Dipeptide compounds, methods of making and using the same

Abstract

The application provides a dipeptide compound, including a dipeptide compound with a general structure of or or a pharmaceutically acceptable salt thereof, wherein R1 is a hydrogen atom, a chain alkane containing C1-C6, a heteroatom-substituted alkane containing C1-C6, or an aromatic ring-containing alkane containing C2-C8; R2 is -NH2, a chain amine group containing C2-C8, a halogenated aliphatic amine group containing C3-C6, a five-membered ring aliphatic amine group, a six-membered ring aliphatic amine group, an aromatic amine, or a heteroaromatic amine; and X is a C, S, or O atom. The application further provides a preparation method of the dipeptide compound. The application further provides an application of the dipeptide compound in preparation of an LSD1 inhibitor. The dipeptide compound has an effect of inhibiting LSD1, thereby opening up a new way for drug development with LSD1 as a target.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, specifically to a dipeptide compound, its preparation method, and its application. Background Technology

[0002] Amino acids are the most common building blocks, exhibiting diverse structures and widely found in natural products and drugs. Introducing amino acid fragments can improve the physicochemical properties of drugs, such as enhancing membrane permeability, increasing target specificity, and improving drug clearance.

[0003] Histone lysine-specific demethylase 1 (LSD1) is the first histone demethylase discovered. It regulates gene expression and transcriptional activity by specifically demethylating and dimethylating methyl groups at H3K4 and H3K9 sites via a flavin adenine dinucleotide (FAD)-dependent mechanism. Current research confirms that LSD1 is overexpressed in various tumor cells. LSD1 can regulate gene expression by activating or inhibiting chromatin domains through histone demethylation, and it also regulates tumorigenesis and development by affecting the expression of factors essential for cell proliferation and differentiation. Furthermore, LSD1 is closely related to the development of other diseases such as viral infections, central nervous system diseases, and cardiovascular diseases. In addition, LSD1 plays an important role in maintaining brown adipose tissue metabolism, and targeting LSD1 provides a new strategy for the treatment of obesity and diabetes. Therefore, LSD1 is a promising drug target and has attracted increasing attention from medicinal chemists. However, amino acid-based LSD1 inhibitors are rarely reported. Summary of the Invention

[0004] In view of this, in order to develop and utilize existing clinical drug resources, the present invention provides a dipeptide compound, its preparation method and application, to solve the above problems.

[0005] Therefore, the technical solution provided by the present invention is: a dipeptide compound, comprising a dipeptide compound represented by the general structural formula j or a pharmaceutically acceptable salt thereof:

[0006]

[0007] Wherein, group R1 is a hydrogen atom, a chain alkane containing C1 to C6, a heteroatom-substituted alkane containing C1 to C6, or an aromatic cycloalkane containing C2 to C8; R2 is an amino group (-NH2), a chain amine group containing C2 to C8, a haloalkyne group containing C3 to C6, a five-membered ring aliphatic amine group, a six-membered ring aliphatic amine group, an aromatic amine group, or a heteroaromatic amine group; and X is an atom such as C, S, or O.

[0008] In this article, "containing five-membered ring aliphatic amines" and "containing six-membered ring aliphatic amines" refer to cyclic amines in which at least one carbon atom on the aliphatic ring is replaced by a nitrogen atom; "aromatic amines" refer to amines containing a benzene ring; and "heteroaromatic amines" refer to aromatic amines in which the carbon atom on the benzene ring is replaced by heteroatoms such as N, S, or O.

[0009] Based on the above, the dipeptide compound represented by the general structural formula j is an (R)-isomer, (S)-isomer, or racemic mixture. Pharmaceutically acceptable salts of the dipeptide compound represented by the general structural formula j include: hydrochloride, trifluoroacetate, sulfate, methanesulfonate, mandelate, formate, tartrate, etc. The dipeptide compound is essentially a liquid, while its pharmaceutically acceptable salt is essentially a solid. Comparatively, the pharmaceutically acceptable salt of the dipeptide compound exhibits better stability and a longer shelf life.

