Heterocyclic GLP-1 receptor agonist compound, preparation method therefor, and use thereof

Abstract

The present invention relates to a compound having a structure represented by formula (I) and having GLP-1 receptor agonistic activity; and the use of said compound and a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof in the preparation of a GLP-1 receptor agonist and in the preparation of a drug for treating and / or preventing metabolic diseases.

Description

A heterocyclic GLP-1 receptor agonist compound, a preparation method thereof and application thereof TECHNICAL FIELD

[0001] The present application belongs to the field of medicinal chemistry, and particularly relates to a heterocyclic GLP-1 receptor agonist compound, a preparation method thereof and application thereof. BACKGROUND

[0002] Glucagon-like peptide-1 (GLP-1) is a peptide hormone secreted by intestinal epithelial L cells, which is widely distributed in the pancreas, stomach and small intestinal mucosa, and in the heart, lung, central nervous system. After GLP-1 and GLP-1 receptor (GLP-1R) in vivo specifically bind, the cyclic adenosine monophosphate (cAMP) and mitogen-activated protein kinase (MAPK) pathways in the cell membrane are activated, and then various effects are exerted, such as promoting glucose-dependent insulin secretion, inhibiting glucagon secretion, inhibiting apoptosis of islet beta cells, delaying gastric emptying, inhibiting food intake, and the like. In addition, many diseases and / or functional disorders are associated with the abnormal, abnormal or disorder of the activity of one or more kinases. Therefore, GLP-1 analogs show effective effects in HbA1c reduction and weight loss, and have been developed as effective therapeutic agents for treating diabetes and obesity. GLP-1 analogs also exhibit efficacy in improving cardiovascular outcomes and preserving renal function in diabetic patients, thereby providing a treatment opportunity for various metabolic disorders and related comorbidities.

[0003] Currently marketed GLP-1 receptor agonists are polypeptide drugs, and have very poor oral bioavailability, and need to be administered by injection, such as liraglutide, taspoglutide, dulaglutide, and the like. To date, no small molecule GLP-1 receptor agonist has been approved for treating diabetes, obesity or other metabolic disorders. Therefore, it is highly desirable to have an orally administered small molecule GLP-1 receptor agonist with good effects. SUMMARY

[0004] One of the purposes of the present application is to provide a GLP-1 receptor agonist compound, such as described in formula (I), formula (II), formula (III), formula (IV), and the like, and a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof.

[0005] Another purpose of the present application is to provide a pharmaceutical composition comprising any of the above compounds, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof as an active ingredient, and a pharmaceutically acceptable excipient;

[0006] Another purpose of the present application is to provide the use of the above compound or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof in the preparation of a GLP-1 receptor agonist drug;

[0007] Another object of the present application is to provide the use of the above-mentioned compound or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, or the pharmaceutical composition in the manufacture of a medicament for treating and / or preventing type I diabetes, type II diabetes, malnutrition-related diabetes, hyperglycemia, diabetic complications, obesity, non-alcoholic steatohepatitis (NASH), insulin resistance, glucose intolerance, hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, cerebral infarction, metabolic syndrome, Parkinson's disease and / or dementia.

[0008] Another object of the present application is to provide a method for preparing the above-mentioned compound.

[0009] To achieve the above object, the technical solution adopted by the present application is as follows:

[0010] The present application provides a compound as shown in formula (I), or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof,

[0011] wherein:

[0012] R1 and R2 are the same or different, and each is independently selected from a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyloxy group or a C1-C6 alkoxy group, wherein the C1-C6 alkoxy group is optionally substituted with 0 or one or more halogen atoms;

[0013] Ring A is selected from:

[0014] R3 is selected from a C1-C6 alkyl group or a C3-C6 cycloalkyl group, wherein the C1-C6 alkyl group is optionally substituted with 0 or one or more halogen atoms;

[0015] is a single bond or a double bond;

[0016] wherein, when is a double bond, ring A is not

[0017] In some embodiments, the compound shown in formula (I) has a structure as shown in formula (II),

[0018] wherein:

[0019] R1 and R2 are the same or different, and each is independently selected from a hydrogen atom, a C1-C6 alkyl group, a C3-C6 cycloalkyl group, a C3-C6 cycloalkyloxy group or a C1-C6 alkoxy group, wherein the C1-C6 alkoxy group is optionally substituted with 0 or one or more halogen atoms;

[0020] R3is selected from: C1-C6alkyl or C3-C6cycloalkyl, wherein C1-C6alkyl is optionally substituted with 0 or one or more halogen atoms;

[0021] R1is selected from a hydrogen atom or C1-C6alkyl and R2is selected from a hydrogen atom or C1-C6alkyl, R3is not C1-C6alkyl;

[0022] Preferably,

[0023] R1and R2are the same or different and each independently selected from: a hydrogen atom, a methyl group, a methoxy group, an ethoxy group, a cyclopropyl group,

[0024] R3is selected from: a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group or a difluoromethyl group.

[0025] wherein, when R1is selected from a hydrogen atom or a methyl group and R2is selected from a hydrogen atom or a methyl group, R3is not a difluoromethyl group.

[0026] In some embodiments, the compound of formula (I) has the structure of formula (III),

[0027] wherein:

[0028] R1and R2are the same or different and each independently selected from: a hydrogen atom, C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkyloxy or C1-C6alkoxy, wherein C1-C6alkoxy is optionally substituted with 0 or one or more halogen atoms;

[0029] R3is selected from: C1-C6alkyl or C3-C6cycloalkyl, wherein C1-C6alkyl is optionally substituted with 0 or one or more halogen atoms;

[0030] Preferably,

[0031] R1and R2are the same or different and each independently selected from: a hydrogen atom, a methyl group, a methoxy group, an ethoxy group, a cyclopropyl group,

[0032] R3is selected from: a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group or a difluoromethyl group.

[0033] In some embodiments, the compound of formula (I) has the structure of formula (IV),

[0034] wherein:

[0035] R1and R2are the same or different and each independently selected from: a hydrogen atom, C1-C6alkyl, C3-C6cycloalkyl, C3-C6cycloalkyloxy or C1-C6alkoxy, wherein C1-C6alkoxy is optionally substituted with 0 or one or more halogen atoms;

[0036] Preferably,

[0037] R1and R2are the same or different, and each independently selected from the group consisting of: a hydrogen atom, a methyl group, a methoxy group, an ethoxy group, a cyclopropyl group,

[0038] In some embodiments, the compound of formula (I) has a structure as shown in formula (V),

[0039] wherein:

[0040] R1and R2are the same or different, and each independently selected from the group consisting of: a hydrogen atom, a methyl group, a methoxy group, an ethoxy group, a cyclopropyl group,

[0041] In some embodiments, the compound is selected from any one of the following compounds,

[0042] In some embodiments, there is provided a pharmaceutical composition comprising at least one compound described herein, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient.

[0043] In some embodiments, there is provided a use of a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, or a pharmaceutical composition of the foregoing, in the manufacture of a GLP-1 receptor agonist medicament.

[0044] In some embodiments, the GLP-1 receptor agonist medicament is a medicament for the treatment and / or prevention of type I diabetes, type II diabetes, malnutrition-related diabetes, hyperglycemia, diabetic complications, obesity, non-alcoholic steatohepatitis (NASH), insulin resistance, impaired glucose tolerance, hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, cerebral infarction, metabolic syndrome, Parkinson's disease, and / or dementia.

[0045] In some embodiments, there is provided a use of a compound described herein, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, or a pharmaceutical composition of the foregoing, in the manufacture of a GLP-1 receptor agonist.

[0046] In some embodiments, there is provided a method of treating and / or preventing a disease related to GLP-1 receptor mediation, comprising administering to a subject in need thereof a therapeutically effective amount of a GLP-1 receptor agonist.

[0047] In some embodiments, the GLP-1 receptor mediated related diseases include type I diabetes, type II diabetes, malnutrition-related diabetes, hyperglycemia, diabetic complications, obesity, non-alcoholic steatohepatitis (NASH), insulin resistance, glucose intolerance, hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, cerebral infarction, metabolic syndrome, Parkinson's disease, and / or dementia.

[0048] In some embodiments, there is provided a compound of formula (I) as shown above, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, for use as a medicament.

[0049] In some embodiments, there is provided a compound of formula (I) as shown above, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, for use in the treatment and / or prevention of GLP-1 receptor mediated related diseases.

[0050] Definitions and general terms:

[0051] The following terms and the like are used to describe the present application. It should be understood that terms not specifically defined herein are given the meaning commonly understood by those of ordinary skill in the art in the context of the present application.

[0052] The term "alkyl" as used herein refers to saturated aliphatic hydrocarbon groups, including straight chain and branched chain hydrocarbons. For example, C1-C6alkyl. "C1-C6alkyl" refers to alkyl groups having from 1 to 6 carbon atoms, for example, alkyl groups having 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms, 6 carbon atoms, including but not limited to methyl, ethyl, propyl (e.g., n-propyl, i-propyl), butyl (e.g., n-butyl, i-butyl, t-butyl), pentyl (e.g., n-pentyl, i-pentyl, neopentyl), hexyl (e.g., n-hexyl), and the like.

[0053] The term "halogen" as used herein refers to fluorine, chlorine, bromine, or iodine; preferably fluorine, chlorine.

[0054] The term "C3-C6cycloalkyl" as used herein refers to cycloalkyl groups having from 3 to 6 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; preferably cyclopropyl.

[0055] The term "C1-C6alkoxy" as used herein refers to a group formed by the attachment of a C1-C6alkyl group to an oxygen atom, i.e., a "C1-C6alkyl-O-" group, wherein the C1-C6alkyl group is the same as defined above for "C1-C6alkyl". This includes, but is not limited to, methoxy, ethoxy, n-propyloxy, i-propyloxy, n-butyloxy, i-butyloxy, sec-butyloxy, t-butyloxy; preferably methoxy, ethoxy.

[0056] The term "C3-C6-cycloalkyl" as used herein refers to saturated carbocyclic hydrocarbon groups having three to six carbon atoms, i.e. "C3-C6-cycloalkyl" groups. Examples are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. The term "C3-C6-cycloalkyloxy" as used herein refers to a group formed by linking a C3-C6-cycloalkyl group to an oxygen atom, i.e. a "C3-C6-cycloalkyl-O-" group, wherein C3-C6-cycloalkyl has the same definition as given above. C3-C6-cycloalkyloxy includes, but is not limited to, cyclopropyl-O-, cyclobutyl-O-, cyclopentyl-O-, cyclohexyl-O-; preferably cyclopropyl-O-.

[0057] The term "pharmaceutically acceptable salt" as used herein refers to salts of the compounds of the present application, prepared from compounds of the present application having specific substituents with pharmaceutically acceptable acids or bases.

[0058] The term "stereoisomer" as used herein refers to compounds having the same chemical constitution, but different spatial arrangement of atoms and groups. These include enantiomers, diastereomers, geometric isomers, atropisomers or conformers.

[0059] "Solvate" is used herein to describe a molecular complex comprising the compound of any of the above formulae or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable solvent molecules (e.g. ethanol). When the solvent is water, the term "hydrate" is used.

[0060] The compounds of the present application can also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds. For example, the compounds can be radiolabeled with radioactive isotopes, such as deuterium ( 3 ), iodine-125 ( 125 ), or carbon-14 ( 14 ). All isotopic variations of the compounds of the present application, whether radioactive or not, are encompassed within the scope of the present application.

[0061] The advantageous technical effects achieved are:

[0062] (1) The compounds of the present application have excellent biological activity, have good agonistic effect on GLP-1 receptor, and are significantly superior to the comparative compound DB01 and DB02.

[0063] (2) The compounds of the present application have significant hypoglycemic effect, and the hypoglycemic effect of the compounds of the present application is significantly superior to the comparative compound DB01 and DB02 when the same dose is orally administered at a single time.

[0064] (3) The compound of the present application has a significant weight loss effect, and when orally administered continuously for multiple times at the same dose, the weight loss effect of the compound of the present application is significantly better than that of the comparative compound DB01, and the duration of weight loss of the compound of the present application is longer; for example, the weight loss curve (0-30 days) shown in Figure 5, the comparative compound DB01 reduces the weight by 11.9% relative to the model group in 30 days, while the compound 19 reduces the weight by 17.5% relative to the model group in 30 days; and the comparative compound DB01 enters the weight loss plateau at about the 20th day after administration, while the compound 19 of the present application still maintains a sustained weight loss trend within 30 days.

[0065] (4) In the weight loss drug efficacy experiment, the weight loss effect of the compound of the present application reaches or exceeds 20% after the experimental period is extended to 8 weeks, and even the weight loss effect of part of the compounds exceeds 30%, which has excellent in vivo biological activity.

[0066] (5) The compound of the present application has excellent pharmacokinetic properties after oral administration, for example, the pharmacokinetic properties are significantly better than those of the comparative compound DB01. BRIEF DESCRIPTION OF DRAWINGS

[0067] Figure 1 shows the blood glucose concentration curves of the compound 1, the compound 3 of the present application, and the comparative compounds DB01, DB02 and the solvent.

[0068] Figure 2 shows the blood glucose AUC (0-120 min) of the compound 1, the compound 3 of the present application, and the comparative compounds DB01, DB02 and the solvent.

[0069] Figure 3 shows the blood glucose concentration curves of the compound 19 of the present application, and the comparative compounds DB01, DB02 and the solvent.

[0070] Figure 4 shows the blood glucose AUC (0-120 min) of the compound 19 of the present application, and the comparative compounds DB01, DB02 and the solvent.

