N-oxalyl-D-phenylalanine compounds and ester prodrugs thereof, preparation methods, pharmaceutical compositions and applications

Abstract

The present invention discloses a N-oxalyl-D-phenylalanine compound and its ester prodrug, preparation method, pharmaceutical composition and application, wherein the N-oxalyl-D-phenylalanine compound is shown in the general formula (I). The present invention provides a series of highly selective and highly active FIH small molecule inhibitors and their prodrugs, which can selectively inhibit FIH activity and effectively reduce triglyceride content at the cellular and animal levels, and can be used to improve fat metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, and non-alcoholic fatty hepatitis. In addition, such FIH small molecule inhibitors are also expected to provide a molecular basis for the study of FIH molecular mechanism and pharmacological function, and to assist in the study of hypoxia response pathway regulation.

Description

Technical Field

[0001] The present invention relates to small molecule compounds, in particular to N-oxalyl-D-phenylalanine compounds and ester prodrugs thereof, preparation methods, pharmaceutical compositions and applications. Background Art

[0002] Adequate and continuous oxygen supply is the basis for the survival of living organisms. Hypoxia-inducible factor HIF-α is the main regulator of cellular oxygen homeostasis, and it is highly sensitive to changes in oxygen concentration. When the body is in a hypoxic state, HIF-α can stably exist and perform its transcription factor function; when in a normoxic state, HIF-α will be regulated by two major cellular oxygen receptors, prolyl hydroxylase (PHD) and asparaginyl hydroxylase, HIF inhibitor (FIH). FIH, as an Fe(II)-dependent oxygenase of the JmjC family, can catalyze the hydroxylation of a specific asparagine residue (Asn803) in the C-terminal transcription activation domain of the HIF-α subunit. This modification hinders the binding of HIF-α to the transcription coactivator p300 / CBP, thereby inhibiting the transcriptional activity of HIF. Compared with the hot research on PHD inhibitors, the research on FIH inhibitors has been neglected. However, FIH inhibitors deserve further in-depth study due to their unique regulatory functions, such as changing the body's metabolism and hypoxia response (J. Med. Chem. 2021, 64(11), 7189-7209.).

[0003] Studies have shown that FIH gene knockout or inhibition can cause significant changes in intracellular metabolism. The reduction of FIH is accompanied by an increase in oxidative metabolism, which means that FIH inhibition can provide a new means for the treatment of metabolic diseases. The lack of FIH can significantly reduce body weight and improve obesity (Cell Metab. 201011 (5): 364-378.). This is because the lack of FIH leads to an increase in oxygen consumption and calorie consumption by about 20%, and the metabolic rate is also significantly increased. At the same time, the lack of FIH also significantly reduces fat cells. For mice with fatty liver induced by a high-fat diet, the lack of FIH has a significant improvement and protective effect. Mice with FIH deficiency can show significantly lower triglyceride and cholesterol levels, and also have a significant improvement in liver hypertrophy (Cell Metab. 2018 27 (4): 898-913.). Therefore, FIH inhibitors can achieve the effect of treating fat metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, and non-alcoholic steatohepatitis by accelerating fat metabolism in the body.

[0004] At present, there are few reports on FIH inhibitors, especially FIH selective inhibitors. The only FIH selective inhibitor N-oxalyl-D-phenylalanine has poor FIH inhibitory activity and no cell activity (J.Am.Chem.Soc.2005,127(21),7680-7681.), which greatly limits the research on the regulatory function of FIH. (J.Med.Chem.2021,64(11),7189-7209.). Summary of the invention

[0005] Objectives of the invention: The objective of the present invention is to provide a highly selective and highly active N-oxalyl-D-phenylalanine compound or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, a prodrug thereof or a pharmaceutically acceptable salt thereof; another objective of the present invention is to provide a method for preparing an N-oxalyl-D-phenylalanine compound; another objective of the present invention is to provide a pharmaceutical composition; another objective of the present invention is to provide an application of an N-oxalyl-D-phenylalanine compound in the preparation of a FIH inhibitor.

[0006] Technical solution: The compound represented by the general formula (I) of the present invention or its mesomorph, racemate, enantiomer, diastereoisomer, or mixture thereof, its prodrug or pharmaceutically acceptable salt thereof,

[0007]

[0008] Where R 1 is hydrogen;

[0009] R 2 Selected from carboxyl, hydroxyl, carbamoyl, cyano, and five-membered aromatic hetero groups;

[0010] L 1 It is a connecting chain with a length of 0-3 atoms between Ar and the meta position of the benzene ring;

[0011] Ar is a monocyclic or bicyclic aromatic or heteroaromatic group having 5 to 10 ring members;

[0012] R 3 is one or more identical or different substituents on Ar, wherein the substituents are optionally selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 cycloalkyloxy, C1-C4 alkylamino, C1-C4 acyl, C1-C4 acylamino, carbamoyl, C1-C4 alkylcarbamoyl, C1-C4 sulfonyl, C1-C4 sulfonylamino, aminosulfonyl, C1-C4 alkylsulfamoyl, halogen, cyano, hydroxyl, and amino.

[0013] Further, Ar is selected from

[0014] Furthermore, the compound is selected from:

[0015]

[0016]

[0017] Further, the compounds according to formula (I) may contain acidic functional groups sufficient to form salts. Representative salts include pharmaceutically acceptable metal salts such as sodium, potassium, lithium, calcium, magnesium, aluminum and zinc salts; pharmaceutically acceptable metal cations such as carbonates and bicarbonates of sodium, potassium, lithium, calcium, magnesium, aluminum and zinc; pharmaceutically acceptable organic primary, secondary and tertiary amines, including aliphatic amines, aromatic amines, aliphatic diamines and hydroxyalkylamines, such as methylamine, ethylamine, 2-hydroxyethylamine, diethylamine, triethylamine, ethylenediamine, ethanolamine, diethanolamine.

[0018] Preferably, the prodrug is R 1 With R 2 Ester prodrugs formed on either or both sides.

[0019] Furthermore, the ester prodrug is selected from:

[0020]

[0021] In another aspect, the present invention provides a method for preparing the compound represented by the above-mentioned general formula (I) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, its prodrug or pharmaceutically acceptable salt thereof, wherein the method is any one of the following methods:

[0022] Method 1:

[0023]

[0024] The raw material II undergoes a condensation reaction with methyl oxalyl chloride under the alkaline condition of triethylamine to obtain an intermediate III; the intermediate III undergoes a coupling reaction under the condition of a catalyst to obtain a target compound or an intermediate IV; finally, the intermediate IV is hydrolyzed with lithium hydroxide to obtain the target compound;

[0025] Method 2:

[0026]

[0027] The raw material II undergoes a condensation reaction with benzyl oxalyl chloride under the alkaline condition of triethylamine to obtain an intermediate V; the intermediate V undergoes a coupling reaction under the catalysis of a catalyst to obtain an intermediate VI; finally, the intermediate VI is reduced with hydrogen and palladium on carbon to obtain the target compound;

[0028] Method 3:

[0029]

[0030] The raw material II is reduced with lithium aluminum hydride to obtain intermediate VII; intermediate VII undergoes condensation reaction with methyl chlorooxalyl under alkaline conditions of triethylamine to obtain intermediate VIII; intermediate VIII undergoes coupling reaction under catalyst conditions to obtain intermediate IX; finally, intermediate IX is hydrolyzed with lithium hydroxide to obtain the target compound;

[0031] Method 4:

[0032]

[0033] The raw material X is condensed with ammonia to obtain an intermediate XI; the intermediate XI is condensed with methyl chlorooxalyl under the alkaline condition of triethylamine to obtain an intermediate XII; the intermediate XIII is coupled under the condition of a catalyst to obtain an intermediate XIII; finally, the intermediate XIII is hydrolyzed with lithium hydroxide to obtain the target compound;

[0034] Method 5:

[0035]

[0036] The intermediate XI is dehydrated under the catalysis of trifluoroacetic anhydride to obtain the intermediate XIX; the intermediate XIX undergoes a condensation reaction with methyl chlorooxalyl under the alkaline condition of triethylamine to obtain the intermediate XX; the intermediate XX undergoes a coupling reaction under the condition of a catalyst to obtain the intermediate XXI; finally, the intermediate XXI is hydrolyzed with lithium hydroxide to obtain the target compound I or the intermediate XXII; the intermediate XXII undergoes a cycloaddition reaction with tetrabutylammonium fluoride to obtain the target compound I.

[0037] On the other hand, the present invention provides a pharmaceutical composition comprising the compound represented by the above-mentioned general formula (I) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, its prodrug or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0038] On the other hand, the present invention provides a compound represented by the above-mentioned general formula (I) or its mesomorph, racemate, enantiomer, diastereomer, or mixture thereof, its prodrug or pharmaceutically acceptable salt thereof, or the above-mentioned pharmaceutical composition for use in preparing FIH inhibitors. Specifically, in the preparation of a compound for inhibiting FIH to achieve hypoxic response, while accelerating fat metabolism and improving fat metabolic diseases, such as hyperlipidemia, hypercholesterolemia, non-alcoholic fatty liver disease, obesity, etc., it can achieve therapeutic effects by inhibiting FIH.

[0039] The clinical dosage of the compound of the present invention is 0.01 mg to 500 mg / day, and may deviate from this range depending on the severity of the disease or the dosage form.