[0010] Based on the above, group R1 is H,

[0011] Based on the above, group R2 is

[0012] The present invention also provides a method for preparing the above-mentioned dipeptide compound, comprising the steps of:

[0013] The preparation of intermediate i involves an amidation reaction using intermediate h and intermediate c as raw materials to synthesize intermediate i, and the general structural formula of intermediate h is as follows: The general structural formula of the intermediate c is: The general structural formula of intermediate i is:

[0014] The target compound j was prepared by removing the tert-butyloxycarbonyl group protecting group from intermediate i under acidic conditions to synthesize the target compound j, i.e., the aforementioned dipeptide compound. The general structural formula of the target compound j is as follows:

[0015] Based on the above, the preparation steps of intermediate i include: adding intermediate h, intermediate c, condensing agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), and catalyst 1-hydroxybenzotriazole (HOBT) to a first organic solvent in a molar ratio of 1:1 to 3:1 to 3:0.1 to 1.5, and stirring at room temperature for 6 to 24 hours; monitoring the reaction by thin-layer chromatography (TLC), and separating intermediate i after the reaction is completed; wherein, the first organic solvent is N,N-dimethylformamide (DMF) or dichloromethane.

[0016] Based on the above, the steps for preparing the target compound j include: first, adding the intermediate i and the first acidic substance to a second organic solvent at a ratio of 1:5 to 30, and stirring at room temperature for 0.5 to 6 hours, wherein the first acidic substance is hydrochloric acid or trifluoroacetic acid, and the second organic solvent is dichloromethane, ethyl acetate, methanol, ethanol, or 1,4-dioxane.

[0017] Based on the above, the preparation method of intermediate c includes: hydrolyzing intermediate b under acidic conditions and adjusting the pH to alkaline to obtain intermediate c, wherein the general structural formula of intermediate b is as follows:

[0018] Specifically, the preparation method of intermediate c includes: first, adding intermediate b and the second acidic substance to a third organic solvent at a ratio of 1:5 to 1:30, stirring at room temperature for 0.5 to 24 hours; after the reaction is completed, adding a first basic substance to adjust the pH to alkaline, and then separating and purifying to obtain intermediate c. The second acidic substance is hydrochloric acid or trifluoroacetic acid; the third organic solvent is dichloromethane, ethyl acetate, methanol, ethanol, or 1,4-dioxane; and the first basic substance is triethylamine (Et3N), diisopropylethylamine (DIPEA), ethylenediamine, potassium carbonate, or sodium bicarbonate.

[0019] Based on the above, the preparation method of intermediate b includes: using raw material a and fatty amine R2H as raw materials, an amidation reaction is carried out to synthesize intermediate b, wherein the general structural formula of raw material a is:

[0020] Specifically, the preparation method of intermediate b includes: adding compound a, fatty amine R2H, condensing agent 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), and catalyst 1-hydroxybenzotriazole (HOBT) into a fourth organic solvent in a molar ratio of 1:1 to 3:1 to 3:0.1 to 1.5, and stirring at room temperature for 4 to 24 hours; monitoring the reaction by thin-layer chromatography (TLC), and separating intermediate b after the reaction is completed; wherein, the fourth organic solvent is DMF or dichloromethane.

[0021] Therefore, the synthetic route for synthesizing the target compound j dipeptide from compound a is shown below:

[0022]

[0023] Based on the above, the preparation method of intermediate h includes: reacting intermediate g in a mixed solvent of methanol and water under the action of lithium hydroxide for 2-24 hours, adjusting the pH to 3-4 with citric acid, and then separating the intermediate to obtain intermediate h. The structural formula of intermediate g is as follows:

[0024] Based on the above, the preparation method of intermediate g includes: reacting intermediate f with di-tert-butyl dicarbonate under the action of a second alkaline substance for 2-24 hours, followed by separation to obtain intermediate g, wherein the structural formula of intermediate f is as follows: The second alkaline substance is Et3N, DIPEA, ethylenediamine, potassium carbonate, or sodium bicarbonate.