[0071] Figure 5 shows the weight curve (0-30 days) of the compound 19 of the present application, the comparative compound DB01 and the model group and the normal control group of mice. DETAILED DESCRIPTION

[0072] The raw materials or reagents used in the present application are commercially available unless otherwise specified. The structure confirmation of the target compound is carried out by the following analytical means: nuclear magnetic resonance spectrum (NMR) detection is completed by using a Bruker Avance III 400MHz nuclear magnetic resonance instrument, the test solvents are deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3) or deuterated methanol (CD3OD), and tetramethylsilane (TMS) is used as an internal standard, and the chemical shift values obtained are expressed in ppm (10 -6) is a unit of measurement. Mass spectrometry (MS) analysis was performed using a Waters Vion IMS QTof mass spectrometer in ESI source mode to ensure accuracy of molecular weights.

[0073] Example 1: Preparation of Intermediate 1

[0074] Step 1: Preparation of Compound 1-A

[0075] Compound 1-A (15.0 g, 42.3 mmol) was weighed into a 1.0 L single-necked flask, and 300 mL of DCM was added to stir and dissolve. 60 mL of trifluoroacetic acid was added dropwise at room temperature, and stirring was continued for 5 h after the dropwise addition was completed. TLC showed that the starting material had disappeared. The solvent was evaporated under reduced pressure, and the residue was added to 200 mL of water. NaHCO3 was added to adjust the pH to 8-9, and 200 mL of DCM was added for extraction. The aqueous phase was extracted again with DCM (150 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1-B (6.53 g, yield 100%) as a red oil.

[0076] Step 2: Preparation of Compound 1-B

[0077] Compound 1-A (15.0 g, 42.3 mmol) was weighed into a 1.0 L single-necked flask, and 300 mL of DCM was added to stir and dissolve. 60 mL of trifluoroacetic acid was added dropwise at room temperature, and stirring was continued for 5 h after the dropwise addition was completed. TLC showed that the starting material had disappeared. The solvent was evaporated under reduced pressure, and the residue was added to 200 mL of water. NaHCO3 was added to adjust the pH to 8-9, and 200 mL of DCM was added for extraction. The aqueous phase was extracted again with DCM (150 mL x 2). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1-B (6.53 g, yield 100%) as a red oil.

[0078] Step 3: Preparation of Compound 1-C

[0079] Compound 1-B (6.53 g, 42.35 mmol) was dissolved in 150 mL of toluene and stirred to dissolve, and the starting material (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (10.09 g, 42.35 mmol) and pyridine hydrochloride (0.49 g, 4.24 mmol) were added. The stirred reaction solution was heated at 90°C for 2 h. TLC showed that the starting material 1-B disappeared, and then the reaction solution was cooled to room temperature. The reaction mixture was poured into water (200 mL), and the aqueous phase was extracted with ethyl acetate (100 mL x 2). The organic phase was combined, dried over anhydrous sodium sulfate, filtered, concentrated, and the concentrated crude product was purified by silica gel column chromatography to obtain compound 1-C (11.7 g, yield 73.6%).

[0080] Step 4: Preparation of compound 1-D

[0081] Compound 1-C (11.7 g, 31.27 mmol) and N-(2,2-dimethoxyethyl)imidazole-1- carboxamide (9.97 g, 50.03 mmol) were dissolved in DMA (N,N-dimethylacetamide, 150 mL) and cooled in an ice bath. To the above cooled solution, t-BuOK (10.53 g, 93.81 mmol) was slowly added in portions. After the addition was completed, the reaction mixture was raised to 25°C and stirred for about 5 h. TLC showed that the starting material 1-C disappeared, and the reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (150 mL x 2). The organic phase was washed with water (150 mL x 3) and saturated sodium chloride solution (150 mL x 3) in sequence, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a solid crude product, which was then slurried with 30 mL of ethyl acetate to obtain compound 1-D (11.5 g, yield 72.7%).

[0082] Step 5: Preparation of intermediate 1

[0083] Compound 1-D (11.5 g, 22.75 mmol) was suspended in THF (115 mL), and MSA (methanesulfonic acid, 1.75 g, 18.2 mmol) was added dropwise. The reaction mixture was stirred at 60°C for about 3 h. TLC showed that the starting material 1-D disappeared, and the reaction mixture was cooled to room temperature, and then the reaction mixture was poured into water (200 mL) and extracted with ethyl acetate (150 mL x 2). The organic phase was washed with water (200 mL x 2) and saturated sodium chloride solution (200 mL x 2) in sequence, dried over anhydrous sodium sulfate, and concentrated to obtain a brown oily crude product, which was purified by silica gel column chromatography to obtain intermediate 1 (7.5 g, yield 74.7%). 1HNMR (400 MHz, CDC13) δ = 10.42 (s, 1H), 7.06 (d, J = 6.1 Hz, 2H), 6.36 (s, 1H), 6.14 (s, 1H), 5.35-5.23 (m, 1H), 4.50-4.33 (m, 1H), 3.12 (s, 1H), 2.79 (s, 2H), 2.23 (d, J = 1.8 Hz, 6H), 1.50 (s, 9H), 1.31-1.24 (m, 3H).

[0084] Example 2: Preparation of Intermediate 2

[0085] Step 1: Preparation of compound 2-A

[0086] Into a 50 mL round bottom flask, was added 3-cyclopropyl-4-fluoroaniline (1.0 g, 6.61 mmol), 5 mL water, 5.5 mL hydrochloric acid (66.15 mmol), after stirring with ice water bath, slowly drop in sodium nitrite (548 mg, 7.94 mmol) in 5 mL water, after dropwise addition, ice water bath stirring for about 30 min, drop in stannous chloride (3.76 g, 19.84 mmol) in 4 mL hydrochloric acid solution, continue ice water bath stirring for 1 h, after reaction is completed, adjust pH to 8-9 with 40% NaOH aqueous solution, filter, filter with ethyl acetate (30 mL x 3), combine the organic phase, dry the organic phase with anhydrous sodium sulfate, filter, concentrate to get 920 mg of compound 2-A, yield 83.7%.

[0087] Step 2: Preparation of compound 2-B

[0088] Into a 100 mL round bottom flask, was added compound 2-A (920 mg, 5.54 mmol), (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (1.1 g, 4.61 mmol), pyridine hydrochloride (53 mg, 0.46 mmol), 18 mL toluene, after stirring uniformly, warm to 90 °C, stir for 5 h, cool to room temperature, add 40 mL water, extract with ethyl acetate (30 mL x 3), combine the organic phase, wash the organic phase with saturated sodium chloride aqueous solution (2 x 30 mL), dry with anhydrous sodium sulfate, filter, concentrate, the crude product is purified by silica gel column chromatography to get 900 mg of compound 2-B, yield 50.4%.

[0089] Step 3: Preparation of compound 2-C

[0090] In a 250 mL round-bottom flask, compound 2-B (2.7 g, 6.99 mmol), N-(2,2-dimethoxyethyl)-lH-imidazole-l-carboxamide (1.67 g, 8.38 mmol), 50 mL of N,N-dimethylacetamide, after stirring and dissolving at room temperature, potassium tert-butoxide (3.14 g, 27.95 mmol) was added in batches, after reaction at room temperature for about 4 h, 150 mL of water was added to quench the reaction, extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated to give 2.7 g of compound 2-C, with a yield of 74.6%.

[0091] Step 4: Preparation of intermediate 2

[0092] In a 250 mL round-bottom flask, compound 2-C (2.7 g, 5.22 mmol), MSA (methanesulfonic acid, 401 mg, 4.17 mmol), 50 mL of tetrahydrofuran, after stirring and dissolving, the temperature was raised to 60 °C for about 2 h, 100 mL of saturated aqueous sodium bicarbonate solution was added to quench the reaction, extracted with ethyl acetate (50 mL x 3), the combined organic phase was washed with saturated aqueous sodium chloride solution (50 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, the crude product was separated and purified by column chromatography to give 1.43 g of intermediate 2, with a yield of 60.3%. 1 HNMR (400 MHz, CDC13) δ = 10.61 (s, 1H), 7.21-7.12 (m, 1H), 7.02 (t, J = 9.1 Hz, 1H), 6.94 (dd, J = 6.5, 2.3 Hz, 1H), 6.37 (t, J = 2.5 Hz, 1H), 6.12 (s, 1H), 5.35-5.22 (m, 1H), 4.51-4.32 (m, 1H), 3.13 (s, 1H), 2.80 (s, 2H), 2.14-2.02 (m, 1H), 1.49 (s, 9H), 1.28 (d, J = 8.0 Hz, 3H), 0.94-0.96 (m, 2H), 0.74-0.57 (m, 2H).

[0093] Example 3: Preparation of intermediate 3

[0094] Step 1: Preparation of compound 3-A

[0095] Into a 125 mL glass tube, add 5-bromo-2-fluorophenol (5 g, 26.18 mmol), cyclopropyl bromide (6.33 g, 52.36 mmol), cesium carbonate (25.6 g, 78.53 mmol), 40 mL NMP (N-methyl pyrrolidone), heat to 130 °C, seal the tube and react for about 25 h, then cool to room temperature, add 120 mL water, extract with ethyl acetate (60 mL x 3), combine the organic phases, wash successively with 60 mL water, saturated aqueous sodium chloride solution (60 mL x 2), dry over anhydrous sodium sulfate, filter, concentrate, and purify the crude product by silica gel column chromatography to obtain 4.53 g of compound 3-A, with a yield of 74.9%.

[0096] Step 2: Preparation of compound 3-B

[0097] Into a 500 mL three-necked flask, add compound 3-A (4.45 g, 19.26 mmol), 45 mL tetrahydrofuran, stir under nitrogen protection, cool to -70 °C, and then drop n-BuLi (2.5 M, 7.7 mL, 19.26 mmol). After dropping, continue stirring the reaction mixture for 1 h. Drop di-tert-butyl azodicarboxylate (abbreviated as: DBAD, 4.43 g, 19.26 mmol), and the temperature of the reaction mixture should not exceed -65 °C. After dropping, continue stirring at -60 °C for 30 min, and then slowly raise the temperature to room temperature and stir overnight. Quench by dropping saturated NH4Cl solution (135 mL), and then extract with ethyl acetate (50 mL x 2). Wash the combined organic phase with water (50 mL x 2), and then dry over anhydrous sodium sulfate, filter, concentrate, and purify by silica gel column chromatography to obtain 2.68 g of compound 3-B, with a yield of 36.4%.

[0098] Step 3: Preparation of compound 3-C

[0099] Into a 100 mL round-bottom flask, add compound 3-B (2.68 g, 7.01 mmol), and then add 50 mL DCM to stir and dissolve. Drop 6 mL trifluoroacetic acid at room temperature, and then continue stirring overnight after dropping. Adjust the pH of the reaction solution to 8-9 with saturated NaHCO3, separate the phases, collect the organic phase, extract the aqueous phase with DCM (50 mL x 2), and combine the organic phases. Dry the organic phase over anhydrous sodium sulfate, filter, concentrate, and purify the crude product by silica gel column chromatography to obtain 1.14 g of compound 3-C, with a yield of 89.1%.

[0100] Step 4: Preparation of compound 3-D

[0101] Into a 250 mL round-bottom flask, was placed compound 3-C (1.83 g, 10.04 mmol), (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (1.99 g, 8.37 mmol), pyridine hydrochloride (97 mg, 0.84 mmol), 36.5 mL of toluene, and the mixture was stirred and heated to 90 °C for 12 h. After cooling, 100 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 1.12 g of compound 3-D in 33.3% yield.

[0102] Step 5: Preparation of compound 3-E

[0103] Into a 250 mL round-bottom flask, was placed compound 3-D (1.12 g, 2.78 mmol) and N-(2,2-dimethoxyethyl)imidazole-1-carboxamide (665 mg, 3.34 mmol), 25 mL of DMA (N,N-dimethylacetamide), and the mixture was stirred at room temperature. Then t-BuOK (1.25 g, 11.14 mmol) was added portionwise. The reaction was continued to stir at room temperature for about 5 h. Then 75 mL of water was added, and the mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with water (50 mL x 3) and saturated aqueous sodium chloride solution (50 mL x 3) sequentially, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 1.32 g of compound 3-E in 89.2% yield.

[0104] Step 6: Preparation of intermediate 3

[0105] Into a 100 mL round-bottom flask, was placed compound 3-E (1.32 g, 2.47 mmol), methanesulfonic acid (190 mg, 1.98 mmol), and 26 mL of tetrahydrofuran, and the mixture was stirred and heated to 60 °C for about 3 h. After cooling to room temperature, 50 mL of saturated aqueous sodium bicarbonate solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (30 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 0.69 g of intermediate 3 in 59.5% yield, MS m / z (ESI): 470.5024 (M+H). + .

[0106] Example 4: Preparation of intermediate 4

[0107] Step 1: Preparation of compound 4-A

[0108] Into a 250 mL round-bottom flask, was placed 3-(difluoromethoxy)-4- fluorophenylamine (3.0 g, 16.94 mmol), 15 mL of water, 14.1 mL of hydrochloric acid (169.37 mmol), and the mixture was stirred under ice water bath cooling. A solution of sodium nitrite (1.40 g, 20.32 mmol) in 15 mL of water was added dropwise. After the addition was completed, the mixture was stirred under ice water bath cooling for about 30 min. A solution of stannous chloride (9.63 g, 50.81 mmol) in 10 mL of hydrochloric acid was added dropwise. The reaction was continued under ice water bath cooling for 1 h. After the reaction was completed, the mixture was adjusted to pH 8-9 with 40% aqueous sodium hydroxide solution. The mixture was filtered. The filtrate was extracted with ethyl acetate (80 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 2.47 g of compound 4-A in 75.9% yield.