[0040] On the other hand, the present invention provides a compound represented by the above general formula (I) or its racemate, racemate, enantiomer, diastereomer, or mixture thereof, its prodrug or pharmaceutically acceptable salt, or use of the above pharmaceutical composition in the preparation of a drug for treating diseases associated with FIH activity.

[0041] Preferably, the disease is selected from fat metabolic diseases, such as obesity, hyperlipidemia, hypercholesterolemia, non-alcoholic fatty liver disease, etc.

[0042] Beneficial effects: Compared with the prior art, the present invention has the following significant advantages: the compound of the present invention is a class of candidate compounds with FIH inhibitory activity in vivo and in vitro, which can selectively and efficiently inhibit FIH activity, thereby enhancing HIF transcriptional activity, playing a role in regulating hypoxic response, and accelerating fat metabolism, and is used to improve fat metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, non-alcoholic fatty hepatitis, etc. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Figure 1 The compounds of the present invention have the effect of improving fat metabolic diseases such as obesity, hyperlipidemia and fatty liver; (A) is a graph showing the weight changes of mice in each group; (B) is a graph showing the serum triglyceride content of mice in each group; (C) is a graph showing the liver triglyceride content of mice in each group. DETAILED DESCRIPTION

[0044] The technical solution of the present invention is further described below.

[0045] Typical compounds involved in the embodiments of the present invention include:

[0046]

[0047]

[0048]

[0049]

[0050]

[0051] Typical ester prodrugs of compounds involved in the embodiments of the present invention include:

[0052]

[0053]

[0054] The present invention provides a method for preparing the above typical compounds:

[0055] Method 1:

[0056]

[0057] The raw material II undergoes a condensation reaction with methyl chlorooxalyl under alkaline conditions of triethylamine to obtain intermediate III; intermediate III undergoes a coupling reaction in the presence of a catalyst to obtain the target compound (Examples 33-36, 45-47, 52-53) or intermediate IV; finally, intermediate IV is hydrolyzed with lithium hydroxide to obtain the target compound (Examples 1-32, 37-40).

[0058] Method 2:

[0059]

[0060] The raw material II undergoes a condensation reaction with benzyl chloride oxalyl under alkaline conditions of triethylamine to obtain intermediate V; intermediate V undergoes a coupling reaction under the catalysis of a catalyst to obtain intermediate VI; finally, intermediate VI is reduced with hydrogen and palladium on carbon to obtain the target compound (Examples 50-51).

[0061] Method 3:

[0062]

[0063] The raw material II is reduced with lithium aluminum hydride to obtain intermediate VII; intermediate VII undergoes condensation reaction with methyl oxalyl chloride under alkaline conditions of triethylamine to obtain intermediate VIII; intermediate VIII undergoes coupling reaction under catalytic conditions to obtain intermediate IX; finally, intermediate IX is hydrolyzed with lithium hydroxide to obtain the target compound (Example 41).

[0064] Method 4:

[0065]

[0066] The raw material X is condensed with ammonia to obtain intermediate XI; intermediate XI undergoes condensation reaction with methyl oxalyl chloride under alkaline conditions of triethylamine to obtain intermediate XII; intermediate XIII undergoes coupling reaction in the presence of a catalyst to obtain intermediate XIII; finally, intermediate XIII is hydrolyzed with lithium hydroxide to obtain the target compound (Example 42).

[0067] Method 5:

[0068]

[0069] Intermediate XI is dehydrated under the catalysis of trifluoroacetic anhydride to obtain intermediate XIX; intermediate XIX undergoes condensation reaction with methyl chlorooxalyl under alkaline conditions of triethylamine to obtain intermediate XX; intermediate XX undergoes coupling reaction under catalyst conditions to obtain intermediate XXI; finally, intermediate XXI is hydrolyzed with lithium hydroxide to obtain target compound I (Example 43) or intermediate XXII; intermediate XXII undergoes cycloaddition reaction with tetrabutylammonium fluoride to obtain target compound I (Example 44).

[0070] Wherein R represents hydrogen, C1-C4 aliphatic hydrocarbon such as methyl, ethyl, tert-butyl, or benzyl; A represents an aliphatic or aromatic N-containing heterocyclic ring; R 1 , R 2 , R 3 , L 1 , L 2 and Ar is as defined above.

[0071] Example

[0072] The following examples (Examples 1-40) were prepared using method 1.

[0073] Example 1: Preparation of I-1

[0074] (R)-2-amino-3-(3-bromophenyl)propionic acid (500 mg, 2.05 mmol) was dissolved in 10 mL methanol, 0.37 mL thionyl chloride was added under ice bath, stirred at room temperature for 30 min, heated to 80°C and stirred for 6 h, and the reaction was complete. After the reaction was completed, the organic solvent was removed by distillation under reduced pressure to obtain a light yellow solid, which was dissolved in 10 mL dichloromethane, 0.43 mL triethylamine was added, stirred at room temperature for 5 min, 0.22 mL methyl oxalyl chloride was added, stirred at room temperature for 30 min, and the reaction was complete. After the reaction is completed, add an appropriate amount of water to quench the reaction, extract with dichloromethane, take the organic layer, wash with saturated brine, dry with anhydrous sodium sulfate, and evaporate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain a white solid dissolved in 10mL tetrahydrofuran, add 67.15mg tetratriphenylphosphine palladium, 0.87mL of 2M potassium phosphate aqueous solution and phenylboric acid (78mg, 0.64mmol), and heat to 65℃ for 4h to complete the reaction. After the reaction is completed, remove the tetratriphenylphosphine palladium by suction filtration, and after reduced pressure distillation, the crude product is chromatographed on a silica gel column (petroleum ether: ethyl acetate = 2:1) to obtain a light yellow oily substance dissolved in 10mL tetrahydrofuran, add 3mL 1M lithium hydroxide solution, and heat to 30℃ for 2h to complete the reaction. After the reaction is completed, remove tetrahydrofuran from the reaction solution by reduced pressure distillation, add 3mmol dilute hydrochloric acid to pH 1-2, extract with ethyl acetate, take the organic layer, wash with saturated brine, and dry with anhydrous sodium sulfate. 103 mg of light yellow oil was obtained by distillation under reduced pressure, with a total yield of 54.1%. δ8.39 (s, 1H), 7.62 (d, J = 7.6 Hz, 2H), 7.48–7.42 (m, 3H), 7.34 (q, J = 8.0 Hz, 2H), 7.17 (d, J = 7.7 Hz, 1H), 4.37 (s, 1H), 3.19–3.15 (m, 2H).; EI-MS m / z: 313 [M] + .

[0075] Example 2: Preparation of I-2

[0076] The preparation method was the same as that of Example 1, except that 3-furanboric acid (78.03 mg, 0.70 mmol) was used to replace phenylboric acid (78 mg, 0.64 mmol) to obtain 98 mg of a light yellow oil with a total yield of 55.61%. δ8.91(d,J=8.4Hz,1H),8.12(t,J=1.2Hz,1H),7.74(t,J=1.7Hz,1H),7.49(d,J=1.8Hz,1H),7.45(dt,J=7.8,1.5Hz,1H),7.28–7. 24(m,1H),7.12(dt,J=7.6,1.4Hz,1H),6.93–6.90(m,1H),4.53–4.48(m,1H),3.15(d,J=2.7Hz,1H),3.08(d,J=4.0Hz,1H).; EI-MS m / z:303[M] + .

[0077] Example 3: Preparation of I-3

[0078] The preparation method was the same as that in Example 1, except that benzofuran-2-boronic acid (112.94 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 101 mg of a light yellow oil with a total yield of 49.44%. δ7.79 (d, J = 7.7 Hz, 2H), 7.58 (s, 1H), 7.49 (s, 2H), 7.34 (d, J = 7.8 Hz, 3H), 7.10 (d, J = 7.4 Hz, 1H), 4.05 (q, J = 7.2 Hz, 1H), 3.27-3.23 (m, 1H), 3.06 (d, J = 5.2 Hz, 1H).; EI-MS m / z: 353 [M] + .

[0079] Example 4: Preparation of I-4

[0080] The preparation method was the same as that in Example 1, except that 4-pyridineboronic acid (85.55 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 96 mg of a light yellow oil with a total yield of 52.22%. δ9.00 (s, 1H), 8.89–8.71 (m, 1H), 8.64 (s, 1H), 7.88 (d, J=5.8 Hz, 1H), 7.71 (s, 2H), 7.63–7.56 (m, 2H), 7.49–7.33 (m, 2H), 4.56 (s, 1H), 3.15 (s, 1H).; EI-MS m / z: 314 [M] + .

[0081] Example 5: Preparation of I-5

[0082] The preparation method was the same as that of Example 1, except that 2-methylphenylboronic acid (94.63 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 95 mg of a light yellow oil with a total yield of 50.04%. δ13.02(s,1H),8.95(d,J=8.4Hz,1H),7.35(t,J=7.6Hz,1H),7.28(d,J=2.0Hz,1H),7.26(dd,J=3.4,1.4Hz,1H),7.24(dt,J=5.1,2. 6Hz,2H),7.19(d,J=1.8Hz,1H),7.18–7.15(m,2H),4.55–4.49(m,1H),3.21(d,J=9.3Hz,1H),3.13–3.07(m,1H),2.18(s,3H).; EI-MS m / z:327[M] + .

