogen, deuterium, halogen, -C 1～6 Alkyl groups (preferably methyl or isopropyl), =O, -(CH2)n-OH, -(CH2)n-CN, -(CH2)nO-(CH2)n-CH3, -O-(CH2)n-CH3, -(CH2)n-CX3, -(CH2)n-CH2X, C 3-10 Cycloalkyl (preferably cyclopropane), 3-10 membered heterocyclic (preferably oxocyclobutane), -NH2, =NH, -CO-NH2, -CO-(CH2)n-CH3, -CO-CH(CH3)OH, -CO-(CH2)n-CX3, -SO2-(CH2)n-CH3, =CF2 or =CHF; wherein, X is F, Cl, Br or I; n is 0 to 6; and (I)-0 satisfies one of the following conditions: 1)R 11 ,R 12 It forms C with the atoms connected to it. 5-10 cycloalkyl groups, 5- to 10-membered heterocyclic groups; 2)R 21 ,R 22 It forms C with the atoms connected to it. 5-10 cycloalkyl groups, 5- to 10-membered heterocyclic groups; 3)R 31 ,R 32 It forms C with the atoms connected to it. 5-10 cycloalkyl groups, 5- to 10-membered heterocyclic groups; (I)-2 satisfies one of the following conditions: 4)R 41 ,R 42 It forms C with the atoms connected to it. 4-9 cycloalkyl groups, 4-9 membered heterocyclic groups; 5)R 51 ,R 52 It forms C with the atoms connected to it. 4-9 cycloalkyl groups, 4-9 membered heterocyclic groups; 6)R 61 ,R 62 It forms C with the atoms connected to it. 4-9 cycloalkyl groups, 4-9 membered heterocyclic groups; 7)R 71 ,R 72 It forms C with the atoms connected to it. 4-9 cycloalkyl groups, 4-9 membered heterocyclic groups; (I)-3 satisfies one of the following conditions: 8)R 16 ,R 17 It forms C with the atoms connected to it. 3-8 cycloalkyl groups, 3- to 8-membered heterocyclic groups; 9)R 18 ,R 19 It forms C with the atoms connected to it. 3-8 cycloalkyl groups, 3- to 8-membered heterocyclic groups; 10)R 23 ,R 24 , and the atoms connected to it form C 3-8 cycloalkyl groups, 3- to 8-membered heterocyclic groups; 11)R 81 ,R 82 It forms C with the atoms connected to it. 3-8 cycloalkyl groups, 3- to 8-membered heterocyclic groups; 12)R 91 ,R 92 It forms C with the atoms connected to it. 3-8 cycloalkyl groups, 3- to 8-membered heterocyclic groups; Wherein, C is optionally mentioned 3-8 cycloalkyl, C 4-9 cycloalkyl, C 5-10 Cycloalkyl, 3-8 membered heterocyclic, 4-9 membered heterocyclic, and 5-10 membered heterocyclic groups are substituted by one or more of the following substituents: deuterium; halogen; -C 1～6 Alkyl group (preferably methyl or isopropyl); =O; -(CH2) n -OH;-(CH2)n-CN;-(CH2) n -O-(CH2) n -CH3; -O-(CH2) n -CH3; -(CH2) n -CX3; -(CH2) n -CH2X; -NH2; =NH; -CO-NH2; -CO-(CH2) n -CH3; -CO-(CH2)n-CX3; -SO2-(CH2)n-CH3; -CO-CH(CH3)OH, =CF2, =CHF; where n is independently 0 to 6; and X is F, Cl, Br, or I; The C 3-8 cycloalkyl, C 4-9 cycloalkyl, C 5-10 Cycloalkyl, 3-8 membered heterocyclic groups, 4-9 membered heterocyclic groups, and 5-10 membered heterocyclic groups include spirocyclic (e.g., spiroheterocyclic or spirocarbon-cyclic) or fused-ring (e.g., fused-heterocyclic or fused-carbon-cyclic); The 3-8 membered heterocyclic group, 4-9 membered heterocyclic group, and 5-10 membered heterocyclic group include one or more heteroatoms each independently selected from N, O, and S, wherein when there are more than two heteroatoms, the heteroatoms are the same, partially the same, or completely different. The structure shown in equation (Ⅰ)-0 includes R 11 ,R 12 R 21 ,R 22 The ring formed by the atoms connected to it, or R 31 ,R 32 The ring formed by the atoms connected to it; The structure shown in equation (Ⅰ)-2 includes R 41 ,R 42 R 51 ,R 52 R 61 ,R 62 The ring formed by the atoms connected to it, or R 71 ,R 72 The ring formed by the atoms connected to it; The structure shown in equation (Ⅰ)-3 includes R 16 ,R 17 R 18 ,R 19 R 23 ,R 24 R 81 ,R 82 The ring formed by the atoms connected to it, or R 91 ,R 92 