[0109] Step 2: Preparation of compound 4-B

[0110] Into a 250 mL round-bottom flask, was placed compound 4-A (2.47 g, 12.86 mmol), (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (2.55 g, 10.71 mmol), pyridine hydrochloride (124 mg, 1.07 mmol), and 50 mL of toluene. The mixture was stirred under warming to 90 °C for 5 h. The mixture was cooled to room temperature. The mixture was added to 100 mL of water. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated aqueous sodium chloride solution (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 2.03 g of compound 4-B in 45.9% yield.

[0111] Step 3: Preparation of compound 4-C

[0112] Into a 250 mL round-bottom flask, was placed compound 4-B (2.0 g, 4.85 mmol), N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (1.16 g, 5.82 mmol), and 50 mL of N,N-dimethylacetamide. The mixture was stirred under room temperature to dissolve. Potassium tert-butoxide (2.18 g, 19.40 mmol) was added portionwise. The mixture was stirred under room temperature for about 4 h. The mixture was added to 150 mL of water to quench the reaction. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with saturated aqueous sodium chloride solution (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give 2.03 g of compound 4-C in 76.9% yield.

[0113] Step 4: Preparation of intermediate 4

[0114] Into a 250 mL round bottom flask, was added compound 4-C (2.0 g, 3.68 mmol), MSA (methanesulfonic acid, 283 mg, 2.94 mmol), 40 mL of tetrahydrofuran, stirred well and heated to 60 °C for about 2 h, quenched with 80 mL of saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (40 mL x 3), combined organic phase, washed with saturated aqueous sodium chloride solution (40 mL x 2), dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by column chromatography to give 0.98 g of intermediate 4 in 55.6% yield, MS m / z (ESI): 480.1992 (M+H) + .

[0115] Example 5: Preparation of intermediate 5

[0116] Step 1: Preparation of compound 5-A

[0117] Into a 150 mL round bottom flask, was added compound 1-C (2.00 g, 5.35 mmol) and 30 mL of pyridine, stirred well and dissolved at room temperature, cooled to 0 °C in an ice bath, and then added dropwise chloroethyl isocyanate (1.13 g, 10.70 mmol), slowly returned to room temperature and stirred overnight. TLC showed that the starting material 1-C remained, and the reaction was stopped. The reaction mixture was poured into water (90 mL) and extracted with ethyl acetate (90 mL x 2). The organic phase was washed successively with citric acid solution (90 mL x 2), water (90 mL x 3), and saturated sodium chloride solution (90 mL x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the residue was concentrated and purified by column chromatography to give compound 5-A (1.33 g, 51.8% yield).

[0118] Step 2: Preparation of intermediate 5

[0119] NaH (168.00 mg, 60%, 4.2 mmol) was weighed into anhydrous THF (9.0 mL) and cooled to 0 °C in an ice bath. Compound 5-A (1.33 g, 2.8 mmol) was dissolved in 18 mL of DMF and then added dropwise to the above reaction solution, which was stirred at low temperature for about 2 h. TLC showed that the starting material 5-A disappeared, then water was added to quench the reaction, and extracted with ethyl acetate (60 mL x 2). The organic phase was washed successively with water (100 mL x 3) and saturated sodium chloride solution (100 mL x 3), and the organic phase was dried over anhydrous sodium sulfate and concentrated to give intermediate 5 (1.2 g, 97% yield). MS m / z (ESI): 466.2035 (M+Na) + .

[0120] Example 6: Preparation of intermediate 6

[0121] Prepared according to the procedure for the synthesis of Intermediate 5, replacing starting material 1-C with 2-B.

[0122] Example 7: Preparation of Intermediate 7

[0123] Prepared according to the procedure for the synthesis of Intermediate 5, replacing starting material 1-C with 3-D.

[0124] Example 8: Preparation of Intermediate 8

[0125] Prepared according to the procedure for the synthesis of Intermediate 5, replacing starting material 1-C with 4-B.

[0126] Example 9: Preparation of Intermediate 9

[0127] Step 1: Preparation of compound 9-A

[0128] Into a 100 mL round-bottom flask, was placed 3-methoxy-4-fluoroaniline (1.0 g, 7.085 mmol), 10 mL water, 6 mL hydrochloric acid (70.85 mmol), and the mixture was stirred in an ice-water bath. A solution of sodium nitrite (0.587 g, 8.5 mmol) in 2 mL water was added dropwise. After the addition was complete, the mixture was stirred in an ice-water bath for about 30 min. A solution of stannous chloride dihydrate (4.03 g, 21.26 mmol) in 5 mL hydrochloric acid was added dropwise. The mixture was stirred in an ice-water bath for 1 h. After the reaction was complete, the mixture was adjusted to pH 8-9 with 40% NaOH aqueous solution. The mixture was filtered, and the filtrate was extracted with ethyl acetate (80 mL x 3). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to give 0.846 g of compound 9-A in 76.5% yield.

[0129] Step 2: Preparation of compound 9-B

[0130] Into a 100 mL round-bottom flask, was placed compound 9-A (0.846 g, 5.417 mmol), (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (1.076 g, 4.514 mmol), pyridine hydrochloride (52 mg, 0.451 mmol), and 20 mL toluene. The mixture was stirred and heated to 90 °C for 5 h. The mixture was cooled to room temperature, and 40 mL water was added. The mixture was extracted with ethyl acetate (20 mL x 3). The combined organic phase was washed with saturated sodium chloride aqueous solution (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography to give 1.058 g of compound 9-B in 62.3% yield.

[0131] Step 3: Preparation of compound 9-C

[0132] In a 100 mL round-bottom flask, add compound 9-B (1.0 g, 2.656 mmol), N-(2,2-dimethoxyethyl)-1H-imidazole-1-carboxamide (0.635 g, 3.188 mmol), 20 mL N,N-dimethylacetamide, stir to dissolve at room temperature, then add potassium tert-butoxide (1.192 g, 10.624 mmol) in batches, add 30 mL water to quench the reaction after reaction at room temperature for about 4 h, extract with ethyl acetate (20 mL x 3), wash the combined organic phase with saturated aqueous sodium chloride solution (20 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate to obtain 0.977 g of compound 9-C with a yield of 72.5%.

[0133] Step 4: Preparation of intermediate 9

[0134] In a 100 mL round-bottom flask, add compound 9-C (0.95 g, 1.872 mmol), MSA (methanesulfonic acid, 144 mg, 1.5 mmol), 20 mL tetrahydrofuran, stir to dissolve, then heat to 60°C for about 3 h, cool to room temperature, add saturated aqueous sodium bicarbonate solution to quench, adjust pH to 7-8, extract with ethyl acetate (30 mL x 3), wash the combined organic phase with saturated aqueous sodium chloride solution (30 mL x 2), dry over anhydrous sodium sulfate, filter, concentrate, and purify the crude product by column chromatography to obtain 1.34 g of intermediate 9 with a yield of 71.6%, MS m / z (ESI): 466.1865 (M+Na). + .

[0135] Example 10: Preparation of intermediate 10

[0136] Step 1: Preparation of compound 10-A

[0137] In a 50 mL round-bottom flask, add 2-fluoro-5-nitrophenol (1.0 g, 6.365 mmol), potassium carbonate (1.759 g, 12.732 mmol), 15 mL DMF, stir to dissolve, then add iodoethane (1.19 g, 7.638 mmol), add 50 mL water dropwise to quench the reaction after reaction at room temperature for about 2 h, extract with ethyl acetate (20 mL x 3), wash the combined organic phase with saturated aqueous sodium chloride solution (20 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate to obtain 1.17 g of compound 10-A with a yield of 99.28%.

[0138] Step 2: Preparation of compound 10-B

[0139] Into a 100-mL round-bottom flask, was placed compound 10-A (1.17 g, 6.319 mmol), iron powder (1.765 g, 31.596 mmol), ammonium chloride (1.69 g, 31.596 mmol), 24 mL of ethanol, 2.4 mL of water, and the reaction was stirred at 80°C under a nitrogen atmosphere for 5 h. The reaction was cooled to room temperature, filtered through celite, and the filtrate was diluted with water. The mixture was extracted with ethyl acetate (20 mL x 3), and the combined organic layers were washed with saturated aqueous sodium chloride (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to give 0.945 g of compound 10-B in 96.4% yield.

[0140] Step 3: Preparation of compound 10-C

[0141] Into a 100-mL round-bottom flask, was placed compound 10-B (0.945 g, 6.09 mmol), 10 mL of water, 6 mL of hydrochloric acid, and the reaction was stirred while cooling in an ice water bath. A solution of sodium nitrite (504 mg, 7.31 mmol) in 2 mL of water was added dropwise. After the addition was complete, the reaction was stirred in an ice water bath for about 30 min. A solution of stannous chloride dehydrate (3.464 g, 18.27 mmol) in 4 mL of hydrochloric acid was added dropwise. The reaction was stirred in an ice water bath for 1 h. After the reaction was complete, the reaction was adjusted to pH 8-9 with 40% aqueous NaOH solution, filtered, and the filtrate was extracted with ethyl acetate (80 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated to give 0.719 g of compound 10-C in 69.4% yield.

[0142] Step 4: Preparation of compound 10-D

[0143] Into a 100-mL round-bottom flask, was placed compound 10-C (0.7 g, 4.11 mmol), (2S)-3-cyano-2-methyl-4-oxopiperidine-1-carboxylic acid tert-butyl ester (0.817 g, 3.43 mmol), pyridine hydrochloride (40 mg, 0.343 mmol), and 14 mL of toluene. The reaction was stirred at 90°C for 6 h. The reaction was cooled to room temperature, diluted with 30 mL of water, and extracted with ethyl acetate (20 mL x 3). The combined organic layers were washed with saturated aqueous sodium chloride (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by column chromatography on silica gel to give 0.715 g of compound 10-D in 53.4% yield.

[0144] Step 5: Preparation of compound 10-E

[0145] In a 100 mL round-bottom flask, add compound 10-D (0.715 g, 1.83 mmol), N-(2,2-dimethoxyethyl)-lH-imidazole-l-carboxamide (0.438 g, 2.20 mmol), 15 mL N,N-dimethylacetamide, stir to dissolve at room temperature, then add potassium tert-butoxide (0.821 g, 7.32 mmol) in portions, add 25 mL water to quench the reaction after reaction at room temperature for about 4 h, extract with ethyl acetate (20 mL x 3), wash the combined organic phase with saturated aqueous sodium chloride solution (20 mL x 3), dry over anhydrous sodium sulfate, filter, and concentrate to obtain 0.72 g of compound 10-E with a yield of 75.5%.

[0146] Step 6: Preparation of intermediate 10

[0147] In a 100 mL round-bottom flask, add compound 10-E (0.72 g, 1.38 mmol), MSA (methanesulfonic acid, 106 mg, 1.1 mmol), 15 mL tetrahydrofuran, stir to dissolve, then heat to 60 °C for reaction for about 3 h, cool to room temperature, add saturated aqueous sodium bicarbonate solution to quench, adjust pH to 7-8, extract with ethyl acetate (20 mL x 3), wash the combined organic phase with saturated aqueous sodium chloride solution (20 mL x 2), dry over anhydrous sodium sulfate, filter, and concentrate, then purify the crude product by column chromatography to obtain 0.443 g of intermediate 10 with a yield of 70.2%, MS m / z (ESI): 458.2235 (M+H). + .

[0148] Example 11: Preparation of intermediate 11

[0149] Prepare according to the synthesis method of intermediate 5, replacing raw material 1-C with 9-B.

[0150] Example 12: Preparation of intermediate 12

[0151] Prepare according to the synthesis method of intermediate 5, replacing raw material 1-C with 10-D.

[0152] Example 13: Preparation of intermediate 13

[0153] Step 1: Preparation of compound 13-A

[0154] In a 25 mL round-bottom flask, add 3-bromo-2-fluoro-6-nitrotoluene (250 mg, 1.068 mmol), N-bromosuccinimide (NBS, 228 mg, 1.282 mmol), azobisisobutyronitrile (AIBN, 351 mg, 2.136 mmol), 4 mL carbon tetrachloride, stir the reaction under nitrogen atmosphere at 80 °C for 20 h, cool to room temperature, quench the reaction by adding 20 mL water, extract with dichloromethane (15 mL x 3), combine the organic phase, wash with saturated aqueous sodium chloride solution (20 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate to give 0.3 g of compound 13-A, which is used directly in the next step.

[0155] Step 2: Preparation of compound 13-B

[0156] In a 25 mL round-bottom flask, add 3-bromo-2-fluoro-6-nitrotoluene (250 mg, 1.068 mmol), N-bromosuccinimide (NBS, 228 mg, 1.282 mmol), azobisisobutyronitrile (AIBN, 351 mg, 2.136 mmol), 4 mL carbon tetrachloride, stir the reaction under nitrogen atmosphere at 80 °C for 20 h, cool to room temperature, quench the reaction by adding 20 mL water, extract with dichloromethane (15 mL x 3), combine the organic phase, wash with saturated aqueous sodium chloride solution (20 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate to give 0.3 g of compound 13-A, which is used directly in the next step.

[0157] Step 3: Preparation of intermediate 13

[0158] In a 25 mL round-bottom flask, add compound 13-B (175 mg, 0.605 mmol), stannous chloride (229 mg, 1.21 mmol), 5 mL ethanol (95%), stir the reaction at 40 °C for 2 h, cool to room temperature, quench the reaction by adding 20 mL water, extract with ethyl acetate (15 mL x 3), combine the organic phase, wash with saturated aqueous sodium chloride solution (20 mL x 3), dry over anhydrous sodium sulfate, filter, concentrate, purify the crude product by column chromatography to give 99 mg of intermediate 13 in 64.3% yield. MS m / z (ESI): 254.9933 (M+H) + , 1 H NMR (400 MHz, DMSO) δ = 8.73 (d, J = 1.2 Hz, 1H), 7.43 - 7.35 (m, 2H), 4.21 - 4.15 (m, 1H), 1.34 - 1.29 (m, 2H), 1.17 - 1.12 (m, 2H).