[0083] Example 6: Preparation of I-6

[0084] The preparation method was the same as that of Example 1, except that 3-methylphenylboronic acid (94.63 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 87 mg of a light yellow oil with a total yield of 45.83%. δ13.01(s,1H),8.99(d,J=8.3Hz,1H),7.53(d,J=1.9Hz,1H),7.50–7.44(m,2H),7.42(d,J=8.0Hz,1H),7.35(q,J=7.5Hz,2H),7.2 2(d,J=7.6Hz,1H),7.18(d,J=7.4Hz,1H),4.52(dt,J=9.0,4.9Hz,1H),3.25–3.20(m,1H),3.17–3.11(m,1H),2.38(s,3H).; EI-MS m / z:327[M] + .

[0085] Example 7: Preparation of I-7

[0086] The preparation method is the same as that in Example 1, except that 4-methylphenylboronic acid (94.63 mg, 0.70 mmol) is used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 90 mg of a light yellow oil with a total yield of 47.41%. δ8.60 (s, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.43-7.39 (m, 2H), 7.24-7.21 (m, 3H), 7.06 (d, J = 7.8 Hz, 1H), 4.40 (s, 1H), 3.17-3.15 (m, 1H), 3.15-3.13 (m, 1H), 2.32 (s, 3H).; EI-MS m / z: 327 [M] + .

[0087] Example 8: Preparation of I-8

[0088] The preparation method was the same as that of Example 1, except that 3-pyridineboronic acid (85.55 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 91 mg of a light yellow oil with a total yield of 49.92%. δ8.94(d,J=8.4Hz,1H),8.87(d,J=2.5Hz,1H),8.57(d,J=4.7Hz,1H),8.05(d,J=7.9Hz,1H),7.62(s,1H),7.57(d,J=3.7Hz,1H),7.49(d d,J=8.0,4.7Hz,1H),7.42(t,J=7.6Hz,1H),7.29(d,J=7.6Hz,1H),4.60–4.47(m,1H),3.24(d,J=9.0Hz,1H),3.16–3.08(m,1H).; EI-MS m / z:314[M] + .

[0089] Example 9: Preparation of I-9

[0090] The preparation method is the same as that in Example 1, except that 2-pyridineboronic acid (85.55 mg, 0.70 mmol) is used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 94 mg of a light yellow oil with a total yield of 51.57%. δ7.68–7.52 (m, 2H), 7.43–7.36 (m, 2H), 7.28–7.19 (m, 3H), 6.90 (dd, J=21.2, 8.3 Hz, 1H), 4.02 (td, J=8.9, 8.2, 4.5 Hz, 1H), 3.05 (d, J=9.3 Hz, 1H), 2.82 (dd, J=13.7, 9.7 Hz, 1H).; EI-MS m / z: 314 [M] + .

[0091] Example 10: Preparation of I-10

[0092] The preparation method is the same as that in Example 1, except that 3-fluorophenylboronic acid (97.38 mg, 0.70 mmol) is used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 103 mg of a light yellow oil with a total yield of 53.60%. δ8.89 (d, J = 8.2 Hz, 1H), 8.05–6.71 (m, 8H), 4.54 (s, 1H), 3.23 (d, J = 13.6 Hz, 1H), 3.16–3.08 (m, 1H).; EI-MS m / z: 331 [M] + .

[0093] Example 11: Preparation of I-11

[0094] The preparation method is the same as that in Example 1, except that 3-chlorophenylboronic acid (108.83 mg, 0.70 mmol) is used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 105 mg of a light yellow oil with a total yield of 52.06%. δ8.93 (d, J = 8.4 Hz, 1H), 7.71 (t, J = 1.9 Hz, 1H), 7.64-7.59 (m, 2H), 7.55-7.47 (m, 2H), 7.44-7.36 (m, 2H), 7.27 (dt, J = 7.6, 1.4 Hz, 1H), 4.58-4.52 (m, 1H), 3.24 (d, J = 9.2 Hz, 1H), 3.13 (d, J = 3.9 Hz, 1H).; EI-MS m / z: 348 [M] + .

[0095] Example 12: Preparation of I-12

[0096] The preparation method was the same as that in Example 1, except that 3-methoxyphenylboronic acid (105.76 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 99 mg of a light yellow oil with a total yield of 49.71%. δ8.94 (d, J = 8.7 Hz, 1H), 7.56-7.48 (m, 2H), 7.36 (td, J = 7.8, 2.4 Hz, 2H), 7.24-7.15 (m, 3H), 6.93 (dd, J = 8.2, 2.6 Hz, 1H), 4.54 (td, J = 9.0, 4.2 Hz, 1H), 3.83 (s, 3H), 3.22 (t, J = 6.8 Hz, 1H), 3.13 (dd, J = 13.9, 9.9 Hz, 1H).; EI-MS m / z: 343 [M] + .

[0097] Example 13: Preparation of I-13

[0098] The preparation method was the same as that in Example 1, except that 3-hydroxyphenylboronic acid (96 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 94 mg of a light yellow oil with a total yield of 49.21%. δ9.55 (s, 1H), 7.65 (d, J = 1.3 Hz, 1H), 7.63 (s, 1H), 7.54 (dd, J = 3.0, 1.3 Hz, 1H), 7.47–7.41 (m, 2H), 7.34 (dd, J = 7.5, 3.5 Hz, 1H), 7.24–7.19 (m, 2H), 4.63 (s, 1H), 3.06 (d, J = 11.3 Hz, 1H), 2.82 (dd, J = 14.1, 10.4 Hz, 1H).; EI-MS m / z: 329 [M] + .

[0099] Example 14: Preparation of I-14

[0100] The preparation method was the same as that of Example 1, except that 3-(trifluoromethyl)phenylboronic acid (132.19 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 102 mg of a light yellow oil with a total yield of 46.12%. δ8.97(d,J=8.4Hz,1H),7.97(dd,J=6.9,2.0Hz,2H),7.74–7.65(m,3H),7.59(dt,J=7.7,1.4Hz,1H),7.41(t,J=7.6 Hz,1H),7.30(d,J=7.6Hz,1H),4.56(ddd,J=10.0,8.3,4.5Hz,1H),3.26(d,J=9.3Hz,1H),3.17–3.11(m,1H).; EI-MS m / z:381[M] + .

[0101] Example 15: Preparation of I-15

[0102] The preparation method is the same as that of Example 1, except that 3-nitrobenzeneboronic acid (116.18 mg, 0.70 mmol) is used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 98 mg of a light yellow oil with a total yield of 47.16%. δ8.97 (d, J = 8.3 Hz, 1H), 8.45 (d, J = 2.3 Hz, 1H), 8.26-8.12 (m, 2H), 7.78-7.61 (m, 3H), 7.43 (t, J = 7.5 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 4.62-4.52 (m, 1H), 3.27 (dd, J = 13.9, 4.6 Hz, 1H), 3.15 (dd, J = 13.8, 9.9 Hz, 1H).; EI-MS m / z: 358 [M]+ .

[0103] Example 16: Preparation of I-16

[0104] The preparation method was the same as that of Example 1, except that 3-acetylphenylboronic acid (114.12 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 101 mg of a light yellow oil with a total yield of 49.00%. δ8.99(d,J=8.4Hz,1H),8.18(q,J=1.7Hz,1H),7.93(ddt,J=13.2,6.5,1.5Hz,2H),7.65–7.57(m,3H),7.41(td,J=7.4,1 .8Hz,1H),7.31–7.26(m,1H),4.56(td,J=9.3,4.4Hz,1H),3.26(d,J=9.3Hz,1H),3.18–3.12(m,1H),2.67(s,3H).; EI-MS m / z:355[M] + .

[0105] Example 17: Preparation of I-17

[0106] The preparation method is the same as that in Example 1, except that 3-biphenylboronic acid (137.83 mg, 0.70 mmol) is used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 107 mg of a light yellow oil with a total yield of 47.37%. δ8.97 (d, J = 8.4 Hz, 1H), 7.90 (s, 1H), 7.77 (d, J = 7.6 Hz, 2H), 7.68–7.48 (m, 7H), 7.44–7.36 (m, 2H), 7.26 (d, J = 7.6 Hz, 1H), 4.57 (ddd, J = 9.9, 8.3, 4.5 Hz, 1H), 3.26 (dd, J = 13.9, 4.6 Hz, 1H), 3.16 (dd, J = 13.9, 9.9 Hz, 1H).; EI-MS m / z: 389 [M] + .

[0107] Example 18: Preparation of I-18

[0108] The preparation method was the same as that of Example 1, except that 3-cyanophenylboronic acid (102.27 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 96 mg of a light yellow oil with a total yield of 48.92%. δ8.98(d,J=8.4Hz,1H),8.14(t,J=1.7Hz,1H),8.03–7.98(m,1H),7.82(dt,J=7.7,1.3Hz,1H),7.69–7.58(m,3H),7.41(t,J=7.6Hz,1H EI-MS m / z:338[M] + .

[0109] Example 19: Preparation of I-19

[0110] The preparation method is the same as that in Example 1, except that 3-tert-butylphenylboronic acid (123.92 mg, 0.70 mmol) is used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 102 mg of a light yellow oil with a total yield of 47.64%. δ8.91 (d, J = 8.3 Hz, 1H), 7.60 (d, J = 2.0 Hz, 1H), 7.54-7.47 (m, 2H), 7.42-7.35 (m, 4H), 7.22 (d, J = 7.7 Hz, 1H), 4.54 (dt, J = 8.8, 4.4 Hz, 1H), 3.25-3.21 (m, 1H), 3.18-3.12 (m, 1H), 1.34 (s, 9H).; EI-MS m / z: 369 [M] + .