A ring formed by atoms connected to it. The GLP-1R agonist according to claim 9 is characterized in that, The R 2 Selected from: M1, M2, and M3 are each independently selected from C, N, O, P, or S; In the structure shown in equation (Ⅰ)-1, R 11 ,R 12 ,R 21 ,R 22 ,R 31 ,R 32 Each is independently selected from: non-existent, hydrogen, deuterium, halogen, -C 1～6 Alkyl (preferably methyl or tert-butyl), CF3, =O, -(CH2)n-OH, -(CH2)nO-(CH2)n-CH3, -O-(CH2)n-CH3, -(CH2)n-CX3, -(CH2)n-CH2X, C 3-6 Cycloalkyl (preferably cyclopropane), 4-7 membered heterocyclic (preferably oxocyclobutane), =NH, -NH2, -CO-NH2, or -CO-(CH2)n-CH3, wherein X is F, Cl, Br, or I, and n is 0 to 6; and satisfies one of the following conditions: 1)R 11 ,R 12 The atoms connected to it form a ring, the ring being selected from C 5-10 Cycloalkyl groups, 5-10 membered heterocyclic groups (preferably C16) 5-9 (Cycloalkyl, 5-9 membered heterocyclic groups); 2)R 21 ,R 22 The atoms connected to it form a ring, the ring being selected from C 5-10 Cycloalkyl groups, 5-10 membered heterocyclic groups (preferably C16) 5-7 (cycloalkyl, 5-7 membered heterocyclic groups); 3)R 31 ,R 32 The atoms connected to it form a ring, the ring being selected from C 5-10 Cycloalkyl or 5-10 cyclic heterocyclic groups (preferably C) 5-9 Cycloalkyl, 5-9 membered heterocyclic groups, more preferably 6 membered heterocyclic groups); The structure shown in equation (Ⅰ)-1 includes R 11 ,R 12 R 21 ,R 22 The ring formed by the atoms connected to it, or R 31 ,R 32 The ring formed by the atoms connected to it; The 5-10 membered heterocyclic group comprises one or more heteroatoms, each independently selected from N, O, and S; optionally, the C 5-10 Cycloalkyl groups and 5-10 membered heterocyclic groups are substituted with one or more of the following substituents: deuterium, halogen, -C 1～6 Alkyl (preferably methyl, ethyl, or isopropyl), =O, -(CH2) n -OH, -(CH2)n-CN, -(CH2) n -O-(CH2) n -CH3, -O-(CH2) n -CH3, -(CH2) n -CX3, -(CH2) n -CH2X, -NH2, =NH, -CO-NH 2、 -CO-(CH2)n-CX3、-CO-(CH2) n -CH3, -SO2-(CH2)n-CH3, -CO-CH(CH3)OH, =CF2 or =CHF; wherein, X is F, Cl, Br, or I, and n is 0 to 6. The GLP-1R agonist according to claim 10 is characterized in that, The R 2 Selected from: M1, M2, and M3 are each independently selected from C, N, O, P, or S; In the structure shown in equation (Ⅰ)-1, R 11 ,R 12 ,R 21 ,R 22 ,R 31 ,R 32 Each is independently selected from: non-existent, hydrogen, deuterium, halogen, methyl, isopropyl, tert-butyl, =O, -(CH2)n-OH, -(CH2)nO-(CH2)n-CH3, -O-(CH2)n-CH3, -(CH2)n-CX3, -(CH2)n-CH2X, C 3-6 Cycloalkyl (preferably cyclopropane), 4-7 membered heterocyclic (preferably oxocyclobutane); =NH, -NH2, -CO-NH2, or -CO-(CH2)n-CH3, wherein X is F, Cl, Br, or I, and n is 0-6; and satisfies one of the following conditions: 1)R 11 ,R 12 It forms a ring with the atoms it connects to, 2)R 21 ,R 22 It forms a ring with the atoms it connects to, or 3)R 31 ,R 32 The atoms connected to it form rings, each ring being independently selected from: The GLP-1R agonist according to claim 9 is characterized in that, The R 2 Selected from: Wherein, the R 13 ,R 14 ,R 15 Each is independently selected from: H, deuterium, and C. 1-6 Alkyl or halogen; M4, M5, M6, and M7 are each independently selected from C, N, O, P, or S; M4 and M5, M5 and M6, and M6 and M7 are each independently single or double bonds, wherein two adjacent chemical bonds are not simultaneously double bonds; In the structure shown in equation (Ⅰ)-2, R 41 ,R 42 ,R 51 ,R 52 ,R 61 ,R 62 ,R 71 ,R 72 Each element is independently selected from: non-existent; hydrogen; deuterium; halogen; -C 1～6 Alkyl (preferably methyl or isopropyl); =O; -(CH2)n-OH; -(CH2)nO-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X; C 3-6 Cycloalkyl (preferably cyclopropane), 4-7 membered heterocyclic (preferably oxobutyric), =NH; -NH2; -CO-NH2; or -CO-(CH2)n-CH3; wherein, X is F, Cl, Br, or I, and n is 0-6; and satisfies one of the following conditions: 1)R 41 ,R 42 The atoms connected to it form a ring, the ring being selected from C 4-9 Cycloalkyl, 4-9 membered heterocyclic groups (preferably C) 4-6 (cycloalkyl, 4-6 membered heterocyclic groups); 2)R 51 ,R 52 The atoms connected to it form a ring, the ring being selected from C 4-9 Cycloalkyl, 4-9 membered heterocyclic groups (preferably C) 4-6 (cycloalkyl, 4-6 membered heterocyclic groups); 3)R 61 ,R 62 The atoms connected to it form a ring, the ring being selected from C 4-9 Cycloalkyl, 4-9 membered heterocyclic groups (preferably C) 4-6 Cycloalkyl groups, 4-6 membered heterocyclic groups, more preferably 6 membered heterocyclic groups; 4)R 71 ,R 72 The atoms connected to it form a ring, the ring being selected from C 4-9 Cycloalkyl, 4-9 membered heterocyclic groups (preferably C) 4-6 (cycloalkyl, 4-6 membered heterocyclic groups); The 4-9 membered heterocyclic group includes one or more independent heteroatoms selected from N, O, and S. When more than two heteroatoms are included, they may be the same, partially the same, or completely different. The structure shown in (Ⅰ)-2 includes R 41 ,R 42 R 51 ,R 52 R 61 ,R 62 The ring formed by the atoms connected to it, or R 71 ,R 72 The ring formed by the atoms connected to it; Optionally, C 4-9 The cycloalkyl group and the 4-9 membered heterocyclic group are replaced by one or more of the following substituents: deuterium; halogen; -C 1～6 Alkyl group (preferably methyl or isopropyl); =O; -(CH2) n -OH;-(CH2) n -O-(CH2) n -CH3; -O-(CH2) n -CH3; -(CH2) n -CH2X, -NH2; -CO-NH2; or -CO-(CH2) n -CH3, wherein X is F, Cl, Br, or I, and n is 0 to 6. The GLP-1R agonist according to claim 12 is characterized in that, The R 2 Selected from: Wherein, the R 13 ,R 14 ,R 15 Each is independently selected from: H, deuterium, and C. 1-6 Alkyl or halogen; M4, M5, M6, and M7 are each independently selected from C, N, O, P, or S; M4 and M5, M5 and M6, and M6 and M7 are each independently single or double bonds, wherein two adjacent chemical bonds are not simultaneously double bonds; In the structure shown in equation (Ⅰ)-2, R 41 ,R 42 ,R 51 ,R 52 ,R 61 ,R 62 ,R 71 ,R 72 Each is independently selected from: non-existent; hydrogen; deuterium; halogen; -C 1～6 Alkyl (preferably methyl or isopropyl); =O; -(CH2)n-OH; -(CH2)nO-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X; C 3-6 Cycloalkyl (preferably cyclopropane), 4-7 membered heterocyclic (preferably oxobutyric); =NH; -NH2; -CO-NH2; or -CO-(CH2)n-CH3; wherein, X is F, Cl, Br, or I, and n is 0-6; and satisfies one of the following conditions: 1)R 41 ,R 42 It forms a ring with the atoms it connects to; 2) R 51 ,R 52 It forms a ring with the atoms it connects with; 3)R 61 ,R 62 It forms a ring with the atoms it connects to; or 4)R 71 ,R 72 It forms a ring with the atoms it connects with; Each ring is independently selected from: The GLP-1R agonist according to claim 9 is characterized in that, The R 2 Selected from: Wherein, the R 13 ,R 14 ,R 15 Each is independently selected from H, deuterium, and C. 1-6 Alkyl or halogen; M8 and M9 are independently selected from C, N, O, P or S; Preferably, in the structure shown in formula (Ⅰ)-3, R 16 ,R 17, R 18 ,R 19 ,R 23 ,R 24 ,R 81 ,R 82 ,R 91 ,R 92 Each element is independently selected from: non-existent; hydrogen; deuterium; halogen; -C 