[0025] Based on the above, the preparation method of intermediate f includes: dissolving intermediate e and ethyl glyoxylate in an ethanol solution, forming an imine intermediate under the catalysis of acetic acid, followed by reduction with sodium cyanoborohydride, separation, and obtaining intermediate f, wherein the structural formula of intermediate e is as follows:

[0026] Based on the above, the preparation method of intermediate e includes: stirring compound d in an alkaline environment at room temperature for 0.5–6 h; followed by extraction and vacuum concentration to obtain intermediate e, wherein compound d is the mandelate of 3,4-difluorocyclopropylamine, and its structural formula is as follows: In this step, the substance providing the alkaline environment is Et3N, DIPEA, ethylenediamine, potassium carbonate, or sodium bicarbonate.

[0027] Therefore, the synthesis route of intermediate h from compound d is as follows:

[0028]

[0029] The present invention also provides the application of the above-mentioned dipeptide compound in the preparation of LSD1 inhibitors.

[0030] Therefore, compared with the prior art, the dipeptide compounds or pharmaceutically acceptable salts provided by the present invention, wherein the dipeptide compounds are structural isomers, can be (R)-isomers, (S)-isomers, or racemates; experimental verification shows that the dipeptide compounds or pharmaceutically acceptable salts provided by the present invention have an inhibitory effect on LSD1, thereby opening a new avenue for the development of a new class of drugs targeting LSD1. Furthermore, experimental verification shows that both the (R)-isomers and (S)-isomers of the dipeptide compounds provided by the present invention have an inhibitory effect on LSD1. Detailed Implementation

[0031] The technical solution of the present invention will be further described in detail below through specific embodiments. Unless otherwise specified, the technical means used in the following embodiments are conventional means well known to those skilled in the art.

[0032] Example 1

[0033] This embodiment provides compound j-1, the structural formula of which is:

[0034] The preparation route of compound 1 is as follows:

[0035]

[0036] The preparation method of compound j-1 includes the following steps:

[0037] Preparation of compound b-1

[0038] Boc-L-phenylglycine (0.50 g, 1.99 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.96 g, 4.97 mmol), and 1-hydroxybenzotriazole (0.40 g, 2.98 mmol) were added to 15 mL of dichloromethane and stirred at room temperature for 30 min. N-methylpiperazine (0.26 mL, 2.39 mmol) was then added to the mixture, and the reaction was carried out at room temperature. The reaction was monitored by TLC. After the reaction was complete, the compound b-1 (0.45 g, 1.35 mmol) was purified by column chromatography, with a yield of approximately 67.83%. 1 H NMR(400MHz,Chloroform-d)δ7.42–7.26(m,5H),6.09(d,J=7.8Hz,1H),5.56(d,J=7.8Hz,1H),3.80–3.72(m,1H),3.6 1–3.52(m,1H),3.47–3.38(m,1H),3.33–3.24(m,1H),2.49–2.33(m,2H),2.31–2.20(m,2H),2.19(s,3H),1.41(s,9H).

[0039] Preparation of compound c-1:

[0040] Compound b-1 (0.45 g, 1.35 mmol) and trifluoroacetic acid (1.55 ml, 20.24 mmol) were added to 10 ml of dichloromethane. After stirring at room temperature for 4 h, the trifluoroacetic acid was removed by concentration under reduced pressure. 10 ml of dichloromethane was added to the system, and triethylamine was gradually added dropwise until the system became weakly alkaline. The crude product c-1 was obtained by concentration under reduced pressure. The crude product was used directly in the next reaction without purification.

[0041] Preparation of compound e:

[0042] Compound d (1.00 g, 3.19 mmol) was added to 70 mL of an aqueous solution containing potassium carbonate (0.88 g, 6.37 mmol), stirred for 1 h, and extracted with ethyl acetate (70 mL × 3) / water solution. The organic phases were combined and concentrated under reduced pressure to obtain compound e (0.54 g, 3.19 mmol), which was used directly in the next reaction without purification.