[0111] Example 20: Preparation of I-20

[0112] The preparation method is the same as that in Example 1, except that 1-naphthaleneboric acid (119.71 mg, 0.70 mmol) is used to replace phenylboric acid (78 mg, 0.64 mmol) to obtain 99 mg of a light yellow oil with a total yield of 46.98%. δ8.94 (d, J = 8.4 Hz, 1H), 8.02–7.93 (m, 2H), 7.79 (d, J = 8.3 Hz, 1H), 7.59–7.40 (m, 5H), 7.37–7.30 (m, 3H), 4.56 (td, J = 9.0, 4.3 Hz, 1H), 3.27–3.23 (m, 1H), 3.15 (dd, J = 13.9, 9.8 Hz, 1H).; EI-MS m / z: 363 [M] + .

[0113] Example 21: Preparation of I-21

[0114] The preparation method is the same as that of Example 1, except that 3-(trifluoromethoxy)phenylboronic acid (143.33 mg, 0.70 mmol) is used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 105 mg of a light yellow oil with a total yield of 46.36%. δ 9.01 (d, J = 8.4 Hz, 1H), 7.71 (dt, J = 7.9, 1.3 Hz, 1H), 7.64–7.54 (m, 4H), 7.42–7.35 (m, 2H), 7.29 (d, J = 7.7 Hz, 1H), 4.55 (td, J = 9.0, 8.4, 4.5 Hz, 1H), 3.25 (dd, J = 13.8, 4.5 Hz, 1H), 3.18–3.13 (m, 1H).; EI-MS m / z: 397 [M] + .

[0115] Example 22: Preparation of I-22

[0116] The preparation method is the same as that in Example 1, except that 3-ethylphenylboronic acid (104.39 mg, 0.70 mmol) is used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 97 mg of a light yellow oil with a total yield of 48.99%. δ8.99 (d, J = 8.1 Hz, 1H), 7.54 (s, 1H), 7.50–7.34 (m, 5H), 7.23 (q, J = 7.7, 7.0 Hz, 2H), 4.54 (td, J = 9.0, 4.3 Hz, 1H), 3.24 (dd, J = 13.8, 4.5 Hz, 1H), 3.15 (dd, J = 8.9, 5.4 Hz, 1H), 2.67 (q, J = 7.5 Hz, 2H), 1.23 (t, J = 7.6 Hz, 3H).; EI-MS m / z: 341 [M] + .

[0117] Example 23: Preparation of I-23

[0118] The preparation method is the same as that in Example 1, except that 3-isopropylphenylboronic acid (114.15 mg, 0.70 mmol) is used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 95 mg of a light yellow oil with a total yield of 46.09%. δ 9.00 (d, J = 8.4 Hz, 1H), 7.55 (t, J = 1.8 Hz, 1H), 7.48 (p, J = 2.2 Hz, 2H), 7.43-7.34 (m, 3H), 7.25-7.22 (m, 2H), 4.55 (ddd, J = 9.7, 8.3, 4.5 Hz, 1H), 3.25 (dd, J = 13.9, 4.5 Hz, 1H), 3.19-3.14 (m, 1H), 1.26 (d, J = 6.9 Hz, 6H).; EI-MS m / z: 355 [M] + .

[0119] Example 24: Preparation of I-24

[0120] The preparation method was the same as that of Example 1, except that 3-methylsulfonylphenylboronic acid (139.21 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 107 mg of a light yellow oil with a total yield of 48.41%. δ9.05(d,J=8.4Hz,1H),8.17(s,1H),8.02(d,J=8.4Hz,1H),7.92(d,J=8.0H z,1H),7.75(t,J=7.8Hz,1H),7.68(s,1H),7.61(d,J=7.9Hz,1H),7.43(t,J =7.7Hz,1H),7.32(d,J=7.6Hz,1H),4.57(ddd,J=10.2,8.3,4.5Hz,1H),3.3 1(s,3H),3.29–3.24(m,1H),3.17(dd,J=9.5,4.4Hz,1H).;EI-MSm / z:391[M] + .

[0121] Example 25: Preparation of I-25

[0122] The preparation method was the same as that of Example 1, except that 3,5-dichlorophenylboronic acid (132.81 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 103 mg of a light yellow oil with a total yield of 46.38%. δ8.99(d,J=8.3Hz,1H),7.73(d,J=1.9Hz,2H),7.66(s,1H),7.62–7.56(m,2H),7.39(t,J=7.7Hz,1H),7.30(d,J=7 .6Hz, 1H), 4.56 (ddd, J=10.2, 8.4, 4.4Hz, 1H), 3.24 (dd, J=13.8, 4.5Hz, 1H), 3.13 (dd, J=10.5, 3.7Hz, 1H).; EI-MS m / z:382[M] + .

[0123] Example 26: Preparation of I-26

[0124] The preparation method was the same as that of Example 1, except that 3,5-difluorophenylboric acid (109.91 mg, 0.70 mmol) was used to replace phenylboric acid (78 mg, 0.64 mmol) to obtain 99 mg of a light yellow oil with a total yield of 48.87%. δ8.99(d,J=8.4Hz,1H),7.65(s,1H),7.59(d,J=7.7Hz,1H),7.41(dd,J=9.7,7.2Hz,3H),7.30(d,J=7.6Hz,1H),7.23( dd,J=9.1,6.5Hz,1H),4.55(td,J=9.3,4.4Hz,1H),3.24(dd,J=13.8,4.5Hz,1H),3.13(dd,J=9.2,4.6Hz,1H).; EI-MS m / z:349[M] + .

[0125] Example 27: Preparation of I-27

[0126] The preparation method was the same as that in Example 1, except that 3-chloro-5-methylphenylboronic acid (118.60 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 98 mg of a light yellow oil with a total yield of 46.70%. δ8.96 (d, J = 8.4 Hz, 1H), 7.58 (s, 1H), 7.55-7.47 (m, 2H), 7.44 (s, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.26 (s, 2H), 4.54 (td, J = 9.2, 4.4 Hz, 1H), 3.23 (dd, J = 13.8, 4.5 Hz, 1H), 3.12 (dd, J = 13.8, 10.0 Hz, 1H), 2.38 (s, 3H).; EI-MS m / z: 362 [M] + .

[0127] Example 28: Preparation of I-28

[0128] The preparation method was the same as that in Example 1, except that 3-fluoro-5-methylphenylboronic acid (107.15 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 95 mg of a light yellow oil with a total yield of 47.48%. δ8.97 (d, J = 8.4 Hz, 1H), 7.62–7.49 (m, 2H), 7.40–7.23 (m, 4H), 7.02 (d, J = 9.8 Hz, 1H), 4.54 (td, J = 9.3, 4.4 Hz, 1H), 3.24 (dd, J = 13.8, 4.5 Hz, 1H), 3.13 (dd, J = 13.8, 10.0 Hz, 1H), 2.39 (s, 3H).; EI-MS m / z: 345 [M] + .

[0129] Example 29: Preparation of I-29

[0130] The preparation method was the same as that in Example 1, except that 3-chloro-5-isopropylphenylboronic acid (138.12 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 106 mg of a light yellow oil with a total yield of 46.87%. δ8.97 (d, J = 8.8 Hz, 1H), 7.71 (s, 1H), 7.60 (s, 1H), 7.48 (d, J = 9.0 Hz, 2H), 7.41-7.35 (m, 2H), 7.28 (s, 1H), 4.57-4.53 (m, 1H), 3.23 (s, 1H), 3.15 (d, J = 10.8 Hz, 1H), 3.02-2.95 (m, 1H), 1.25 (d, J = 6.5 Hz, 6H).; EI-MS m / z: 390 [M] + .

[0131] Example 30: Preparation of I-30

[0132] The preparation method was the same as that in Example 1, except that 3-fluoro-5-isopropylphenylboronic acid (126.67 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 103 mg of a light yellow oil with a total yield of 47.56%. δ 9.02 (d, J = 10.6 Hz, 1H), 7.60–7.47 (m, 3H), 7.35 (s, 1H), 7.26 (d, J = 9.8 Hz, 2H), 7.08 (d, J = 9.6 Hz, 1H), 4.51 (d, J = 11.4 Hz, 1H), 3.22 (s, 1H), 3.14 (d, J = 4.1 Hz, 1H), 3.01–2.95 (m, 1H), 1.25 (d, J = 6.9 Hz, 6H).; EI-MS m / z: 373 [M] + .

[0133] Example 31: Preparation of I-31

[0134] The preparation method is the same as that in Example 1, except that 2-fluoro-5-methylphenylboronic acid (107.15 mg, 0.70 mmol) is used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 103 mg of a light yellow oil with a total yield of 51.45%. δ8.94 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 7.30 (d, J = 7.3 Hz, 1H), 7.24 (d, J = 10.6 Hz, 3H), 7.10 (t, J = 7.4 Hz, 1H), 6.99 (d, J = 9.7 Hz, 1H), 4.55-4.49 (m, 1H), 3.22 (dd, J = 13.9, 4.5 Hz, 1H), 3.15-3.10 (m, 1H), 2.15 (s, 3H).; EI-MS m / z: 345 [M] + .