1～6 Alkyl (preferably methyl or isopropyl); =O; -(CH2)n-OH; -(CH2)nO-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X, where X is F, Cl, Br, or I; C 3-6 Cycloalkyl (preferably cyclopropane), 4-7 membered heterocyclic (preferably oxobutyric); =NH-NH2; =NH; -CO-NH2; or -CO-(CH2)n-CH3, where n is 0-6; and satisfying one of the following conditions: 1)R 16 ,R 17 The atoms connected to it form a ring, the ring being selected from C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups (preferably 4 membered heterocyclic groups); 2)R 18 ,R 19 The atoms connected to it form a ring, the ring being selected from C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups (preferably 4 membered heterocyclic groups); 3)R 23 ,R 24 The atoms connected to it form a ring, the ring being selected from C 3-8 Cycloalkyl groups, 3-8 membered heterocyclic groups (preferably 4 membered heterocyclic groups); 4)R 81 ,R 82 The atoms connected to it form a ring, the ring being selected from C 3-8 cycloalkyl groups, 3-8 membered heterocyclic groups; 5)R 91 ,R 92 The atoms connected to it form a ring, the ring being selected from C 3-8 cycloalkyl groups, 3-8 membered heterocyclic groups; The structure shown in equation (Ⅰ)-3 includes R 16 ,R 17 R 18 ,R 19 R 23 ,R 24 R 81 ,R 82 The ring formed by the atoms connected to it, or R 91 ,R 92 The ring formed by the atoms connected to it; Each of the 3-8 membered heterocyclic groups independently includes one or more heteroatoms selected from N, O, and S. When two or more heteroatoms are included, they are the same, partially the same, or completely different. The C 3-8 The cycloalkyl group and the 3-8 membered heterocyclic group are each independently replaced by one or more of the following substituents: deuterium; halogen; -C 1～6 Alkyl group, preferably methyl or isopropyl; =O; -(CH2) n -OH;-(CH2) n -O-(CH2) n -CH3; -O-(CH2) n -CH3; -(CH2) n -CH2X, where X is F, Cl, Br, or I; -NH2; -CO-NH2; or -CO-(CH2) n -CH3, where n is 0 to 6. The GLP-1R agonist according to claim 14 is characterized in that, The R 2 Selected from: in, The R 13 ,R 14 ,R 15 Each is independently selected from H, deuterium, and C. 1-6 Alkyl or halogen; M8 and M9 are each independently selected from C, N, O, P or S; Preferably, in the structure shown in formula (Ⅰ)-3, R 16 ,R 17, R 18 ,R 19 ,R 23 ,R 24 ,R 81 ,R 82 ,R 91 ,R 92 Each element is independently selected from: non-existent; hydrogen; deuterium; halogen; -C 1～6 Alkyl (preferably methyl or isopropyl); =O; -(CH2)n-OH; -(CH2)nO-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X,C 3-6 Cycloalkyl (preferably cyclopropane), 4-7 membered heterocyclic (preferably oxocyclobutane); =NH; -NH2; -CO-NH2; or -CO-(CH2)n-CH3, wherein X is F, Cl, Br, or I; n is 0-6; and satisfies one of the following conditions: 1)R 16 ,R 17 It forms a ring with the atoms it connects to; 2) R 18 ,R 19 It forms a ring with the atoms it connects with; 3)R 23 ,R 24 It forms a ring with the atoms it connects with; 4)R 81 ,R 82 It forms a ring with the atoms it connects to; or 5)R 91 ,R 92 It forms a ring with the atoms it connects with; Each ring is independently selected from: The GLP-1R agonist according to claim 9 is characterized in that, The R 2 Selected from: (preferred) )， in, The R 13 ,R 14 ,R 15 ,R 30 Each is independently selected from H, deuterium, and C. 1-6 Alkyl or halogen; The M 10 M 11 M 12 M 13 M 14 M 15 M 16 Each is independently selected from C, N, O, P, or S; M 10 and M 11 Between, M 11 and M 12 Between, M 11 and M 16 Between, M 12 and M 13 Between, M 13 and M 14 Between, M 14 and M 15 Between, M 15 and M 16 Each bond can be a single