[0159] Example 14: Preparation of compound 1

[0160] Synthetic route:

[0161] Step 1: Preparation of compound 1-1

[0162] Compound intermediate 1 (280 mg, 0.63 mmol), intermediate 13 (322.28 mg, 1.26 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (132.25 mg, 0.95 mmol) and Na2CO3(134.50 mg, 1.26 mmol) were weighed into NMP (N-methyl pyrrolidone, 9 mL) and CuI (181.25 mg, 0.95 mmol) was added. The reaction mixture was replaced with nitrogen and stirred at 115 °C for about 6-7 h. TLC showed that intermediate 1 was substantially completely reacted. It was cooled to room temperature and filtered through celite. The filtrate was poured into water (20 mL) and extracted with ethyl acetate (15 mL x 3). The organic phase was washed with water (25 mL x 3) and saturated sodium chloride solution (25 mL x 3) successively, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (PE / EA = 80 / 20) to obtain compound 1-1 (335 mg, yield 86.4%).

[0163] Step 2: Preparation of compound 1-2

[0164] Compound 1-1 (335 mg, 0.54 mmol) was dissolved in DCM (4.0 mL) and HCl / dioxane (4 M, 2.0 mL) was added dropwise. The reaction mixture was stirred at 25 °C for about 4-5 h. TLC showed that the starting material disappeared. The excess solvent was removed under reduced pressure, 8.0 mL of water was added and the pH was adjusted to 8-9 with saturated NaHCO3. It was extracted with ethyl acetate (10 mL x 3), the organic phase was combined and washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 1-2 crude (306.0 mg, yield 109%) which was directly used in the next step.

[0165] Step 3: Preparation of compound 1

[0166] Compound SM01 (292.1 mg, 0.71 mmol) and compound 1-2 (306 mg, 0.59 mmol) were weighed into a 25 mL reaction bottle, and DMF (8 mL) was added to stir and dissolve. HATU (338.4 mg, 0.89 mmol) was added to stir for 10 min, and DIPEA (457.5 mg, 3.54 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. TLC showed that the starting material SM01 disappeared, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 2), and the organic phase was combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative plate (DCM / MeOH = 20 / 1) to obtain compound 1 (297 mg, yield 55.4%). MS m / z (ESI): 909.4021 (M+H) + , 1 H NMR (400 MHz, DMSO-d6) δ 11.76 (s, 1H), 8.85 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.26 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 6.4 Hz, 2H), 7.07 (d, J = 3.2 Hz, 1H), 6.95 (s, 2H), 5.58 (d, J = 6.8 Hz, 1H), 4.40-4.37 (m, 1H), 4.24-4.19 (m, 1H), 3.73-3.71 (m, 2H), 3.64-3.61 (m, 1H), 3.19-3.16 (m, 1H), 3.07-3.01 (m, 1H), 2.91-2.86 (m, 1H), 2.27-2.23 (m, 6H), 1.68-1.59 (m, 4H), 1.44 (d, J = 6.8 Hz, 2H), 1.36-1.31 (m, 4H), 1.28 (s, 4H), 1.21-1.14 (m, 9H).

[0167] Example 15: Preparation of compound 2

[0168] Synthetic route:

[0169] Step 1: Preparation of compound 2-1

[0170] Compound intermediate 2 (300 mg, 0.66 mmol), intermediate 13 (336.72 mg, 1.32 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (140.82 mg, 0.99 mmol) and Na2CO3 (139.9 mg, 1.32 mmol) were weighed into NMP (N-methyl pyrrolidone, 9 mL) and CuI (188.55 mg, 0.99 mmol) was added. The reaction mixture was nitrogen purged and stirred at 115 °C for about 6-7 h. TLC showed that intermediate 2 was substantially reacted completely, cooled to room temperature, and filtered with celite. The filtrate was poured into water (18 mL) and extracted with ethyl acetate (15 mL x 3). The organic phase was washed with water (25 mL x 3) and saturated sodium chloride solution (25 mL x 3) successively, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude was purified by silica gel column chromatography (PE / EA = 80 / 20) to give compound 2-1 (313.20 mg, yield 75.6%).

[0171] Step 2: Preparation of compound 2-2

[0172] Compound 2-1 (300 mg, 0.48 mmol) was dissolved in DCM (3.0 mL) and HCl / dioxane (4 M, 1.5 mL) was added dropwise. The reaction mixture was stirred at 25 °C for about 3 h. TLC showed that the starting material disappeared, the excess solvent was removed under reduced pressure, 6.0 mL of water was added and the pH was adjusted to 8-9 with saturated NaHCO3, then extracted with ethyl acetate (10 mL x 3), the organic phase was combined and washed with saturated sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 2-2 crude (242.3 mg, yield 95.7%), which was used directly for the next step.

[0173] Step 3: Preparation of compound 2

[0174] Compound SM01 (242.8 mg, 0.59 mmol) and compound 2-2 (240 mg, 0.45 mmol) were weighed into a 25 mL reaction bottle, and DMF (6 mL) was added to stir and dissolve. HATU (256.7 mg, 0.68 mmol) was added to stir for 10 min, and DIPEA (348.9 mg, 2.70 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. TLC showed that the starting material SM01 disappeared, the reaction mixture was diluted with water (18 mL) and extracted with ethyl acetate (15 mL x 2), and the organic phase was combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative plate (DCM / MeOH = 25 / 1) to obtain compound 2 (189.0 mg, yield 45.6%). MS m / z (ESI): 921.4025 (M+H) + , 1 H NMR (400 MHz, DMSO-d6) δ 11.75 (s, 1H), 8.84 (s, 1H), 7.55 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 7.6 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H), 7.10 (s, 1H), 6.99 - 6.65 (m, 3H), 5.57 (d, J = 6.8 Hz, 1H), 4.40 - 4.37 (m, 1H), 4.23 - 4.19 (m, 1H), 3.72 (d, J = 8.4 Hz, 2H), 3.63 (s, 1H), 3.19 (s, 1H), 3.07 - 3.01 (m, 1H), 2.92 - 2.89 (m, 1H), 2.74 (s, 1H), 2.12 - 2.05 (m, 1H), 1.80 - 1.77 (m, 1H), 1.76 - 1.65 (m, 4H), 1.43 (d, J = 6.8 Hz, 2H), 1.36 - 1.31 (m, 5H), 1.21 - 1.11 (m, 10H), 1.01 (d, J = 8.8 Hz, 2H), 0.73 - 0.62 (m, 2H).

[0175] Example 16: Preparation of compound 3

[0176] Synthetic route

[0177] Step 1: Preparation of compound 3-1

[0178] Compound intermediate 9 (292.7 mg, 0.66 mmol), intermediate 13 (336.72 mg, 1.32 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (140.82 mg, 0.99 mmol) and Na2CO3(139.9 mg, 1.32 mmol) were weighed into NMP (N-methyl pyrrolidone, 9 mL) and CuI (188.55 mg, 0.99 mmol) was added. The reaction mixture was nitrogen purged and stirred at 115 °C for about 8 h. TLC showed that intermediate 9 was substantially reacted completely, cooled to room temperature, and filtered with celite. The filtrate was poured into water (18 mL) and extracted with ethyl acetate (12 mL x 3). The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) successively, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude was purified by silica gel column chromatography (PE / EA = 80 / 20) to give compound 3-1 (319.20 mg, yield 78.3%).

[0179] Step 2: Preparation of compound 3-2

[0180] Compound 3-1 (310 mg, 0.50 mmol) was dissolved in DCM (3.0 mL) and HCl / dioxane (4 M, 1.5 mL) was added dropwise. The reaction mixture was stirred at room temperature for about 4 h. TLC showed that the starting material disappeared, the excess solvent was removed under reduced pressure, 6.0 mL of water was added and the pH was adjusted to 8-9 with saturated NaHCO3, then extracted with ethyl acetate (10 mL x 3), the organic phase was combined and washed with saturated sodium chloride solution (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give compound 3-2 crude (233.9 mg, yield 90.4%), which was used directly in the next step.

[0181] Step 3: Preparation of compound 3

[0182] Compound SM01 (209.8 mg, 0.51 mmol) and compound 3-2 (200 mg, 0.39 mmol) were weighed into a 25 mL reaction bottle, DMF (6 mL) was added to stir and dissolve. HATU (222.4 mg, 0.59 mmol) was added to stir for 10 min, DIPEA (302.4 mg, 2.34 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. TLC showed that the starting material SM01 disappeared, the reaction mixture was diluted with water (18 mL) and extracted with ethyl acetate (12 mL x 2), the organic phase was combined. The organic phase was washed with water (15 mL x 3) and saturated sodium chloride solution (15 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative plate (DCM / MeOH = 20 / 1) to obtain compound 3 (136.4 mg, yield 38.4%). MS m / z (ESI): 911.3811 (M+H) + , 1 H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.84 (s, 1H), 7.58-7.51 (m, 2H), 7.42-7.35 (m, 2H), 7.27-7.24 (m, 3H), 7.09 (d, J = 3.2 Hz, 1H), 7.02 (d, J = 8.8 Hz, 2H), 6.95 (s, 1H), 5.60 (d, J = 6.8 Hz, 1H), 4.24-4.18 (m, 1H), 3.83-3.80 (m, 4H), 3.74-3.70 (m, 2H), 3.64-3.61 (m, 1H), 3.23-3.17 (m, 1H), 3.08-3.00 (m, 1H), 2.93-2.89 (m, 1H), 1.75-1.64 (m, 4H), 1.44 (d, J = 6.8 Hz, 2H), 1.37-1.29 (m, 5H), 1.26-1.22 (m, 2H), 1.22-1.13 (m, 10H).

[0183] Example 17: Preparation of compound 4

[0184] Prepared according to the synthesis method of reference compound 3, only intermediate 9 was replaced by intermediate 10. MS m / z (ESI): 925.4138 (M+H) + , 1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.84 (s, 1H), 7.60 - 7.53 (m, 2H), 7.44 - 7.37 (m, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 6.8 Hz, 1H), 7.10 - 7.09 (m, 1H), 7.06 - 6.99 (m, 2H), 6.95 (s, 1H), 5.59 (d, J = 6.8 Hz, 1H), 4.41 - 4.38 (m, 1H), 4.24 - -4.19 (m, 1H), 4.11 - 4.04 (m, 2H), 3.73 - 3.61 (m, 3H), 3.20 (s, 1H), 3.06 - 3.00 (m, 1H), 2.96 - 2.88 (m, 1H), 2.18 (t, J = 8.4 Hz, 1H), 1.95 - 1.86 (m, 1H), 1.73 - 1.62 (m, 5H), 1.44 (d, J = 6.4 Hz, 2H), 1.36 - 1.31 (m, 4H), 1.28 (s, 4H), 1.24 - 1.23 (m, 1H), 1.20 - 1.14 (m, 8H).

[0185] Example 18: Preparation of Compound 5

[0186] Prepared according to the synthesis method of Reference Compound 1, only replacing Intermediate 1 with Intermediate 3. MS m / z (ESI): 937.3963 (M+H) + .

[0187] Example 19: Preparation of Compound 6

[0188] Prepared according to the synthesis method of Reference Compound 1, only replacing Intermediate 1 with Intermediate 4. MS m / z (ESI): 947.3617 (M+H) + .

[0189] Example 20: Preparation of Compound 7

[0190] Synthesis Route:

[0191] Step 1: Preparation of Compound 7-1

[0192] Compound 5-bromo-4-fluoro-lH-indazole (1.00 g, 4.65 mmol) was weighed into a 100 mL reaction flask, stirred to dissolve in dichloromethane (25 mL), cooled to 0 °C, KOH solution (1.565 g, 27.9 mmol, dissolved in 7.5 mL water) was added, followed by addition of difluorobromomethyltrimethylsilane (1.89 g, 9.3 mmol), and the reaction was stirred at low temperature. TLC showed that the starting material 5-bromo-4-fluoro-lH-indazole was completely reacted, water (30 mL) was added to the reaction mixture, the liquid was separated, the aqueous phase was extracted with dichloromethane (20 mL x 2), the combined organic phase was washed with saturated sodium chloride solution (20 mL x 2), dried over anhydrous sodium sulfate, and concentrated to obtain a residue which was purified by silica gel column chromatography (PE / EA = 90 / 10) to obtain compound 7-1 (0.87 g, yield 70.6%).

[0193] Step 2: Preparation of compound 7-2

[0194] Compound intermediate 2 (427 mg, 0.941 mmol), compound 7-1 (500 mg, 1.881 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-l,2-diamine (200 mg, 1.412 mmol), and Na2CO3 (250 mg, 2.353 mmol) were dissolved in NMP (N-methyl pyrrolidone, 7.5 mL), and CuI (269 mg, 1.412 mmol) was added. The reaction mixture was replaced with nitrogen, and the reaction was stirred at 115 °C for 8 h. TLC showed that a small amount of both starting materials remained, the reaction mixture was cooled to room temperature, and filtered through celite. The filtrate was poured into water (30 mL) and extracted with ethyl acetate (10 mL x 3). The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 7-2 (518 mg, yield 86.3%).