[0135] Example 32: Preparation of I-32

[0136] The preparation method was the same as that of Example 1, except that 2-chloro-5-methylphenylboronic acid (107.15 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 103 mg of a light yellow oil with a total yield of 51.45%. δ8.95(d,J=8.4Hz,1H),7.36(t,J=7.6Hz,1H),7.32(d,J=1.4Hz,2H),7.26(d,J=7.8Hz,1H),7.20(t,J=8.4Hz,3H),4 .54(ddd,J=10.0,8.4,4.5Hz,1H),3.22(dd,J=13.8,4.5Hz,1H),3.11(dd,J=13.8,10.0Hz,1H),2.16(s,3H).; EI-MS m / z:362[M] + .

[0137] Example 33: Preparation of I-33

[0138] The preparation method is the same as that of Example 1, except that (R)-2-(3-bromophenyl)-1-furan-3-yl)ethylamine (500 mg, 1.88 mmol) is used to replace (R)-2-amino-3-(3-bromophenyl)propionic acid (500 mg, 2.05 mmol), and (3-acetyl-5-carbamoylphenyl)boric acid (411.91 mg, 1.99 mmol) is used to replace phenylboric acid (78 mg, 0.64 mmol) to obtain 127 mg of a light yellow oil with a total yield of 47.63%. 1 H NMR(500MHz,Chloroform-d)δ8.26(t,J=2.1Hz,1H),8.17(dt,J=11.9,2.2Hz,2 H),7.77(d,J=8.6Hz,1H),7.55–7.47(m,2H),7.44(dd,J=1.8,0.9Hz,2H),7.40( t,J=1.6Hz,1H),7.39(s,2H),7.26(dtt,J=6.4,2.0,1.1Hz,1H),6.32(t,J=1.1 Hz, 1H), 5.11 (dt, J=8.8, 6.4Hz, 1H), 3.04 (qdt, J=14.1, 6.4, 0.9Hz, 2H).; EI-MS m / z:420[M] + .

[0139] Example 34: Preparation of I-34

[0140] The preparation method was the same as that of Example 1, except that (R)-2-(3-bromophenyl)-1-(1H-imidazol-4-yl)ethane-1-amine (500 mg, 1.88 mmol) was used to replace (R)-2-amino-3-(3-bromophenyl)propionic acid (500 mg, 2.05 mmol), and (3-(isopropylamino)-5-aminosulfonylphenyl)boric acid (513.62 mg, 1.99 mmol) was used to replace phenylboric acid (78 mg, 0.64 mmol) to obtain 125 mg of a light yellow oil with a total yield of 44.78%. 1 H NMR(500MHz,Chloroform-d)δ8.27(d,J=8.8Hz,1H),7.96(t,J=2.1Hz,1H),7.74(dd,J=5.9,1.7Hz,1H),7.58(ddd,J=7 .7,1.9,1.2Hz,1H),7.54–7.47(m,2H),7.33(d,J=9.3Hz,1H),7.30(dd,J=4.9,1.6Hz,1H),7.28–7.21(m,2H),7.12(t, J=2.1Hz,1H),6.94(t,J=2.2Hz,1H),6.77(dd,J=6.0,4.9Hz,1H),5.45(dt,J=8.6,6.4Hz,1H),5.01(d,J=7.5Hz,1H),3 .63(dhept,J=7.5,6.2Hz,1H),3.25(qdt,J=15.6,6.6,1.1Hz,2H),1.20(d,J=6.2Hz,3H),1.15(d,J=6.2Hz,3H).; EI-MS m / z:472[M] + .

[0141] Example 35: Preparation of I-35

[0142] The preparation method was the same as that of Example 1, except that (R)-2-(3-bromophenyl)-1-isoxazol-4-yl)ethane-1-amine (500 mg, 1.87 mmol) was used to replace (R)-2-amino-3-(3-bromophenyl)propionic acid (500 mg, 2.05 mmol), and 3-(methylcarbamoyl)-5-(N-methylaminosulfonyl)phenyl)boric acid (527.39 mg, 1.94 mmol) was used to replace phenylboric acid (78 mg, 0.64 mmol) to obtain 130 mg of a light yellow oil with a total yield of 46.21%. 1H NMR(500MHz,Chloroform-d)δ8.60(d,J=1.6Hz,1H),8.38(d,J=1.8Hz,1H),8.20(p,J=2.2Hz,2H),8.17(t,J=2.2Hz,1H),8.05(q,J=5.1Hz,1H),7.85(d,J =9.2Hz,1H),7.59(dt,J=7.8,1.5Hz,1H),7.54–7.47(m,2H),7.26(ddq,J=7. 9,2.0,1.0Hz,1H),6.80(q,J=6.8Hz,1H),5.28(dt,J=9.2,6.8Hz,1H),3.12–

[0143] 2.99(m,2H),2.93(d,J=5.1Hz,3H),2.58(d,J=6.6Hz,3H).;EI-MS m / z:486[M] + .

[0144] Example 36: Preparation of I-36

[0145] The preparation method is the same as that of Example 1, except that (R)-2-(3-bromophenyl)-1-oxazol-4-yl)ethylamine (500 mg, 1.87 mmol) is used to replace (R)-2-amino-3-(3-bromophenyl)propionic acid (500 mg, 2.05 mmol), and (3-acetylamino-5-(methylsulfonyl)phenyl)boric acid (532.28 mg, 1.95 mmol) is used to replace phenylboric acid (78 mg, 0.64 mmol) to obtain 133 mg of a light yellow oil with a total yield of 47.32%. 1 H NMR(500MHz,Chloroform-d)δ9.25(s,1H),8.31(s,1H),7.95(d,J=1.6Hz,1H),7.83(d,J=8.6Hz,1H),7.59–7.54(m,2H),7.54–7.47(m,2H),7.43(dt,J= 8.1,2.2Hz,2H),7.39(t,J=2.2Hz,1H),7.27(ddt,J=6.9,2.2,1.1Hz,1H),5 .27(dt,J=8.6,6.3Hz,1H),3.17(dq,J=6.4,1.0Hz,2H),2.94(s,2H).; EI-MS m / z:486[M] + .

[0146] Example 37: Preparation of I-37

[0147] (R)-2-amino-3-(3-bromophenyl)propionic acid (500 mg, 2.05 mmol) was dissolved in 10 mL methanol, 0.37 mL thionyl chloride was added under ice bath, stirred at room temperature for 30 min, heated to 80°C and stirred for 6 h, and the reaction was complete. After the reaction was completed, the organic solvent was removed by distillation under reduced pressure to obtain a light yellow solid, which was dissolved in 10 mL dichloromethane, 0.43 mL triethylamine was added, stirred at room temperature for 5 min, 0.22 mL methyl oxalyl chloride was added, stirred at room temperature for 30 min, and the reaction was complete. After the reaction is completed, add an appropriate amount of water to quench the reaction, extract with dichloromethane, take the organic layer, wash with saturated brine, dry with anhydrous sodium sulfate, and evaporate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1) to obtain a white solid dissolved in 10 mL of toluene, add 13.05 mg of palladium acetate, 72.37 mg of BINAP, 378.68 mg of cesium carbonate and benzylamine (124.54 mg, 1.16 mmol), and conventionally heat to 110 ° C, react overnight, and the reaction is complete. After the reaction is completed, remove the palladium acetate by suction filtration, and after reduced pressure distillation, the crude product is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1) to obtain a light yellow oily substance dissolved in 10 mL of tetrahydrofuran, add 3 mL of 1M lithium hydroxide solution, and heat to 30 ° C for 2 h to complete the reaction. After the reaction, tetrahydrofuran was removed from the reaction solution by vacuum distillation, 3 mmol of dilute hydrochloric acid was added to pH 1-2, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. 72 mg of light yellow oil was obtained by vacuum distillation with a total yield of 36.2%. δ7.36–7.21 (m, 5H), 7.12 (q, J = 8.1 Hz, 1H), 6.72 (ddd, J = 33.5, 19.0, 8.7 Hz, 3H), 4.55 (s, 1H), 4.30 (d, J = 12.8 Hz, 2H), 3.07 (dd, J = 14.0, 4.6 Hz, 1H), 2.87 (dd, J = 13.8, 7.8 Hz, 1H).; EI-MS m / z: 342 [M] + .

[0148] Example 38: Preparation of I-38

[0149] The preparation method was the same as that of Example 37, except that benzylamine (124.54 mg, 1.16 mmol) was replaced by benzamide (140.52 mg, 1.16 mmol) to obtain 88 mg of a light yellow oil with a total yield of 42.58%. δ10.25(s,1H),8.96(d,J=8.2Hz,1H),7.97(d,J=7.4Hz,2H),7.72(s,1H),7.65(t,J=7.9Hz,2H),7.57(d,J=7.3Hz, 2H), 7.28 (t, J=7.8Hz, 1H), 7.01 (d, J=7.5Hz, 1H), 4.51 (td, J=8.9, 4.9Hz, 1H), 3.14 (dd, J=11.9, 7.1Hz, 2H).; EI-MS m / z:356[M] + .

[0150] Example 39: Preparation of I-39

[0151] The preparation method was the same as that of Example 37, except that benzylamine (124.54 mg, 1.16 mmol) was replaced by methylbenzylamine (140.57 mg, 1.16 mmol) to obtain 89 mg of a light yellow oil with a total yield of 44.59%. δ8.76(d,J=8.2Hz,1H),7.36(dd,J=7.5,2.1Hz,2H),7.28(t,J=7.4Hz,2H),7.19–7.15(m,1H),6.85(t,J=7.8Hz,1H),6.42(dt ,J=9.1,1.9Hz,1H),6.34–6.27(m,2H),4.35(dd,J=10.2,5.8Hz,1H),2.90(q,J=9.8,8.9Hz,2H),1.39(d,J=6.7Hz,3H).; EI-MS m / z:356[M] + .