or double bond independently, where no two adjacent chemical bonds are double bonds at the same time; R 101 ,R 102 ,R 121 ,R 131 ,R 141 Each element is independently selected from: non-existent; hydrogen; deuterium; halogen; -C 1～6 Alkyl (preferably methyl or isopropyl); =O; -(CH2)n-OH; -(CH2)nO-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X; C 3-10 Cycloalkyl (preferably cyclopropane), 3-10 membered heterocyclic (preferably oxocyclobutane); -NH2; =NH; -CO-NH2; -CO-(CH2)n-CH3, wherein X is F, Cl, Br, or I, and n is 0-6. The GLP-1 R agonist according to claim 9 is characterized in that, The R 2 Selected from: Among them, R 13 ,R 14 ,R 15 Each is independently selected from H, deuterium, and C. 1-6 Alkyl or halogen; M 17 M 18 M 19 M 20 M 21 M 22 M 23 Each is independently selected from C, N, O, P, or S; M 17 and M 18 Between, M 18 and M 19 Between, M 19 and M 20 Between, M 19 and M 23 Between, M 20 and M 21 Between, M 21 and M 22 Between, M 22 and M 23 Each bond can be a single or double bond independently, where two adjacent chemical bonds are not both double bonds at the same time; In the structure shown in equation (Ⅱ)-2, R 211 ,R 221 Each is independently selected from hydrogen, deuterium; halogen; -C 1～6 Alkyl (preferably methyl or isopropyl); =O; -(CH2)n-OH; -(CH2)nO-(CH2)n-CH3; -O-(CH2)n-CH3; -(CH2)n-CH2X; C 3-10 Cycloalkyl (preferably cyclopropane), 3-10 membered heterocyclic group (preferably oxocyclobutane); =NH; -NH2; -CO-NH2; -CO-(CH2)n-CH3, wherein X is F, Cl, Br, or I, and n is 0 to 6. The GLP-1R agonist according to any one of claims 9 to 17 is characterized in that, The R 13 ,R 14 ,R 15 Each is independently selected from H or F. The GLP-1R agonist according to claim 9 is characterized in that, The R 2 Selected from: Among them, R 13 ,R 14 ,R 15 Each is independently selected from H, deuterium, and C. 1-6 Alkyl or halogen; M 24 M 25 Each is independently selected from CH or N; M 26 Selected from N, O, or S; M 24 and M 25 M 25 and M 26 Each is an independent single bond or a double bond, wherein the two adjacent chemical bonds are not both double bonds at the same time; R 261 Selected from: hydrogen, deuterium, halogens, -C 1～6 alkyl. The GLP-1R agonist according to any one of claims 1 to 11 is characterized in that, The R 2 Selected from: Wherein, Q1 is selected from N or CR 13 Q2 is selected from N or CR. 15 Q3 is selected from N or CR. 14 Preferably, Q1 is selected from CR. 13 Q2 is selected from CR 15 Q3 is selected from CR 14 ; R 13 R 14 R 15 Each is independently selected from H, deuterium, and C. 1-6 Alkyl or halogen; preferably, R 13 Selected from H, R 14 Selected from H or halogens (e.g., F), R 15 Selected from H; more preferably, R 13 R 14 R 15 Selected from H; R 11 Selected from H, C 1-6 Alkyl, C 1-6 Halogenated alkyl, hydroxyl C 1-6 Alkylene-, C 1-6 Alkoxy C 1-6 Alkylene-, C 3-6 cycloalkyl, 4-7 membered heterocyclic group; preferably, R 11 Selected from H, C 1-4 Alkyl, C 1-4 Haloalkyl, C 1-4 Alkoxy C 1-4 Alkylene-, C 3-6 Saturated cycloalkyl groups, 4-7 membered saturated heterocyclic groups; R 31 R 32 Together with the carbon atoms it is attached to, they form C 3-6 Monocyclic cycloalkyl, 4-7 membered monocyclic heterocyclic groups, C 7-9 Fused bicyclic cycloalkyl groups, 7-9 membered fused bicyclic heterocyclic groups, C 7-9 Spirobicyclic cycloalkyl, 7-9 membered spirobicyclic heterocyclic group; the C 3-6 Monocyclic cycloalkyl, 4-7 membered monocyclic heterocyclic groups, C 7-9 Fused bicyclic cycloalkyl groups, 7-9 membered fused bicyclic heterocyclic groups, C 7-9 Spirobicyclic cycloalkyl groups and 7-9 membered spirobicyclic heterocyclic groups are optionally substituted with one or more of the following groups: halogen, oxo, C. 