[0195] Step 3: Preparation of compound 7-3

[0196] Compound 7-2 (370 mg, 0.58 mmol) was dissolved in DCM (4.0 mL), and HCl / dioxane (4 M, 2.0 mL) was added dropwise. The reaction mixture was stirred at room temperature for about 4-5 h. TLC showed that the starting material disappeared, the excess solvent was removed under reduced pressure, 7.0 mL of water was added, and the pH was adjusted to 8-9 with saturated NaHCO3, then extracted with ethyl acetate (8 mL x 3), the combined organic phase was washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 7-3 crude product (291 mg, yield 93.4%), which was directly used as the feedstock for the next step.

[0197] Step 4: Preparation of compound 7

[0198] Compound SM01 (263 mg, 0.640 mmol) and compound 7-3 (286 mg, 0.533 mmol) were weighed into a 25 mL reaction flask, and DMF (5 mL) was added to stir and dissolve. HATU (304.0 mg, 0.80 mmol) was added to stir for 15 min, and DIPEA (413.31 mg, 3.20 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature for 3 h. TLC showed that the starting material SM01 disappeared, water (15 mL) was added to dilute the reaction mixture, and ethyl acetate (15 mL x 2) was added to extract, and the organic phase was combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in sequence, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative plate (DCM / MeOH = 20 / 1) to obtain compound 7 (304 mg, yield 61.2%). MS m / z (ESI): 953.3490 (M+Na) + .

[0199] Example 21: Preparation of compound 8

[0200] Synthetic route:

[0201] Step 1: Preparation of compound 8-1

[0202] Compound 5-bromo-4-fluoro-1H-indazole (2.0 g, 9.30 mmol) was weighed into a 250 mL reaction flask, and ethyl acetate (40 mL) was added to stir and dissolve, and Me3OBF4 (trimethyl oxonium tetrafluoroborate, 2.06 g, 13.95 mmol) was added at room temperature to stir for 2-3 h. TLC showed that the starting material 5-bromo-4-fluoro-1H-indazole was completely reacted, and saturated NaHCO3 solution (30 mL) was added to the reaction mixture to extract and separate, and the organic phase was washed with water (20 mL x 2) and saturated sodium chloride solution (20 mL x 2) in sequence, dried over anhydrous sodium sulfate, and concentrated to obtain brown-red solid compound 8-1 (2.05 g, yield 96%). It was used directly in the next step without purification. 1 HNMR (400 MHz, CDCl3) δ = 7.98 (s, 1H), 7.40-7.32 (m, 2H), 4.24 (s, 3H).

[0203] Step 2: Preparation of compound 8-2

[0204] Compound intermediate 5 (500 mg, 1.13 mmol), compound 8-1 (518.0 mg, 2.26 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (241 mg, 1.70 mmol) and Na2CO3(240 mg, 2.26 mmol) were weighed into NMP (15 mL), and CuI (322.8 mg, 1.70 mmol) was added. The reaction mixture was replaced with nitrogen and stirred at 115 °C for about 7-8 h. TLC showed a small amount of intermediate 5 remained, cooled to room temperature, and filtered with celite. The filtrate was poured into water (30 mL) and extracted with ethyl acetate (25 mL x 2), and the organic phase was combined. The organic phase was washed with water (30 mL x 3) and saturated sodium chloride solution (30 mL x 3) successively, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (PE / EA = 70 / 30) to obtain compound 8-2 (210.0 mg, yield 31.4%).

[0205] Step 3: Preparation of compound 8-3

[0206] Compound 8-2 (200 mg, 0.34 mmol) was dissolved in DCM (2.0 mL), and HCl / dioxane (4 M, 1.0 mL) was added dropwise. The reaction mixture was stirred at room temperature for about 3-4 h. TLC showed that the starting material disappeared, the excess solvent was removed under reduced pressure, 10 mL of water was added, and the pH was adjusted to 8-9 with saturated NaHCO3, and then extracted with ethyl acetate (8 mL x 3), and the organic phase was combined. The organic phase was washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain compound 8-3 crude product (165.0 mg, yield 98.8%), which was directly used in the next step.

[0207] Step 3: Preparation of compound 8

[0208] Compound SM01 (176.5 mg, 0.43 mmol) and compound 8-3 (160 mg, 0.33 mmol) were weighed into a 25 mL reaction bottle, DMF (5 mL) was added to stir and dissolve. HATU (188.2 mg, 0.50 mmol) was added to stir for 10 min, DIPEA (255.90 mg, 1.98 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. TLC showed that the raw material SM01 disappeared, saturated NaCl solution (15 mL) was added to the reaction mixture and extracted with ethyl acetate (15 mL x 2), the organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative plate (DCM / MeOH = 20 / 1) to obtain compound 8 (131.4 mg, yield 45.0%). MS m / z (ESI): 885.4013 (M+H) + , 1 H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.63 (s, 1H), 7.59-7.47 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.33-7.30 (m, 2H), 7.29-7.24 (m, 2H), 6.95 (s, 1H), 5.66 (d, J = 6.8 Hz, 1H), 4.37-4.33 (m, 1H), 4.20 (s, 3H), 4.17 (s, 1H), 3.95-3.89 (m, 2H), 3.77-3.70 (m, 3H), 3.66-3.61 (m, 1H), 3.15 (s, 1H), 3.07-3.00 (m, 1H), 2.88-2.76 (m, 1H), 2.33-2.30 (m, 6H), 1.75-1.66 (m, 4H), 1.56-1.52 (m, 3H), 1.46-1.32 (m, 2H), 1.28 (s, 4H), 1.23-1.19 (m, 6H).

[0209] Example 22: Preparation of compound 9

[0210] Prepared according to the synthesis method of compound 8, only intermediate 5 was replaced by intermediate 6. MS m / z (ESI): 897.4014 (M+H) + .

[0211] Example 23: Preparation of compound 10

[0212] Prepared according to the synthesis method of compound 8, only intermediate 5 was replaced by intermediate 11. MS m / z (ESI): 887.3815 (M+H)+ .

[0213] Example 24: Preparation of compound 11

[0214] Prepared according to the synthetic procedure of compound 8, only replacing intermediate 5 with intermediate 12. MS m / z (ESI): 901.3967 (M+H) + .

[0215] Example 25: Preparation of compound 12

[0216] Prepared according to the synthetic procedure of compound 8, only replacing intermediate 5 with intermediate 7. MS m / z (ESI): 913.3973 (M+H) + .

[0217] Example 26: Preparation of compound 13

[0218] Prepared according to the synthetic procedure of compound 8, only replacing intermediate 5 with intermediate 8. MS m / z (ESI): 923.3637 (M+H) + .

[0219] Example 27: Preparation of compound 14

[0220] Prepared according to the synthetic procedure of compound 7, only replacing intermediate 2 with intermediate 5. MS m / z (ESI): 921.3825 (M+H) + .

[0221] Example 28: Preparation of compound 15

[0222] Synthetic route:

[0223] Step 1: Preparation of compound 15-1

[0224] Compound 5-bromo-4-fluoro-lH-indazole (1.5 g, 6.98 mmol) was weighed into a 150 mL reaction flask, stirred to dissolve in ethyl acetate (30 mL), and (C2H5)3OBF4 (1.99 g, 10.47 mmol) was added at room temperature. The reaction was stirred for about 3 h. TLC showed that the starting material 5-bromo-4-fluoro-lH-indazole was completely reacted. Saturated NaHCO3 solution (45 mL) was added to the reaction mixture, and the mixture was extracted and separated. The organic phase was washed with water (20 mL x 2) and saturated sodium chloride solution (20 mL x 2) in sequence, dried over anhydrous sodium sulfate, and concentrated to obtain compound 15-1 (1.62 g, yield 95.3%). It was used directly in the next step without purification.

[0225] The remaining steps were prepared according to the synthesis method of compound 8. The crude product was purified by preparative plate (DCM / MeOH = 20 / 1) to obtain compound 15 (128.5 mg, yield 43.7%). MS m / z (ESI): 899.4170 (M+H) + .

[0226] Example 29: Preparation of compound 16

[0227] Step 1: Preparation of compound 16-1

[0228] Compound 5-bromo-4-fluoro-lH-indazole (1.0 g, 4.65 mmol) was weighed into a 48 mL sealed tube, stirred to dissolve in DMF (10 mL), and potassium tert-butoxide (782.7 mg, 6.98 mmol) was added in portions. After stirring uniformly, 2-iodopropane (1.2 g, 6.98 mmol) was added, and the sealed tube was heated at 75°C overnight. TLC showed that the starting material 5-bromo-4-fluoro-lH-indazole was substantially completely reacted. Saturated brine (20 mL) and ethyl acetate (15 mL x 2) were added to the reaction mixture to extract, and the organic phase was washed with water (20 mL x 2) and saturated sodium chloride solution (20 mL x 2) in sequence, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. Silica gel column chromatography was used to purify to obtain compound 16-1 (316.8 mg, yield 26.5%).

[0229] The remaining steps were prepared according to the synthesis method of compound 8. The crude product was purified by preparative plate (DCM / MeOH = 20 / 1) to obtain compound 16 (138 mg, yield 45.6%). MS m / z (ESI): 913.4331 (M+H) + .

[0230] Example 30: Preparation of compound 17

[0231] Synthesis route:

[0232] Step 1: Preparation of compound 17-1

[0233] Compound intermediate 5 (262 mg, 0.59 mmol), intermediate 13 (301 mg, 1.18 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (126.0 mg, 0.89 mmol) and Na2CO3(125.3 mg, 1.18 mmol) were weighed into NMP (N-methyl pyrrolidone, 8 mL) and CuI (168.8 mg, 0.89 mmol) was added. The reaction mixture was replaced with nitrogen and stirred at 115 °C for about 6-7 h. TLC showed that intermediate 5 was substantially completely reacted. It was cooled to room temperature and filtered through celite. The filtrate was poured into water (20 mL) and extracted with ethyl acetate (15 mL x 3). The organic phase was washed with water (25 mL x 3) and saturated sodium chloride solution (25 mL x 3) successively, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (PE / EA = 70 / 30) to obtain compound 17-1 (210 mg, yield 57.6%).

[0234] Step 2: Preparation of compound 17-2

[0235] Compound 17-1 (210 mg, 0.34 mmol) was dissolved in DCM (2.0 mL) and HCl / dioxane (4 M, 1.0 mL) was added dropwise. The reaction mixture was stirred at 25 °C for about 4-5 h. TLC showed that the starting material disappeared. The excess solvent was removed under reduced pressure, 8.0 mL of water was added and the pH was adjusted to 8-9 with saturated NaHCO3. It was extracted with ethyl acetate (10 mL x 3), the organic phase was combined and washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 17-2 crude (175.0 mg, yield 99.4%), which was directly used in the next step.

[0236] Step 3: Preparation of compound 17

[0237] Compound SM01 (156 mg, 0.38 mmol) and compound 17-2 (175 mg, 0.34 mmol) were weighed into a 25 mL reaction vial, and DMF (6 mL) was added to stir and dissolve. HATU (196.2 mg, 0.51 mmol) was added to stir for 10 min, and DIPEA (266.8 mg, 2.06 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. TLC showed that the starting material SM01 disappeared, the reaction mixture was diluted with water (18 mL) and extracted with ethyl acetate (15 mL x 2), and the organic phase was combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative plate (DCM / MeOH = 20 / 1) to obtain compound 17 (187 mg, yield 60.4%). MS m / z (ESI): 911.4193 (M+H) + , 1 H NMR (400 MHz, DMSO-d6) δ 11.83 (s, 1H), 8.76 (s, 1H), 7.56-7.45 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.33-7.29 (m, 2H), 7.28-7.25 (m, 2H), 6.94 (s, 1H), 5.65 (d, J = 6.8 Hz, 1H), 4.36-4.33 (m, 1H), 4.21-4.16 (m, 1H), 3.94-3.87 (m, 2H), 3.72 (d, J = 8.4 Hz, 3H), 3.64-3.58 (m, 2H), 3.48 (s, 1H), 3.23-3.10 (m, 1H), 3.09-2.99 (m, 1H), 2.89-2.81 (m, 1H), 2.32-2.28 (m, 6H), 1.73-1.67 (m, 4H), 1.56-1.50 (m, 3H), 1.33-1.30 (m, 2H), 1.28 (s, 4H), 1.23-1.10 (m, 9H).

[0238] Example 31: Preparation of compound 18

[0239] Reference to the synthesis method of compound 17, intermediate 5 was replaced by intermediate 6. MS m / z (ESI): 923.4054 (M+H) + .

[0240] Example 32: Preparation of compound 19

[0241] Synthetic route:

[0242] Step 1: Preparation of compound 19-1

[0243] Compound 5-bromo-4-fluoro-lH-indazole (1.0 g, 4.65 mmol) was weighed into a 100 mL reaction flask, 1,2-dichloroethane (15 mL) was added to stir and dissolve, cooled in an ice bath, then cyclopropylboronic acid (599 mg, 6.98 mmol), Na2CO3(1.23 g, 11.63 mmol), copper acetate (1.27 g, 6.98 mmol), 2,2-bipyridine (1.45 g, 9.30 mmol) were added, slowly raised to room temperature, stirred for 48 h. TLC showed that the starting material 5-bromo-4-fluoro-lH-indazole was completely reacted, filtered with celite, the filtrate was concentrated under reduced pressure to obtain a residue, which was purified by silica gel column chromatography to obtain compound 19-1 (1.09 g, yield 92.0%). 1 HNMR (400 MHz, DMSO-d6) δ = 8.16 (d, J = 0.8 Hz, 1H), 7.61 (dd, J = 8.8, 6.4 Hz, 1H), 7.53 (dd, J = 8.8, 0.8 Hz, 1H), 3.84 - 3.79 (m, 1H), 1.18 - 1.08 (m, 4H).