[0152] Example 40: Preparation of I-40

[0153] The preparation method was the same as that of Example 37, except that benzylamine (124.54 mg, 1.16 mmol) was replaced by phenethylamine (140.57 mg, 1.16 mmol) to obtain 85 mg of a light yellow oil with a total yield of 41.12%. δ9.03(d,J=8.1Hz,1H),7.71(ddt,J=7.5,4.3,1.4Hz,1H),7.63–7.62(m,1H),7.39(dd,J=5.2,2.5Hz,1H),7.29(d,J=2.3Hz,2H),6.97(t,J=7.7Hz ,1H),6.47–6.41(m,2H),4.42(dd,J=8.6,5.0Hz,1H),3.22–3.19(m,2H), 3.06–3.03(m,1H),3.01–2.98(m,1H),2.82(dd,J=8.5,6.5Hz,2H).; EI-MS m / z:356[M] + .

[0154] The following Example 41 was prepared using method three.

[0155] Example 41: Preparation of I-41

[0156] (R)-2-amino-3-(3-bromophenyl)propionic acid (500mg, 2.05mmol) was dissolved in 10mL methanol, 0.37mL thionyl chloride was added under ice bath, stirred at room temperature for 30min, heated to 80℃ and stirred for 6h, and the reaction was complete. After the reaction was completed, the organic solvent was removed by vacuum distillation to obtain a light yellow solid, which was dissolved in 10mL anhydrous tetrahydrofuran, 233.21mg lithium aluminum hydride was added under ice bath, and the reaction was stirred overnight at room temperature, and the reaction was complete. After the reaction was completed, an appropriate amount of water and 10% sodium hydroxide were added to quench the reaction, and dichloromethane was extracted. The organic layer was taken, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1), and the white solid was dissolved in 10mL dichloromethane, 0.54ml triethylamine was added, and stirred at room temperature for 5min, 0.16mL methyl oxalyl chloride was added, and stirred at room temperature for 30min, and the reaction was complete. After the reaction is completed, add an appropriate amount of water to quench the reaction, extract with dichloromethane, take the organic layer, wash with saturated brine, dry with anhydrous sodium sulfate, and evaporate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain a light yellow oily substance dissolved in 10 mL of tetrahydrofuran, add 71.64 mg of tetrakistriphenylphosphine palladium, 0.31 mL of 2M potassium phosphate aqueous solution and 3-fluoro-5-methylphenylboronic acid (114.54 mg, 0.74 mmol), and conventionally heat to 65 ° C for 4 h to complete the reaction. After the reaction is completed, remove the tetrakistriphenylphosphine palladium by suction filtration, and after reduced pressure distillation, the crude product is chromatographed on a silica gel column (petroleum ether: ethyl acetate = 2: 1) to obtain a light yellow oily substance dissolved in 10 mL of tetrahydrofuran, add 3 mL of 1M lithium hydroxide solution, and heat to 30 ° C for 2 h to complete the reaction. After the reaction, tetrahydrofuran was removed from the reaction solution by vacuum distillation, 3 mmol of dilute hydrochloric acid was added to pH 1-2, extracted with ethyl acetate, the organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. 117 mg of light yellow oil was obtained by vacuum distillation, with a total yield of 48.82%. 1 H NMR(400MHz,Chloroform-d)δ7.51–7.35(m,4H),7.25(d,J=7.5Hz,1H),7.18(s,1H),7.09(d,J=9.9Hz,1H),6.89(d,J=9 .5Hz, 1H), 4.30 (qd, J=7.2, 2.9Hz, 1H), 3.91 (s, 3H), 3.81–3.66 (m, 2H), 3.02 (dd, J=7.3, 2.2Hz, 2H), 2.43 (s, 3H).; EI-MS m / z:331[M] + .

[0157] The following Example 42 was prepared using Method 4.

[0158] Example 42: Preparation of I-42

[0159] (R)-2-amino-3-(3-bromophenyl)propionic acid (500mg, 2.05mmol) was dissolved in 10mL methanol, 0.37mL thionyl chloride was added under ice bath, stirred at room temperature for 30min, heated to 80℃ and stirred for 6h, and the reaction was complete. After the reaction was completed, the organic solvent was removed by vacuum distillation to obtain a light yellow solid, which was dissolved in 10mL anhydrous tetrahydrofuran, 233.21mg lithium aluminum hydride was added under ice bath, and the reaction was stirred overnight at room temperature, and the reaction was complete. After the reaction was completed, an appropriate amount of water and 10% sodium hydroxide were added to quench the reaction, and dichloromethane was extracted. The organic layer was taken, washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1), and the white solid was dissolved in 10mL dichloromethane, 0.54ml triethylamine was added, and stirred at room temperature for 5min, 0.16mL methyl oxalyl chloride was added, and stirred at room temperature for 30min, and the reaction was complete. After the reaction is completed, add an appropriate amount of water to quench the reaction, extract with dichloromethane, take the organic layer, wash with saturated brine, dry with anhydrous sodium sulfate, and evaporate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain a light yellow oily substance dissolved in 10 mL of tetrahydrofuran, add 71.64 mg of tetrakistriphenylphosphine palladium, 0.31 mL of 2M potassium phosphate aqueous solution and 3-fluoro-5-methylphenylboronic acid (114.54 mg, 0.74 mmol), and conventionally heat to 65 ° C for 4 h to complete the reaction. After the reaction is completed, remove the tetrakistriphenylphosphine palladium by suction filtration, and after reduced pressure distillation, the crude product is chromatographed on a silica gel column (petroleum ether: ethyl acetate = 2: 1) to obtain a light yellow oily substance dissolved in 10 mL of tetrahydrofuran, add 3 mL of 1M lithium hydroxide solution, and heat to 30 ° C for 2 h to complete the reaction. After the reaction, tetrahydrofuran was removed from the reaction solution by vacuum distillation, 3 mmol of dilute hydrochloric acid was added to pH 1-2, extracted with ethyl acetate, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. 117 mg of light yellow oil was obtained by vacuum distillation with a total yield of 48.82%. δ8.94 (d, J = 8.4 Hz, 1H), 7.36 (s, 1H), 7.30 (d, J = 7.3 Hz, 1H), 7.24 (d, J = 10.6 Hz, 3H), 7.10 (t, J = 7.4 Hz, 1H), 6.99 (d, J = 9.7 Hz, 1H), 4.55–4.49 (m, 1H), 3.22 (dd, J = 13.9, 4.5 Hz, 1H), 3.15–3.10 (m, 1H), 2.15 (s, 3H).; EI-MS m / z: 344 [M] + .

[0160] The following examples (Examples 43-444) were prepared using method five.

[0161] Example 43: Preparation of I-44

[0162] (R)-2-amino-3-(3-bromophenyl)propionic acid (500 mg, 2.05 mmol) was dissolved in 10 mL of dichloromethane, and ammonia was slowly added dropwise under ice bath. The mixture was stirred at room temperature for 6 h to complete the reaction. After the reaction, the organic solvent was removed by vacuum distillation, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (dichloromethane: methanol = 100: 1). The light yellow oil was dissolved in 10 mL of tetrahydrofuran, and 0.37 ml of triethylamine and 187.48 ml of trifluoroacetic anhydride were added under ice bath. The mixture was stirred at 0°C for 2 h to complete the reaction. After the reaction is completed, the organic solvent is removed by rotary evaporation, extracted with ethyl acetate, the organic layer is taken, washed with saturated brine, dried over anhydrous sodium sulfate, and after reduced pressure rotary evaporation, the crude product is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 4:1), and the white solid is dissolved in 10mL of dichloromethane, 0.42ml of triethylamine is added, and after stirring at room temperature for 5min, 0.12mL of methyl oxalyl chloride is added, and the reaction is stirred at room temperature for 30min, and the reaction is complete. After the reaction is completed, an appropriate amount of water is added to quench the reaction, extracted with dichloromethane, the organic layer is taken, washed with saturated brine, dried over anhydrous sodium sulfate, and after reduced pressure rotary evaporation, the crude product is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2:1), and the light yellow oil is dissolved in 10mL of tetrahydrofuran, 84.36mg of tetratriphenylphosphine palladium, 1.10mL of 2M potassium phosphate aqueous solution and 3-fluoro-5-methylphenylboronic acid (134.86mg, 0.88mmol) are added, and conventional heating is performed to 65°C for 4h, and the reaction is complete. After the reaction is completed, tetrakistriphenylphosphine palladium is removed by suction filtration, and after vacuum distillation, the crude product is chromatographed on a silica gel column (petroleum ether: ethyl acetate = 2:1) to obtain a light yellow oily substance which is dissolved in 10 mL of tetrahydrofuran, and 3 mL of 1M lithium hydroxide solution is added, and the reaction is heated to 30°C for 2 hours until the reaction is complete. After the reaction is completed, the tetrahydrofuran in the reaction solution is removed by vacuum distillation, 3 mmol of dilute hydrochloric acid is added to a pH of 1-2, and the mixture is extracted with ethyl acetate, the organic layer is taken, washed with saturated brine, and dried over anhydrous sodium sulfate. Vacuum distillation is performed to obtain 127 mg of a light yellow oily substance with a total yield of 53.78%. 1 H NMR (400MHz, DMSO-d6) δ8.44(s,1H),8.28(s,1H),7.43(d,J=7.6Hz,1H),7.29(d,J=13.5Hz,2H),7.24(s,1H),7.16(d, EI-MS m / z:326[M]+ .