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -CO-C 1-6 Alkyl, -CO-C 1-6 Alkyl hydroxyl, -CO-C 1-6 Halogenated alkyl groups, -SO2-C 1-6 Alkyl, cyano C 1-6 alkylene-; wherein R e R f Each is independently selected from H or halogen; Preferably, R 31 R 32 Together with the attached carbon atom, a 5-6 membered monocyclic epoxy heterocyclic group is formed; optionally, the 5-6 membered monocyclic epoxy heterocyclic group is substituted by one or more of the following substituents: deuterium, halogen, -C 1～6 Alkyl (preferably methyl or ethyl), =O, -(CH2) n -OH, -(CH2)n-CN, -(CH2) n -O-(CH2) n -CH3, -O-(CH2) n -CH3, -(CH2) n -CX3, -(CH2) n -CH2X, -NH2, =NH, -CO-NH 2、 -CO-(CH2)n-CX3、-CO-(CH2) n -CH3, -SO2-(CH2)n-CH3 or -CO-CH(CH3)OH, =CF2, =CHF; wherein, X is F, Cl, Br or I, and n is 0 to 6. The GLP-1R agonist according to claim 20 is characterized in that, The R 2 Selected from: in, Represents a single or double bond; preferably, Represents a single key; Z0 is selected from CH, CH2, O, S, NH or N; preferably, Z0 is selected from O; Z1, Z2, and Z3 are each independently selected from CH2 or O; v1, v2, v3, v4, and v5 are each independently selected from 0 or 1; preferably, v1 is selected from 1; s is selected from 0, 1, or 2; preferably, s is selected from 0; Ring D is selected from C 3-6 cycloalkyl or phenyl; R' is selected from halogen, oxo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, -CO-C 1-6 Alkyl, -CO-C 1-6 Halogenated alkyl groups, -SO2-C 1-6 Alkyl, cyano C 1-6 Alkylene-, -CO-C 1-6 alkyl hydroxyl; wherein R e R f Each is independently selected from H or halogen; "R" is selected from H or C. 1-6 alkyl; Q1, Q2, Q3, R 11 As defined in claim 20. The GLP-1R agonist according to claim 20 or 21 is characterized in that, The R 2 Selected from Q1, Q2, Q3, R 11 R', s, v1 as defined in claim 20 or 21. The GLP-1R agonist according to claim 20 or 21 is characterized in that, The R 2 Selected from: in: Q1 is selected from N or CR 13 Q2 is selected from N or CR. 15 Q3 is selected from N or CR. 14 ; Preferably, Q1 is selected from CR 13 Q2 is selected from CR 15 Q3 is selected from CR 14 ; R 13 R 14 R 15 Each is independently selected from H or halogens (e.g., F); Preferably, R 13 R 14 R 15 One of them is selected from halogens (e.g., F), and the rest are H; Preferably, R 13 R 14 R 15 All are H; R 11 Selected from H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Deuterated alkyl, hydroxy C 1-6 Alkylene-, C1-4 alkoxy-C1-4 alkylene-, C3-6 saturated cycloalkyl, 4-7 membered saturated heterocyclic groups; Preferably, R 11 Selected from C 1-6 alkyl; v3, v4, and v5 are each independently selected from 0 or 1; Preferably, both v3 and v4 are 0; Preferably, both v3 and v4 are 1; Preferably, v5 is 0; Preferably, v5 is 1. The GLP-1R agonist according to any one of claims 1-9, 12, and 13 is characterized in that, The R 2 Selected from: Among them, R 13 R 14 R 15 Each is independently selected from H, deuterium, and C. 1-6 Alkyl or halogen; preferably, R 13 R 14 R 15 Each is independently selected from H or a halogen (e.g., F); preferably, R 13 R 14 R 15 One of them is selected from halogens (e.g., F), and the rest are selected from H; or, preferably, R 13 R 14 R 15 Selected from H; Z4 is selected from CH2, CF2, or O; preferably, Z4 is selected from O. Z5 is selected from CH2, CF2, and NR. 71 Or O; preferably, Z5 is selected from CH2; Preferably, for formula (I)-2-A, when Z5 is selected from NR 71 When Z4 is selected from O, Z4 is chosen from O. Preferably, for formula (I)-2-A, when Z5 is selected from CH2 or