[0244] Step 2: Preparation of compound 19-2

[0245] Compound intermediate 5 (200 mg, 0.451 mmol), compound 19-1 (287.60 mg, 1.13 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-l,2-diamine (96.44 mg, 0.678 mmol) and Na2CO3(95.80 mg, 0.904 mmol) were dissolved in NMP (10 mL), and Cul (129.13 mg, 0.678 mmol) was added. The reaction mixture was replaced with nitrogen, stirred at 115°C for about 8 h. TLC showed that there was a small amount of intermediate 5 left, cooled to room temperature, filtered with celite. The filtrate was poured into water (20 mL) and extracted with ethyl acetate (20 mL x 2), the organic phase was combined. The organic phase was washed with water (30 mL x 3) and saturated sodium chloride solution (30 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 19-2 (206.0 mg, yield 73.9%).

[0246] Step 3: Preparation of compound 19-3

[0247] Compound 19-2 (200 mg, 0.324 mmol) was dissolved in DCM (2.0 mL), and HCl / dioxane (4 M, 1.0 mL) was added dropwise. The reaction mixture was stirred at 25 °C for about 3 h. TLC showed that the starting material disappeared, the excess solvent was removed under reduced pressure, 10 mL of water was added, and the pH was adjusted to 8-9 with saturated NaHC03, and then extracted with ethyl acetate (8 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, concentrated to give compound 19-3 crude (148.0 mg, yield 88.3%), which was directly used in the next step.

[0248] Step 4: Preparation of compound 19

[0249] Compound SM01 (133.72 mg, 0.33 mmol) and compound 19-3 (130 mg, 0.25 mmol) were weighed in a 25 mL reaction bottle, and DMF (5 mL) was added to stir and dissolve. HATU (142.6 mg, 0.38 mmol) was added and stirred for 10 min, and DIPEA (193.86 mg, 1.50 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. TLC showed that the starting material SM01 disappeared, saturated NaCl solution (15 mL) was added to the reaction mixture and extracted with ethyl acetate (15 mL x 2), the organic phase was combined, and the organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative plate (DCM / MeOH = 20 / 1) to give compound 19 (170 mg, yield 74.8%). MS m / z (ESI): 911.4189 (M+H) + , 1H NMR (400 MHz, DMSO-d6) δ 11.82 (s, 1H), 8.22 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.54 - 7.78 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.31 (d, J = 6.0 Hz, 2H), 7.26 (d, J = 8.4 Hz, 1H), 6.94 (s, 1H), 5.65 (d, J = 7.2 Hz, 1H), 4.37 - 4.33 (m, 1H), 3.95 - 3.91 (m, 2H), 3.85 - 3.79 (m, 1H), 3.78 - 3.70 (m, 3H), 3.64 - 3.61 (m, 2H), 3.15 (s, 1H), 3.06 - 3.00 (m, 1H), 2.90 - 2.81 (m, 1H), 2.32 - 2.29 (m, 6H), 1.73 - 1.63 (m, 4H), 1.54 - 1.52 (m, 2H), 1.41 (s, 1H), 1.28 (s, 4H), 1.20 - 1.12 (m, 12H).

[0250] Example 33: Preparation of compound 20

[0251] Synthetic route:

[0252] Step 1: Preparation of compound 20-1

[0253] Compound intermediate 6 (178 mg, 0.392 mmol), compound 19-1 (200 mg, 0.784 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (84 mg, 0.588 mmol) and Na2CO3(104 mg, 0.98 mmol) were weighed into NMP (3 mL), and Cul (112 mg, 0.588 mmol) was added. The reaction mixture was replaced with nitrogen and stirred at 115 °C for about 8 h. TLC showed that intermediate 6 was substantially completely reacted, cooled to room temperature, and filtered with celite. The filtrate was poured into water (20 mL) and extracted with ethyl acetate (15 mL x 3), and the organic phases were combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 20-1 (182 mg, yield 73.8%).

[0254] Step 2: Preparation of compound 20-2

[0255] The compound 20-1 (182 mg, 0.289 mmol) from the previous step was dissolved in DCM (2.0 mL), and HCl / dioxane (4 M, 1.0 mL) was added dropwise. The reaction mixture was stirred at 25 °C for about 4 h. TLC showed that the starting material disappeared, the excess solvent was removed under reduced pressure, 10 mL of water was added, and the pH was adjusted to 8-9 with saturated NaHC03, and then extracted with ethyl acetate (8 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain compound 20-2 crude (143.0 mg, yield 93.6%), which was directly used in the next step.

[0256] Step 3: Preparation of compound 20

[0257] Compound SM01 (144 mg, 0.35 mmol) and compound 20-2 (143 mg, 0.27 mmol) were weighed into a 25 mL reaction bottle, and DMF (5 mL) was added to stir and dissolve. HATU (154 mg, 0.405 mmol) was added and stirred for 10 min, and DIPEA (209 mg, 1.62 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. TLC showed that the starting material SM01 disappeared, saturated NaCl solution (15 mL) was added to the reaction mixture and extracted with ethyl acetate (15 mL x 2), the organic phase was combined, and the organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative plate (DCM / MeOH = 20 / 1) to obtain compound 20 (194 mg, yield 77.8%). MS m / z (ESI): 923.4125 (M+H) + , 1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 8.22 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.54 (s, 1H), 7.51 - 7.47 (m, 1H), 7.42 - 7.33 (m, 3H), 7.26 (d, J = 8.8 Hz, 1H), 7.15 - 7.05 (m, 1H), 6.94 (s, 1H), 5.66 (d, J = 6.8 Hz, 1H), 4.37 - 4.34 (m, 1H), 3.94 - 3.90 (m, 1H), 3.85 - 3.79 (m, 1H), 3.73 - 3.70 (m, 4H), 3.61 - 3.58 (m, 2H), 3.46 (s, 1H), 3.14 - 3.11 (m, 1H), 3.07 - 3.00 (m, 1H), 2.86 - 2.82 (m, 1H), 2.16 - 2.11 (m, 1H), 1.83 - 1.64 (m, 5H), 1.55 - 1.53 (m, 2H), 1.28 - 1.20 (m, 5H), 1.22 - 1.13 (m, 10H), 1.07 - 1.02 (m, 2H), 0.76 - 0.72 (m, 2H).

[0258] Example 34: Preparation of compound 21

[0259] Synthetic route:

[0260] Step 1: Preparation of compound 21-1

[0261] Compound intermediate 11 (175 mg, 0.392 mmol), compound 19-1 (200 mg, 0.784 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (84 mg, 0.588 mmol) and Na2CO3(104 mg, 0.98 mmol) were weighed into NMP (3 mL), and Cul (112 mg, 0.588 mmol) was added. The reaction mixture was replaced with nitrogen and stirred at 115 °C for about 8 h. TLC showed that intermediate 11 was substantially completely reacted, and the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was poured into water (20 mL) and extracted with ethyl acetate (15 mL x 3), and the organic phases were combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 21-1 (184 mg, yield 75.8%).

[0262] Step 2: Preparation of compound 21-2

[0263] Compound 21-1 (182 mg, 0.297 mmol) was dissolved in DCM (2.0 mL), and HCl / dioxane (4 M, 1.0 mL) was added dropwise. The reaction mixture was stirred at 25 °C for about 4 h. TLC showed that the starting material disappeared, the excess solvent was removed under reduced pressure, 10 mL of water was added, and the pH was adjusted to 8-9 with saturated NaHC03, and then extracted with ethyl acetate (8 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain compound 21-2 crude (147.0 mg, yield 95.6%), which was directly used in the next step.

[0264] Step 3: Preparation of compound 21

[0265] Compound SM01 (151 mg, 0.368 mmol) and compound 21-2 (147 mg, 0.283 mmol) were weighed in a 25 mL reaction bottle, and DMF (5 mL) was added to stir and dissolve. HATU (161 mg, 0.425 mmol) was added and stirred for 10 min, and DIPEA (219 mg, 1.698 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. TLC showed that the starting material SM01 disappeared, saturated NaCl solution (15 mL) was added to the reaction mixture and extracted with ethyl acetate (15 mL x 2), the organic phase was combined, and the organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative plate (DCM / MeOH = 20 / 1) to obtain compound 21 (187 mg, yield 72.4%). MS m / z (ESI): 913.3963 (M+H) + .

[0266] Example 35: Preparation of compound 22

[0267] Synthetic route:

[0268] Step 1: Preparation of compound 22-1

[0269] Compound intermediate 12 (180 mg, 0.392 mmol), compound 19-1 (200 mg, 0.784 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (84 mg, 0.588 mmol) and Na2CO3(104 mg, 0.98 mmol) were weighed into NMP (3 mL), and CuI (112 mg, 0.588 mmol) was added. The reaction mixture was replaced with nitrogen and stirred at 115 °C for about 6 h. TLC showed that intermediate 12 was substantially completely reacted. The reaction mixture was cooled to room temperature and filtered through celite. The filtrate was poured into water (20 mL) and extracted with ethyl acetate (15 mL x 3), and the organic phases were combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 22-1 (193 mg, yield 77.8%).

[0270] Step 2: Preparation of compound 22-2

[0271] Compound 22-1 (193 mg, 0.304 mmol) was dissolved in DCM (2.0 mL), and HCl / dioxane (4 M, 1.0 mL) was added dropwise. The reaction mixture was stirred at 25 °C for about 3 h. TLC showed that the starting material disappeared. The excess solvent was removed under reduced pressure, 10 mL of water was added, and the pH was adjusted to 8-9 with saturated NaHCO3, and then extracted with ethyl acetate (8 mL x 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain compound 22-2 crude (158 mg, yield 97.6%), which was directly used in the next step.

[0272] Step 3: Preparation of compound 22

[0273] Compound SM01 (158 mg, 0.385 mmol) and compound 22-2 (158 mg, 0.296 mmol) were weighed into a 25 mL reaction bottle, and DMF (5 mL) was added to stir and dissolve. HATU (169 mg, 0.444 mmol) was added to stir for 10 min, and DIPEA (229 mg, 1.776 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. TLC showed that the starting material SM01 disappeared, saturated NaCl solution (15 mL) was added to the reaction mixture, and extracted with ethyl acetate (15 mL x 2), the organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative plate (DCM / MeOH = 20 / 1) to obtain compound 22 (197 mg, yield 71.8%). MS m / z (ESI): 927.4128 (M+H) + .

[0274] Example 36: Preparation of compound 23

[0275] Synthetic route:

[0276] Step 1: Preparation of compound 23-1

[0277] Compound intermediate 7 (185 mg, 0.392 mmol), compound 19-1 (200 mg, 0.784 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (84 mg, 0.588 mmol) and Na2CO3 (104 mg, 0.98 mmol) were dissolved in NMP (3 mL), and CuI (112 mg, 0.588 mmol) was added. The reaction mixture was replaced with nitrogen, and stirred at 115°C for about 7 h. TLC showed that intermediate 7 was substantially completely reacted, cooled to room temperature, and filtered with celite. The filtrate was poured into water (20 mL) and extracted with ethyl acetate (15 mL x 3), and the organic phase was combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 23-1 (180 mg, yield 71.3%).

[0278] Step 2: Preparation of compound 23-2

[0279] The compound 23-1 (180 mg, 0.279 mmol) from the previous step was dissolved in DCM (2.0 mL), and HCl / dioxane (4 M, 1.0 mL) was added dropwise. The reaction mixture was stirred at 25 °C for about 4 h. TLC showed that the starting material disappeared, the excess solvent was removed under reduced pressure, 10 mL of water was added, and the pH was adjusted to 8-9 with saturated NaHC03, and then extracted with ethyl acetate (8 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain compound 23-2 crude (144 mg, yield 94.6%), which was directly used in the next step.

[0280] Step 3: Preparation of compound 23

[0281] Compound SM01 (141 mg, 0.343 mmol) and compound 23-2 (158 mg, 0.264 mmol) were weighed into a 25 mL reaction bottle, and DMF (5 mL) was added to stir and dissolve. HATU (151 mg, 0.396 mmol) was added and stirred for 10 min, and DIPEA (205 mg, 1.584 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. TLC showed that the starting material SM01 disappeared, saturated NaCl solution (15 mL) was added to the reaction mixture and extracted with ethyl acetate (15 mL x 2), the organic phase was combined, and the organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative plate (DCM / MeOH = 20 / 1) to obtain compound 23 (190 mg, yield 69.9%). MS m / z (ESI): 939.4125 (M+H) + .

[0282] Example 37: Preparation of compound 24

[0283] Synthetic route:

[0284] Step 1: Preparation of compound 24-1

[0285] Compound intermediate 8 (189 mg, 0.392 mmol), compound 19-1 (200 mg, 0.784 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (84 mg, 0.588 mmol) and Na2CO3 (104 mg, 0.98 mmol) were weighed into NMP (3 mL), and CuI (112 mg, 0.588 mmol) was added. The reaction mixture was replaced with nitrogen and stirred at 115 °C for about 6 h. TLC showed that intermediate 8 was substantially reacted completely, and the mixture was cooled to room temperature and filtered with celite. The filtrate was poured into water (20 mL) and extracted with ethyl acetate (15 mL x 3), and the organic phases were combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 24-1 (188 mg, yield 73.2%).