[0163] Example 44: Preparation of I-44

[0164] The preparation method is the same as that of Example 43. The yellow oil is dissolved in 10 mL of tetrahydrofuran, 0.24 mL of trimethylsilyl azido and 2 mL of 1 M tetrabutylammonium fluoride are added, and the mixture is heated to 85°C overnight to complete the reaction. After the reaction is completed, the mixture is evaporated under reduced pressure, and the crude product is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 1:1) to obtain 113 mg of a light yellow oil with a total yield of 48.91%. 1 H NMR (400MHz, DMSO-d6) δ9.63–9.45(m,1H),7.66(s,1H),7.58(d,J=7.4Hz,1H),7.41(t,J=7.7Hz,1H),7.35(s,1 EI-MS m / z:369[M] + .

[0165] The following examples (Examples 45-49) were prepared using method 1.

[0166] Example 45: Preparation of I-45

[0167] The preparation method was the same as that of Example 1, except that 3-chloro-5-isopropylphenylboronic acid (138.12 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 114 mg of a light yellow oil with a total yield of 47.03%. δ7.54(s,1H),7.48(d,J=7.9Hz,1H),7.40(d,J=7.6Hz,1H),7.35(s,1H),7.30(s,1H),7.22(s,1H),7.13(d,J=7.4Hz,1H),4.9 7(d,J=8.5Hz,1H),3.92(s,3H),3.79(s,3H),3.27(dd,J=8.1,5.8Hz,2H),3.00–2.94(m,1H),1.32(s,3H),1.30(s,3H).; EI-MS m / z:418[M] + .

[0168] Example 46: Preparation of I-46

[0169] The preparation method was the same as that of Example 1, except that 3-fluoro-5-methylphenylboronic acid (107.15 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 108 mg of a light yellow oil with a total yield of 49.87%. δ7.56(d,J=8.3Hz,1H),7.48(d,J=7.8Hz,1H),7.39(t,J=7.6Hz,1H),7.31(s,1H),7.15(d,J=8.1Hz,1H),7.05(d,J=9.9Hz ,1H),6.89(d,J=9.4Hz,1H),4.99–4.94(m,1H),3.92(s,3H),3.78(s,3H),3.26(dd,J=8.6,5.9Hz,2H),2.43(s,3H).; EI-MS m / z:373[M] + .

[0170] Example 47: Preparation of I-47

[0171] The preparation method was the same as that of Example 1, except that 3-chloro-5-methylphenylboronic acid (118.60 mg, 0.70 mmol) was used to replace phenylboronic acid (78 mg, 0.64 mmol) to obtain 111 mg of a light yellow oil with a total yield of 49.09%. δ7.55(d,J=8.2Hz,1H),7.47(d,J=7.9Hz,1H),7.39(t,J=7.6Hz,1H),7.34(s,1H),7.29(d,J=6.0Hz,1H),7.18(s,1H) ,7.13(d,J=7.5Hz,1H),4.96(dt,J=8.4,5.8Hz,1H),3.92(s,3H),3.78(s,3H),3.31–3.22(m,2H),2.42(s,3H).; EI-MS m / z:390[M] + .

[0172] Example 48: Preparation of I-48

[0173] (R)-2-amino-3-(3-bromophenyl)propionic acid (500 mg, 2.05 mmol) was dissolved in 10 mL methanol, 0.37 mL thionyl chloride was added under ice bath, stirred at room temperature for 30 min, heated to 80°C and stirred for 6 h, and the reaction was complete. After the reaction was completed, the organic solvent was removed by distillation under reduced pressure to obtain a light yellow solid, which was dissolved in 10 mL dichloromethane, 0.43 mL triethylamine was added, stirred at room temperature for 5 min, 871.78 mg benzyl oxalyl chloride was added, stirred at room temperature for 30 min, and the reaction was complete. After the reaction is completed, add an appropriate amount of water to quench the reaction, extract with dichloromethane, take the organic layer, wash with saturated brine, dry with anhydrous sodium sulfate, and evaporate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain a white solid dissolved in 10mL tetrahydrofuran, add 68.74mg tetratriphenylphosphine palladium, 0.89mL of 2M potassium phosphate aqueous solution and 3-fluoro-5-methylphenylboric acid (109.90mg, 0.71mmol), and conventionally heat to 65℃ for 4h to complete the reaction. After the reaction is completed, remove the tetratriphenylphosphine palladium by suction filtration, and after reduced pressure distillation, the crude product is chromatographed on a silica gel column (petroleum ether: ethyl acetate = 1: 1) to obtain a light yellow oily substance dissolved in 10mL methanol, add 100mg palladium hydroxide, replace hydrogen, and stir the reaction at room temperature overnight to complete the reaction. After the reaction is completed, remove the palladium hydroxide by suction filtration, and obtain 83mg of a light yellow oily substance after reduced pressure distillation, with a total yield of 39.59%. δ9.16(d,J=8.2Hz,1H),7.72(s,1H),7.68(s,1H),7.59(s,1H),7.53(d,J=7.8Hz,1H),7.33(s,1H),7.26(s,1H),7.03( d,J=9.7Hz,1H),4.61(q,J=6.9,4.6Hz,1H),3.67(s,3H),3.22(d,J=9.1Hz,1H),3.16–3.09(m,1H),2.39(s,3H).; EI-MS m / z:359[M] + .

[0174] Example 49: Preparation of I-49

[0175] The preparation method was the same as that of Example 45, except that 3-chloro-5-methylphenylboronic acid (121.64 mg, 0.71 mmol) was used to replace 3-fluoro-5-methylphenylboronic acid (109.90 mg, 0.71 mmol) to obtain 87 mg of a light yellow oil with a total yield of 39.24%. δ 9.23 (s, 1H), 7.60 (s, 1H), 7.52 (d, J = 14.2 Hz, 2H), 7.44 (s, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.26 (s, 2H), 4.62 (s, 1H), 3.66 (s, 3H), 3.23 (dd, J = 14.0, 4.5 Hz, 1H), 3.16–3.10 (m, 1H), 2.38 (s, 3H).; EI-MS m / z: 376 [M] + .

[0176] The following examples (Examples 50-51) were prepared using method 2.

[0177] Example 50: Preparation of I-50

[0178] (R)-2-amino-3-(3-bromophenyl)propionic acid (500 mg, 2.05 mmol) was dissolved in 10 mL of acetonitrile, and 710 mg of potassium carbonate and 0.49 mL of benzyl bromide were added. The mixture was stirred at room temperature for 4 hours to complete the reaction. After the reaction, the organic solvent was removed by distillation under reduced pressure to obtain a light yellow solid, which was dissolved in 10 mL of dichloromethane, and 0.43 mL of triethylamine was added. After stirring at room temperature for 5 minutes, 871.78 mg of methyl oxalyl chloride was added, and the mixture was stirred at room temperature for 30 minutes to complete the reaction. After the reaction is completed, add an appropriate amount of water to quench the reaction, extract with dichloromethane, take the organic layer, wash with saturated brine, dry with anhydrous sodium sulfate, and evaporate under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether: ethyl acetate = 2: 1) to obtain a white solid dissolved in 10mL tetrahydrofuran, add 68.74mg tetratriphenylphosphine palladium, 0.89mL of 2M potassium phosphate aqueous solution and 3-fluoro-5-methylphenylboric acid (109.90mg, 0.71mmol), and conventionally heat to 65°C for 4h to complete the reaction. After the reaction is completed, remove the tetratriphenylphosphine palladium by suction filtration, and after reduced pressure distillation, the crude product is chromatographed on a silica gel column (petroleum ether: ethyl acetate = 1: 1) to obtain a light yellow oily substance dissolved in 10mL methanol, add 100mg palladium hydroxide, replace hydrogen, and stir the reaction at room temperature overnight to complete the reaction. After the reaction is completed, remove the palladium hydroxide by suction filtration, and obtain 87mg of a light yellow oily substance after reduced pressure distillation, with a total yield of 40.70%. δ9.14(d,J=8.2Hz,1H),7.53(s,1H),7.49–7.44(m,2H),7.42(d,J=7.8Hz,1H),7.35(d,J=2.6Hz,1H),7.22(d,J=7.9Hz,1H),7.1 8(d,J=7.5Hz,1H),4.52(ddd,J=9.8,8.1,4.4Hz,1H),3.75(s,3H),3.23(d,J=9.4Hz,1H),3.14–3.08(m,1H),2.38(s,3H).; EI-MS m / z:359[M] + .

[0179] Example 51: Preparation of I-51

[0180] The preparation method was the same as that of Example 50, except that 3-chloro-5-methylphenylboronic acid (121.64 mg, 0.71 mmol) was used to replace 3-fluoro-5-methylphenylboronic acid (109.90 mg, 0.71 mmol) to obtain 86 mg of a light yellow oil with a total yield of 38.02%. δ 9.13–8.99 (m, 1H), 7.54 (d, J = 20.8 Hz, 2H), 7.29 (d, J = 24.2 Hz, 4H), 7.03 (s, 1H), 4.52 (s, 1H), 3.75 (s, 3H), 3.28–3.19 (m, 1H), 3.11 (t, J = 12.1 Hz, 1H), 2.38 (s, 3H).; EI-MS m / z: 376 [M] + .