CF2, Z4 is selected from CH2, CF2 or O, preferably CF2 or O, and more preferably O; R 41 R 71 Each is independently selected from C 1-6 Alkyl; preferably, R 41 R 71 Each is independently selected from C 1-4 Alkyl groups (e.g., methyl groups); V6 and v7 are each independently selected from 0 or 1; preferably, V6 and v7 are both selected from 0 or V6 and v7 are both selected from 1. The GLP-1R agonist according to claim 24 is characterized in that, The R 2 Selected from: Wherein, the R 13 R 14 R 15 Each is independently selected from H, deuterium, and C. 1-6 Alkyl or halogen; preferably, R 13 R 14 R 15 Each is independently selected from H or a halogen (e.g., F); preferably, R 13 R 14 R 15 One of them is selected from halogens (e.g., F), and the rest are selected from H; or, preferably, R 13 R 14 R 15 All are H; R 41 C 1-6 Alkyl (e.g., methyl). The GLP-1R agonist according to any one of claims 1-9, 16 is characterized in that, The R 2 Selected from: in: R 13 R 14 and R 15 Each is independently selected from hydrogen or halogen (e.g., F), preferably R. 13 R 14 and R 15 One of them is a halogen (e.g., F), and the rest are hydrogen; or, more preferably, R. 13 R 14 and R 15 All are hydrogen; M 10 Selected from N, O, or S, with N being preferred; R 101 Selected from non-existent, hydrogen, C 1-6 Alkyl; the condition is that when M 10 When selected from O or S, R 101 Selected from non-existent; M 12 M 13 M 14 M 15 Each is independently selected from C or N; M is preferred. 12 M 13 M 14 M 15 One of them is N; more preferably M 12 M 13 M 14 M 15 All are C; R 121 R 131 R 141 Each is independently selected from non-existent, hydrogen, halogens (e.g., F or Cl), C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Haloalkyl, C 1-6 Halogenated alkoxy group; preferably, R 121 R 131 R 141 Each is independently selected from non-existent, hydrogen, or halogens (e.g., F or Cl); the condition is that when M 12 M 13 M 14 When selected from N, R 121 R 131 R 141 Selected from non-existent. The GLP-1R agonist according to any one of claims 1 to 26 is characterized in that, In the compound, optical isomer or pharmaceutically acceptable salt thereof represented by formula (I), the R 2 Selected from: The GLP-1R agonist according to claim 1, characterized in that, It is a compound with the structure shown below, and its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates, or solvates are selected from the following compounds: A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of claims 1-28, an isomer thereof, an isotopically labeled compound thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, ester thereof, hydrate thereof, or solvate thereof. The use of the compound of any one of claims 1-28, its isomers, isotopically labeled compounds, prodrugs, or pharmaceutically acceptable salts, esters, hydrates or solvates thereof, or the pharmaceutical composition of claim 29 in the preparation of medicaments for treating metabolic diseases, cardiovascular diseases, liver diseases, kidney diseases, neurodegenerative diseases, and other diseases regulated by GLP-1 receptors. The application according to claim 30 is characterized in that, The metabolic diseases include diabetes, diabetic complications, and obesity; the cardiovascular diseases include hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, and cerebral infarction; the liver diseases include non-alcoholic steatohepatitis; the kidney diseases include type 2 diabetes mellitus complicated with chronic kidney disease; and the neurodegenerative diseases include Parkinson's disease or dementia.

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