[0286] Step 2: Preparation of compound 24-2

[0287] Compound 24-1 (188 mg, 0.287 mmol) was dissolved in DCM (2.0 mL), and HCl / dioxane (4 M, 1.0 mL) was added dropwise. The reaction mixture was stirred at 25 °C for about 3 h. TLC showed that the starting material disappeared, the excess solvent was removed under reduced pressure, 10 mL of water was added, and the pH was adjusted to 8-9 with saturated NaHCO3, and then extracted with ethyl acetate (8 mL x 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, and concentrated to obtain compound 24-2 crude product (153 mg, yield 96%), which was directly used in the next step.

[0288] Step 3: Preparation of compound 24

[0289] Compound SM01 (147 mg, 0.358 mmol) and compound 24-2 (153 mg, 0.275 mmol) were weighed into a 25 mL reaction bottle, and stirred and dissolved in DMF (5 mL). HATU (157 mg, 0.413 mmol) was added and stirred for 10 min, and DIPEA (213 mg, 1.65 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. TLC showed that the starting material SM01 disappeared, saturated NaCl solution (15 mL) was added to the reaction mixture and extracted with ethyl acetate (15 mL x 2), and the organic phases were combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative plate (DCM / MeOH = 20 / 1) to obtain compound 24 (202 mg, yield 77.3%). MS m / z (ESI): 949.3548 (M+H)+ .

[0290] Example 38: Preparation of compound 25

[0291] Synthetic route:

[0292] Step 1: Preparation of compound 25-1

[0293] Compound intermediate 1 (500 mg, 1.13 mmol), compound 19-1 (575.50 mg, 2.26 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (241.70 mg, 1.70 mmol) and Na2CO3 (240.17 mg, 2.26 mmol) were weighed into NMP (N-methyl pyrrolidone, 15 mL) and CuI (323.67 mg, 1.70 mmol) was added. The reaction mixture was replaced with nitrogen and stirred at 115 °C for about 6.0 h. TLC showed that a small amount of both starting materials remained, cooled to room temperature and filtered through celite. The filtrate was poured into water (30 mL) and extracted with ethyl acetate (15 mL x 3). The organic phase was washed with water (25 mL x 3) and saturated sodium chloride solution (25 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated and the crude product was purified by silica gel column chromatography to obtain compound 25-1 (380 mg, yield 54.6%).

[0294] Step 2: Preparation of compound 25-2

[0295] Compound 25-1 (380 mg, 0.62 mmol) was dissolved in DCM (4.0 mL) and HCl / dioxane (4 M, 2.0 mL) was added dropwise. The reaction mixture was stirred at 25 °C for about 4-5 h. TLC showed that the starting material disappeared, the excess solvent was removed under reduced pressure, 7.0 mL of water was added and the pH was adjusted to 8-9 with saturated NaHCO3, then extracted with ethyl acetate (8 mL x 3), the organic phase was combined and washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, concentrated to obtain compound 25-2 crude product (286.4 mg, yield 90.0%), which was directly used in the next step.

[0296] Step 3: Preparation of compound 25

[0297] Compound SM01 (288.0 mg, 0.70 mmol) and compound 25-2 (280 mg, 0.54 mmol) were weighed into a 25 mL reaction bottle, and DMF (7 mL) was added to stir and dissolve. HATU (308.0 mg, 0.81 mmol) was added to stir for 10 min, and DIPEA (418.74 mg, 3.24 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. TLC showed that the starting material SM01 disappeared, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 2), and the organic phase was combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative plate (DCM / MeOH = 20 / 1) to obtain compound 25 (147 mg, yield 30.0%). MS m / z (ESI): 909.3978 (M+H) + , 1 H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.28 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.57-7.48 (m, 2H), 7.41 (d, J = 8.4 Hz, 1H), 7.27 (d, J = 8.4 Hz, 1H), 7.19 (d, J = 6.4 Hz, 2H), 7.09 (s, 1H), 6.96 (s, 2H), 5.59 (d, J = 6.8 Hz, 1H), 4.41-4.37 (m, 1H), 3.89-3.83 (m, 1H), 3.73-3.71 (m, 2H), 3.64-3.61 (m, 1H), 3.23-3.17 (m, 1H), 3.07-3.00 (m, 1H), 2.91-2.88 (m, 1H), 2.27-2.23 (m, 6H), 1.73-1.64 (m, 4H), 1.44 (d, J = 6.4 Hz, 2H), 1.36-1.33 (m, 1H), 1.28 (s, 4H), 1.22-1.03 (m, 12H).

[0298] Example 39: Preparation of compound 26

[0299] Synthetic route:

[0300] Step 1: Preparation of compound 26-1

[0301] Compound intermediate 2 (178 mg, 0.392 mmol), compound 19-1 (200 mg, 0.784 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (84 mg, 0.588 mmol) and Na2CO3 (104 mg, 0.98 mmol) were weighed into NMP (3 mL), and CuI (112 mg, 0.588 mmol) was added. The reaction mixture was replaced with nitrogen and stirred at 115 °C for about 8 h. TLC showed that intermediate 2 was substantially reacted completely, and the reaction mixture was cooled to room temperature and filtered with celite. The filtrate was poured into water (20 mL) and extracted with ethyl acetate (15 mL x 3), and the organic phases were combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 26-1 (240 mg, yield 97.5%).

[0302] Step 2: Preparation of compound 26-2

[0303] The compound 26-1 (240 mg, 0.382 mmol) from the previous step was dissolved in DCM (5 mL), and HCl / dioxane (4 M, 1.5 mL) was added dropwise. The reaction mixture was stirred at room temperature for about 3 h. TLC showed that the starting material disappeared, the excess solvent was removed under reduced pressure, 10 mL of water was added, and the pH was adjusted to 8-9 with saturated NaHCO3, then extracted with ethyl acetate (8 mL x 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 26-2 crude (184 mg, yield 91.5%), which was directly used as the feedstock for the next step.

[0304] Step 3: Preparation of compound 26

[0305] Compound SM01 (187 mg, 0.454 mmol) and compound 26-2 (184 mg, 0.349 mmol) were weighed into a 25 mL reaction bottle, and DMF (5 mL) was added to stir and dissolve. HATU (199 mg, 0.524 mmol) was added and stirred for 10 min, and DIPEA (271 mg, 2.094 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. TLC showed that the starting material SM01 disappeared, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 2), and the organic phases were combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative plate (DCM / MeOH = 20 / 1) to obtain compound 26 (244 mg, yield 75.8%). MS m / z (ESI): 921.4014 (M+H)+ , 1 H NMR (400 MHz, DMSO-d6) δ 11.84 (s, 1H), 8.27 (s, 1H), 7.68 (d, J = 8.8 Hz, 1H), 7.54 - 7.47 (m, 2H), 7.40 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.8 Hz, 2H), 7.11 (s, 1H), 7.00 - 6.94 (m, 3H), 5.60 - 5.55 (m, 1H), 4.40 - 4.37 (m, 1H), 3.88 - 3.81 (m, 1H), 3.73 - 3.70 (m, 2H), 3.61 - 3.59 (m, 1H), 3.21 - 3.15 (m, 1H), 3.11 - 2.98 (m, 1H), 2.96 - 2.86 (m, 1H), 2.81 - 2.66 (m, 1H), 2.13 - 2.07 (m, 1H), 2.04 - 1.89 (m, 1H), 1.70 - 1.64 (m, 4H), 1.43 (d, J = 6.4 Hz, 2H), 1.27 (s, 5H), 1.21 - 1.13 (m, 10H), 1.03 - 1.00 (m, 2H), 0.70 - 0.61 (m, 2H).

[0306] Example 40: Preparation of compound 27

[0307] Synthetic route:

[0308] Step 1: Preparation of compound 27-1

[0309] Compound intermediate 9 (174 mg, 0.392 mmol), compound 19-1 (200 mg, 0.784 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (84 mg, 0.588 mmol) and Na2CO3 (104 mg, 0.98 mmol) were weighed into NMP (3 mL), and CuI (112 mg, 0.588 mmol) was added. The reaction mixture was replaced with nitrogen and stirred at 115 °C for about 8 h. TLC showed that intermediate 9 was substantially completely reacted, and the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was poured into water (20 mL) and extracted with ethyl acetate (15 mL x 3), and the organic phases were combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 27-1 (200 mg, yield 82.6%).

[0310] Step 2: Preparation of compound 27-2

[0311] Compound 27-1 (200 mg, 0.324 mmol) was dissolved in DCM (5 mL), and HCl / dioxane (4 M, 1.0 mL) was added dropwise. The reaction mixture was stirred at room temperature for about 2 h. TLC showed that the starting material disappeared, the excess solvent was removed under reduced pressure, 10 mL of water was added, and the pH was adjusted to 8-9 with saturated NaHC03, and then extracted with ethyl acetate (8 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 27-2 crude (160 mg, yield 95.5%), which was directly used in the next step.

[0312] Step 3: Preparation of compound 27

[0313] Compound SM01 (165 mg, 0.402 mmol) and compound 27-2 (160 mg, 0.309 mmol) were weighed into a 25 mL reaction bottle, and DMF (5 mL) was added to stir and dissolve. HATU (176 mg, 0.464 mmol) was added and stirred for 10 min, and DIPEA (240 mg, 1.854 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. TLC showed that the starting material SM01 disappeared, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 2), and the organic phase was combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative plate (DCM / MeOH = 20 / 1) to obtain compound 27 (185 mg, yield 65.9%). MS m / z (ESI): 911.3745 (M+H) + , 1H NMR (400 MHz, DMSO-d6) δ 11.78 (s, 1H), 8.27 (s, 1H), 7.66 (d, J = 8.8 Hz, 1H), 7.57 - 7.47 (m, 2H), 7.42 - 7.35 (m, 2H), 7.28 - 7.23 (m, 2H), 7.11 (s, 1H), 7.02 (s, 2H), 6.95 (s, 1H), 5.60 (d, J = 6.8 Hz, 1H), 4.41 - 4.38 (m, 1H), 3.88 - 3.81 (m, 4H), 3.73 - 3.71 (m, 2H), 3.65 - 3.61 (m, 1H), 3.25 - 3.21 (m, 1H), 3.07 - 3.00 (m, 1H), 2.98 - 2.89 (m, 1H), 1.74 - 1.64 (m, 4H), 1.45 (d, J = 6.4 Hz, 2H), 1.36 - 1.32 (m 1H), 1.28 (s, 4H), 1.22 - 1.09 (m, 12H).

[0314] Example 41: Preparation of compound 28

[0315] Synthetic route:

[0316] Step 1: Preparation of compound 28-1

[0317] Compound intermediate 10 (179 mg, 0.392 mmol), compound 19-1 (200 mg, 0.784 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (84 mg, 0.588 mmol) and Na2CO3(104 mg, 0.98 mmol) were weighed into NMP (3 mL), and Cul (112 mg, 0.588 mmol) was added. The reaction mixture was replaced with nitrogen and stirred at 115 °C for about 6 h. TLC showed that intermediate 10 was substantially completely reacted, and the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was poured into water (20 mL) and extracted with ethyl acetate (15 mL x 3), and the organic phases were combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 28-1 (194 mg, yield 78.5%).

[0318] Step 2: Preparation of compound 28-2

[0319] Compound 28-1 (194 mg, 0.307 mmol) was dissolved in DCM (5 mL), and HCl / dioxane (4 M, 1.0 mL) was added dropwise. The reaction mixture was stirred at room temperature for about 3 h. TLC showed that the starting material disappeared, the excess solvent was removed under reduced pressure, 10 mL of water was added, and the pH was adjusted to 8-9 with saturated NaHC03, and then extracted with ethyl acetate (8 mL x 3), the organic phase was combined, washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 28-2 crude (151 mg, yield 92.5%), which was directly used in the next step.

[0320] Step 3: Preparation of compound 28

[0321] Compound SM01 (152 mg, 0.369 mmol) and compound 28-2 (151 mg, 0.284 mmol) were weighed into a 25 mL reaction bottle, and DMF (5 mL) was added to stir and dissolve. HATU (162 mg, 0.426 mmol) was added and stirred for 10 min, and DIPEA (220 mg, 1.704 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. TLC showed that the starting material SM01 disappeared, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 2), and the organic phase was combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative plate (DCM / MeOH = 20 / 1) to obtain compound 28 (182 mg, yield 69.2%). MS m / z (ESI): 925.3945 (M+H) + .

[0322] Example 42: Preparation of compound 29

[0323] Synthetic route:

[0324] Step 1: Preparation of compound 29-1

[0325] Compound intermediate 3 (184 mg, 0.392 mmol), compound 19-1 (200 mg, 0.784 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (84 mg, 0.588 mmol) and Na2CO3 (104 mg, 0.98 mmol) were weighed into NMP (3 mL), and CuI (112 mg, 0.588 mmol) was added. The reaction mixture was replaced with nitrogen and stirred at 115 °C for about 6 h. TLC showed that intermediate 3 was substantially reacted completely, and the mixture was cooled to room temperature and filtered with celite. The filtrate was poured into water (20 mL) and extracted with ethyl acetate (15 mL x 3), and the organic phases were combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 29-1 (202 mg, yield 80.3%).

[0326] Step 2: Preparation of compound 29-2

[0327] The compound 29-1 (202 mg, 0.314 mmol) from the previous step was dissolved in DCM (5 mL), and HCl / dioxane (4 M, 1.0 mL) was added dropwise. The reaction mixture was stirred at room temperature for about 5 h. TLC showed that the starting material disappeared, the excess solvent was removed under reduced pressure, 10 mL of water was added, and the pH was adjusted to 8-9 with saturated NaHCO3, then extracted with ethyl acetate (8 mL x 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 29-2 crude (163 mg, yield 95.5%), which was directly used as the feedstock for the next step.