[0181] Example 52: Preparation of I-52

[0182] The preparation method is the same as that of Example 1, except that (R)-2-amino-3-(3-bromophenyl)propionic acid (500 mg, 2.05 mmol) is replaced by (R)-2-amino-3-(3-bromophenyl)propionic acid ethyl ester (500 mg, 1.84 mmol), 2-chloro-2-oxoacetic acid cyclopropyl ester (300.20 mg, 2.02 mmol) is replaced by methyl chlorooxalyl ester (0.22 ml), and 3-chloro-5-methylphenylboric acid (322.06 mg, 1.89 mmol) is replaced by phenylboric acid (78 mg, 0.64 mmol) to obtain 113 mg of a light yellow oil with a total yield of 47.52%. 1 H NMR(500MHz,Chloroform-d)δ8.49(d,J=9.5Hz,1H),7.58(t,J=2.1Hz,1H),7.52–7.36(m,4H),7.19–7.12(m,2H),4.75(p,J=4.9Hz,1H),4 .64(dt,J=9.3,7.3Hz,1H),4.15(q,J=6.3Hz,2H),3.10–2.98(m,2H),1.69–1.57(m,2H),1.54–1.42(m,2H),1.25(t,J=6.4Hz,3H).; EI-MS m / z:430[M] + .

[0183] Example 53: Preparation of I-53

[0184] The preparation method was the same as that of Example 1, except that (R)-2-amino-3-(3-bromophenyl)propionic acid (500 mg, 2.05 mmol) was replaced with (R)-2-amino-3-(3-bromophenyl)propionic acid phenyl ester (500 mg, 1.56 mmol), and 3-chloro-5-methylphenylboric acid (275.56 mg, 162 mmol) was replaced with phenylboric acid (78 mg, 0.64 mmol) to give 118 mg of a light yellow oil with a total yield of 46.37%. 1 H NMR(500MHz,Chloroform-d)δ8.40(d,J=9.1Hz,1H),7.58(t,J=2.1Hz,1H),7.49(dt,J=7.9,1.6Hz,1H),7.45(t,J=7.8Hz ,1H),7.42–7.35(m,4H),7.19–7.10(m,5H),4.66(dt,J=9.2,7.1Hz,1H),3.82(s,2H),3.06(dq,J=7.1,1.0Hz,2H).; EI-MS m / z:452[M] + .

[0185] The following are some pharmacological experiments and results of the compounds described in the present invention:

[0186] The FIH inhibitory activity was tested by fluorescence polarization (FP experiment):

[0187] The ability of the test compound to competitively bind to the FIH protein with the fluorescent group-labeled HIF-1α peptide (FITC-HIF-1α788-822) was tested. A 384-well black plate (model: Corining#3575) was used in the test. The final test volume was selected to be 60 μL. The tested compound and FITC-HIF-1α788-822 were dissolved in DMSO and pure water respectively for use. The compound was diluted three-fold with assay buffer to 12 concentration gradients, and 20 μL of the diluted 300nM / LFIH protein was added to each well. Two attached wells were set for each compound concentration, and a blank control (20 μL FITC-HIF-1α788-822+40 μL assay buffer) and a negative control (20 μL FITC-HIF-1α788-822+20 μL FIH+20 μL assay buffer) were set for each test. Incubate at room temperature for 1 hour, scan the plate with Synergy plate reader, set the excitation wavelength to 485nm, and the emission wavelength to 535nm. Calculation formula: % inhibition rate = 100*(1-(measured value-blank) / (negative value-blank)), and obtain the inhibition rate corresponding to the specific concentration. The obtained data were imported into Graphpad prism 8.0 for analysis and fitting to obtain IC 50The FP test results of representative compounds are shown in Table 1 and Table 2.

[0188] Table 1 FIH inhibitory activity of some compounds in the present invention

[0189]

[0190] As shown in Table 1, the compounds of the present invention have strong FIH inhibitory activity. The IC 50 Less than 100nM, 7 compounds IC 50 Less than 10nM. Where: A represents IC 50 Values ​​range from 1 nM to 10 nM; B represents IC 50 Values ​​range from 10nM to 100nM; C represents IC 50 Values ​​range from 100nM to 1000nM; D represents IC 50 The value was greater than 1 μM.

[0191] The lipid-lowering activity of ester prodrugs of some compounds was evaluated at the cellular level: Pre-adipocytes 3T3-L1 are a type of precursor cells that have the ability to proliferate and differentiate into mature adipocytes. Under the action of different growth factors, hormones and other substances, these precursor cells undergo four stages: mitotic cloning, growth arrest, further cloning, and terminal differentiation. The fibroblast state of the cells themselves changes, and mature adipocytes are formed through the aggregation of intracytoplasmic triglycerides. FIH inhibitor ester prodrugs were given to induced differentiated mature adipocytes. After two days of action, the intracellular triglyceride level was measured. The results are shown in Table 2.

[0192] Table 2 FIH inhibitory activity and cellular lipid-lowering activity of ester prodrugs of some compounds in the present invention

[0193]

[0194]

[0195] As can be seen from Table 2, the ester prodrugs of some compounds of the present invention can maintain good FIH inhibitory activity and have obvious lipid-lowering activity at the cellular level.

[0196] Some ester prodrugs in Table 2 were tested for improving fatty liver at the animal level (dose: 10 mg / kg, model: C57BL / 6J male mice 7-8 weeks old), and the method was referred to (J. Med. Chem. 2021, 64 (2), 1037-1053). Figure 1 It can be seen that the compounds of the present invention can significantly reduce the body weight of mice with fatty liver and improve obesity at the animal level, while reducing serum and liver triglycerides, improving hyperlipidemia and fatty liver, among which I-47 and I-48 have the best effects.

Claims

1. A compound represented by general formula (I) or a pharmaceutically acceptable salt thereof, characterized in that: Where R 1 is hydrogen; R 2 Selected from carboxyl, hydroxymethyl, carbamoyl, cyano, and five-membered aromatic hetero groups; L 1 It is a connecting chain with a length of 0-3 atoms between Ar and the meta position of the benzene ring; Ar is selected from R 3 is one or more identical or different substituents on Ar, wherein the substituents are optionally selected from hydrogen, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, C1-C4 acyl, C1-C4 acylamino, carbamoyl, C1-C4 alkylcarbamoyl, C1-C4 sulfonyl, C1-C4 sulfonylamino, aminosulfonyl, C1-C4 alkylsulfamoyl, halogen, cyano, hydroxyl, and amino.

2. The compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, characterized in that: The compound is selected from:

3. An ester prodrug of the compound represented by general formula (I) according to claim 1, characterized in that: The ester prodrug is selected from:

4. A method for preparing a compound represented by general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, characterized in that: The method is any one of the following: Method 1: The raw material II undergoes a condensation reaction with methyl oxalyl chloride under the alkaline condition of triethylamine to obtain an intermediate III; the intermediate III undergoes a coupling reaction under the condition of a catalyst to obtain a target compound or an intermediate IV; finally, the intermediate IV is hydrolyzed with lithium hydroxide to obtain the target compound; Method 2: The raw material II undergoes a condensation reaction with benzyl oxalyl chloride under the alkaline condition of triethylamine to obtain an intermediate V; the intermediate V undergoes a coupling reaction under the catalysis of a catalyst to obtain an intermediate VI; finally, the intermediate VI is reduced with hydrogen and palladium on carbon to obtain the target compound; Method 3: The raw material II is reduced with lithium aluminum hydride to obtain intermediate VII; intermediate VII undergoes condensation reaction with methyl chlorooxalyl under alkaline conditions of triethylamine to obtain intermediate VIII; intermediate VIII undergoes coupling reaction under catalyst conditions to obtain intermediate IX; finally, intermediate IX is hydrolyzed with lithium hydroxide to obtain the target compound; Method 4: The raw material X is condensed with ammonia to obtain an intermediate XI; the intermediate XI is condensed with methyl chlorooxalyl under the alkaline condition of triethylamine to obtain an intermediate XII; the intermediate XIII is coupled under the condition of a catalyst to obtain an intermediate XIII; finally, the intermediate XIII is hydrolyzed with lithium hydroxide to obtain the target compound; Method 5: The intermediate XI is dehydrated under the catalysis of trifluoroacetic anhydride to obtain the intermediate XIX; the intermediate XIX undergoes a condensation reaction with methyl chlorooxalyl under the alkaline condition of triethylamine to obtain the intermediate XX; the intermediate XX undergoes a coupling reaction under the condition of a catalyst to obtain the intermediate XXI; finally, the intermediate XXI is hydrolyzed with lithium hydroxide to obtain the target compound I or the intermediate XXII; the intermediate XXII undergoes a cycloaddition reaction with tetrabutylammonium fluoride to obtain the target compound I.

5. A pharmaceutical composition, characterized in that It contains the compound represented by the general formula (I) according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

6. Use of the compound represented by general formula (I) according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to claim 5 in the preparation of a FIH inhibitor.

7. Use of a compound represented by general formula (I) according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 5, in the preparation of a drug for treating a disease associated with FIH activity.

8. The use according to claim 7, characterized in that The medicine is used for treating fat metabolic diseases.

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