[0328] Step 3: Preparation of compound 29

[0329] Compound SM01 (160 mg, 0.390 mmol) and compound 29-2 (151 mg, 0.300 mmol) were weighed into a 25 mL reaction bottle, and DMF (5 mL) was added to stir and dissolve. HATU (171 mg, 0.450 mmol) was added and stirred for 10 min, and DIPEA (233 mg, 1.8 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. TLC showed that the starting material SM01 disappeared, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 2), and the organic phases were combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative plate (DCM / MeOH = 20 / 1) to obtain compound 29 (229 mg, yield 88.1%). MS m / z (ESI): 937.3946 (M+H)+ .

[0330] Example 43: Preparation of compound 30

[0331] Synthetic route:

[0332] Step 1: Preparation of compound 30-1

[0333] Compound intermediate 4 (188 mg, 0.392 mmol), compound 19-1 (200 mg, 0.784 mmol), (1S,2S)-(+)-N,N-dimethylcyclohexane-1,2-diamine (84 mg, 0.588 mmol) and Na2CO3(104 mg, 0.98 mmol) were weighed into NMP (3 mL), and CuI (112 mg, 0.588 mmol) was added. The reaction mixture was replaced with nitrogen and stirred at 115 °C for about 7 h. TLC showed that intermediate 4 was substantially completely reacted, and the reaction mixture was cooled to room temperature and filtered through celite. The filtrate was poured into water (20 mL) and extracted with ethyl acetate (15 mL x 3), and the organic phases were combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography to obtain compound 30-1 (198 mg, yield 77.4%).

[0334] Step 2: Preparation of compound 30-2

[0335] Compound 30-1 (198 mg, 0.303 mmol) was dissolved in DCM (5 mL), and HCl / dioxane (4 M, 1.0 mL) was added dropwise. The reaction mixture was stirred at room temperature for about 5 h. TLC showed that the starting material disappeared, and the excess solvent was removed under reduced pressure, 10 mL of water was added, and the pH was adjusted to 8-9 with saturated NaHCO3, and then extracted with ethyl acetate (8 mL x 3), and the organic phases were combined. The organic phase was washed with saturated sodium chloride solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated to obtain compound 30-2 crude product (162 mg, yield 96.5%), which was directly used as the next step feedstock.

[0336] Step 3: Preparation of compound 30

[0337] Compound SM01 (157 mg, 0.381 mmol) and compound 30-2 (162 mg, 0.293 mmol) were weighed into a 25 mL reaction bottle, and DMF (5 mL) was added to stir and dissolve. HATU (167 mg, 0.440 mmol) was added to stir for 10 min, and DIPEA (227 mg, 1.758 mmol) was added dropwise. After the dropwise addition was completed, the mixture was stirred at room temperature overnight. TLC showed that the starting material SM01 disappeared, the reaction mixture was diluted with water (15 mL) and extracted with ethyl acetate (15 mL x 2), and the organic phase was combined. The organic phase was washed with water (20 mL x 3) and saturated sodium chloride solution (20 mL x 3) in turn, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was purified by preparative plate (DCM / MeOH = 20 / 1) to obtain compound 30 (217 mg, yield 78.4%). MS m / z (ESI): 947.3625 (M+H) + , 1 H NMR (400 MHz, DMSO-d6) δ 11.77 (s, 1H), 8.27 (s, 1H), 7.68-7.59 (m, 2H), 7.54 (s, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.42-7.38 (m, 2H), 7.27 (d, J = 8.8 Hz, 1H), 7.13 (s, 1H), 7.05 (s, 1H), 6.95 (s, 1H), 5.66-5.54 (m, 1H), 4.42-4.38 (m, 1H), 4.13-4.09 (m, 2H), 3.88-3.85 (m, 1H), 3.73-3.64 (m, 3H), 3.07-3.02 (m, 1H), 2.92-2.90 (m, 1H), 2.79 (s, 1H), 1.68-1.63 (m, 4H), 1.44-1.40 (m, 2H), 1.28 (s, 4H), 1.19-1.14 (d, J = 5.7 Hz, 12H).

[0338] Comparative Example 1: Compound DB01

[0339] Compound DB01 is compound 67 in patent CN109790161B.

[0340] Comparative Example 2: Compound DB02

[0341] Compound DB02 is compound 73 in patent CN116390926A.

[0342] Experimental Example 1: In vitro activity experiment of compounds of the application

[0343] Experimental method:

[0344] GLP1R / CRE-LUC HEK293 cells (purchased from Nanjing Kebai) in logarithmic growth phase were digested with trypsin. The digested cells were resuspended in DMEM + 10% FBS medium, and the cell density was adjusted to 3.5*102. 5 / mL. Seed 100 μL / well in a 96-well cell culture plate and incubate the plate overnight (37°C, 5% CO2).

[0345] The test compounds were dissolved in DMSO and prepared into 10 mM or 2 mM stock solutions, then serially diluted 5-fold with DMSO to 10 concentration points. The 11th concentration point used as a control only required the addition of DMSO. 1 μL of each DMSO-diluted sample was then added to 99 μL of DMEM cell culture medium, mixed thoroughly, and 11 μL was transferred to a 96-well cell culture plate. The cell culture plate was incubated in an incubator for 5 hours (37°C, 5% CO2). The 96-well cell culture plate was then removed, and the following solution was added to each well: The luciferase reagent was gently mixed by pipetting and incubated at room temperature for 10 minutes. The chemiluminescence signal value was then measured using a microplate reader. The data were processed and analyzed using Microsoft Excel and GraphPad Prism 6 to obtain the EC50 of the compounds. 50 value.

[0346] Experimental results:

[0347] Table 1. Agonistaltic activity of the compounds on GLP1R / CRE-Luc / HEK293 cells.

[0348] Table 2. Agonistaltic activity of the compounds on GLP1R / CRE-Luc / HEK293 cells.

[0349] Tables 1 and 2 above show the results of two EC tests comparing compounds DB01 and DB02 from different batches of experiments. 50 The value is within the error range.

[0350] in conclusion:

[0351] The compounds of the present invention possess excellent biological activity. Compounds 1, 2, 3, 8, 19, and 21 of the embodiments of the present invention have good agonistic effects on GLP-1 receptors.

[0352] Experimental Example 2: In vivo pharmacodynamics experiment

[0353] Experimental methods:

[0354] Genetically engineered hGLP1R mice, male, purchased from Jiangsu Jinchihe Biotechnology Co., Ltd., the animals were fasted overnight before the glucose tolerance test (IPTGG) was carried out, and were not given water. A single dose of solvent or corresponding compound was orally administered, and 60 minutes after administration, a glucose solution (2 g / kg) was intraperitoneally injected. The blood glucose was measured before the administration of glucose (equivalent to the 0 min blood glucose value), and the blood glucose value was measured at 15 min, 30 min, 60 min and 120 min after the administration of glucose. The solvent was 5% DMSO + 40% PEG400 + 55% normal saline, and the compound dose was 0.3 mg / kg (n = 3).

[0355] Experimental results:

[0356] Conclusion:

[0357] As shown in Figures 1 and 2, the compounds 1 and 3 of the present application and the comparative compound DB01 and DB02 have a significant glucose-lowering effect at the same dose (0.3 mg / kg) of single oral administration, and the glucose curve (Figure 1) and the glucose AUC (0-120 min) (Figure 2) show that the compounds of the present application have a significantly better effect than the comparative compound DB02, and the effect is better than that of the comparative compound DB01; as shown in Figures 3 and 4, the compound 19 of the present application and the comparative compound DB01 and DB02 have a significant glucose-lowering effect at the same dose (0.3 mg / kg) of single oral administration, and the glucose curve (Figure 3) and the glucose AUC (0-120 min) (Figure 4) show that the compounds of the present application have a significantly better effect than the comparative compound DB02, and the effect is better than that of the comparative compound DB01.

[0358] Experimental Example 3: Weight loss efficacy test

[0359] Experimental method:

[0360] B-hGLP1R transgenic mice (Biosoft) were used in the experiment. First, 6 mice were randomly selected as a normal control group and fed with ordinary feed. The remaining transgenic mice were fed with high-fat feed (Research Diets) for 7 weeks to establish an obesity model. The successful model animals were randomly divided into a model control group, a positive control group (DB01-10 mg / kg), and a test product group (compound 19-10 mg / kg), with 7-8 mice in each group. After grouping, the normal control group and the model control group were given a solvent, and each test product group was given a corresponding test product. The mice were given a gavage once a day, and the gavage was administered continuously for 30 days, and the mice were weighed twice a week.

[0361] Experimental results:

[0362] As shown in Figure 5, when the compound 19 of the present application and the comparative compound DB01 were orally administered at the same dose (10 mg / kg) for multiple times (30 days), the weight loss of the comparative compound DB01 was 11.9% relative to the model group, and the weight loss of the compound 19 was 17.5% relative to the model group, as shown by the weight curve (0-30 days). The compound 19 of the present application has a significant weight loss effect, and the weight loss effect is better than that of the comparative compound DB01. The comparative compound DB01 entered the weight loss plateau at about the 20th day after administration, while the compound 19 of the present application still maintained a continuous weight loss trend within 30 days.

[0363] After the experimental period was extended to 8 weeks according to the above experimental method, the compound of the present application still had excellent in vivo biological activity. The weight loss effects of the compounds 1, 3, 8, 19 and 21 reached or exceeded 20%, and the weight loss effects of the compounds 1 and 19 even exceeded 30%.

[0364] Experimental Example 4: Pharmacokinetic experiment

[0365] Experimental method:

[0366] Three healthy male SD rats (Beijing Huafukang Biotechnology Co., Ltd., weighing 250-300 g) were selected per compound, and after overnight fasting, the rats were respectively given 10 mpk of the compound 1 or the comparative compound DB01 suspension (solvent: 10% DMSO / 10% Cremophor EL / 15% PEG400 / 65% 100 mM glycine-NaOH pH 10) by gavage, and the administration volume was 10 mL / kg. Before administration and at 0.5, 1, 2, 4, 8, 12, 24 and 48 h after administration, about 200 μL of whole blood was collected from the rat orbital venous plexus, placed in a centrifuge tube containing EDTA-K2 anticoagulant, then centrifuged at 3000-4000 rpm for 10 min, and the upper plasma was transferred to another clean centrifuge tube. The blood plasma samples were detected for blood drug concentration by LC-MS / MS method, and the pharmacokinetic parameters were calculated by non-compartment model. The results are shown in Table 3.

[0367] Table 3. Pharmacokinetic parameters of rats after oral administration

[0368] Conclusion: The pharmacokinetic results of SD rats after oral administration showed that under the same administration dose, the oral absorption of the compound 1 of the present application was better than that of the comparative compound DB01.

Claims

1. A compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, wherein: R1and R2are the same or different and each independently selected from the group consisting of a hydrogen atom, a Ci-C6alkyl group, a C3-C6cycloalkyl group, a C3-C6cycloalkyloxy group or a Ci-C6alkoxy group, wherein the Ci-C6alkoxy group is optionally substituted with 0 or one or more halogen atoms; Ring A is selected from: R3is selected from the group consisting of a Ci-C6alkyl group or a C3-C6cycloalkyl group, wherein the Ci-C6alkyl group is optionally substituted with 0 or one or more halogen atoms; is a single bond or a double bond; wherein, when when the double bond is in the (E) form, ring A is other than 2. The compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof according to claim 1, wherein, The compound of formula (I) has the structure shown below as formula (II), wherein: R1and R2are the same or different, and each independently selected from the group consisting of: a hydrogen atom, a methyl group, a methoxy group, an ethoxy group, a cyclopropyl group, R3is selected from the group consisting of a cyclopropyl group or a difluoromethyl group; wherein, when R1is selected from a hydrogen atom or a methyl group and R2is selected from a hydrogen atom or a methyl group, R3is not a difluoromethyl group.

3. The compound of claim 2, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, selected from any one of the following:

4. The compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof according to claim 1, wherein, The compound of formula (I) has the structure shown below as formula (III), wherein: R1and R2are the same or different, and each independently selected from the group consisting of: a hydrogen atom, a methyl group, a methoxy group, an ethoxy group, a cyclopropyl group, R3is selected from the group consisting of a methyl group, an ethyl group, an isopropyl group, a cyclopropyl group or a difluoromethyl group.

5. The compound of claim 4, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, selected from any one of the following:

6. The compound of Formula (I) or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof according to claim 1, wherein, The compound of formula (I) has the structure shown below as formula (IV), wherein: R1and R2are the same or different, and each independently selected from the group consisting of: a hydrogen atom, a methyl group, a methoxy group, an ethoxy group, a cyclopropyl group, 7. The compound of claim 6, or a pharmaceutically acceptable salt, stereoisomer, solvate, or hydrate thereof, selected from any one of the following:

8. A pharmaceutical composition comprising a compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, and a pharmaceutically acceptable excipient.

9. Use of a compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, or of a pharmaceutical composition according to claim 8, for the manufacture of a GLP-1 receptor agonist medicament.

10. Use according to claim 9, characterized in that, The GLP-1 receptor agonist medicament is a medicament for the treatment and / or prevention of diabetes mellitus type I, diabetes mellitus type II, malnutrition-related diabetes, hyperglycemia, diabetic complications, obesity, non-alcoholic steatohepatitis (NASH), insulin resistance, impaired glucose tolerance, hypertension, hyperlipidemia, arteriosclerosis, coronary heart disease, cerebral infarction, metabolic syndrome, Parkinson's disease and / or dementia.

11. Use of a compound according to any one of claims 1-7, or a pharmaceutically acceptable salt, stereoisomer, solvate or hydrate thereof, or of a pharmaceutical composition according to claim 8, for the manufacture of a GLP-1 receptor agonist.

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