[0043] Preparation of compound f:

[0044] Compound e (0.54 g, 2.96 mmol) and a 50% toluene solution of glyoxylate (0.70 mL, 3.55 mmol) were added to 20 mL of ethanol and reacted at room temperature for 2 h. Sodium cyanoborohydride (0.28 g, 4.43 mmol) was slowly added and the reaction was continued at room temperature. The reaction system was monitored by TLC. After the reaction was complete, the resulting system was concentrated under reduced pressure and extracted with ethyl acetate (60 mL × 3) / water solution. The organic phases were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was used directly in the next step without purification.

[0045] Preparation of compound g:

[0046] The crude product of compound f, di-tert-butyl dicarbonate (0.78 ml, 3.41 mmol), and triethylamine (0.47 ml, 3.41 mmol) were added to 15 ml of dichloromethane and reacted at room temperature. The reaction was monitored by TLC. After the reaction was complete, the mixture was concentrated under reduced pressure and extracted with ethyl acetate (60 × 3) / water solution. The organic phases were combined and column chromatography was performed to give compound g (0.75 g, 2.11 mmol). The yield of the above three steps was 59.1%. 1 H NMR(400MHz,Chloroform-d)δ7.08–6.78(m,3H),4.20(q,J=7.1Hz,2H),4.12–3.86(m,2H),2.87( br,1H),2.17(br,1H),1.55–1.49(m,1H),1.42(s,9H),1.28(t,J=7.1Hz,3H),1.14–1.04(m,1H).

[0047] Preparation of compound h:

[0048] Compound g (0.75 g, 2.11 mmol) was added to 10 mL of methanol solution, and 10 mL of aqueous solution containing lithium hydroxide (0.2 g, 8.44 mmol) was gradually added dropwise. The reaction was carried out at room temperature, and the reaction system was monitored by TLC. After the reaction was complete, the methanol in the system was evaporated to dryness, and the system was diluted with 20 mL of water. Citric acid was slowly added to adjust the pH to 3-4. The mixture was extracted with ethyl acetate (50 mL × 3) / water. The organic phases were combined and concentrated under reduced pressure to give compound h (0.59 g, 1.80 mmol), with a yield of 85.41%. 1 H NMR(400MHz,Chloroform-d)δ7.08–7.00(m,1H),6.89(br,2H),4.13–3.91(m,2 H),2.86(br,1H),2.17(br,1H),1.42(s,9H),1.27–1.23(m,1H),1.11(br,1H).

[0049] Preparation of compound i-1:

[0050] Compound h (0.20 g, 0.61 mmol), EDCI (0.29 g, 1.53 mmol), and HOBT (0.12 g, 0.92 mmol) were added to 10 mL of dichloromethane and stirred at room temperature for 30 min. The crude product of compound c-1 (0.17 g, 0.73 mmol) was then added, and the reaction was carried out at room temperature. The reaction was monitored by TLC. After the reaction was complete, compound i-1 (0.21 g, 0.39 mmol) was purified by column chromatography, with a yield of 63.34%. 1 H NMR(400MHz,Chloroform-d)δ7.44–7.30(m,5H),7.06–6.96(m,1H),6.95–6.74(m ,2H),5.85–5.78(m,1H),3.95–3.81(m,2H),3.76(br,1H),3.58(d,J=9.4Hz,1H),3 .46–3.36(m,1H),3.32–3.23(m,1H),2.84–2.74(m,1H),2.46–2.35(m,1H),2.30–2 .11(m,6H),1.84–1.74(m,1H),1.33(s,9H),1.25–1.20(m,1H),1.10–1.01(m,1H).

[0051] Preparation of compound j-1:

[0052] Compound i-1 (0.21 g, 0.39 mmol) was dissolved in 10 mL of ethyl acetate solution. Concentrated hydrochloric acid (0.32 mL, 3.87 mmol) in ethyl acetate solution was added dropwise to the above system. The mixture was stirred at room temperature for 2 h. After the reaction was complete, the mixture was concentrated under reduced pressure to give compound j-1 (0.14 g, 0.28 mmol), with a yield of 70.74%. Compound j-1 was a white solid. 1 ¹H NMR (400MHz, Methanol-d⁴) δ 7.49–7.38 (m, 5H), 7.22–7.13 (m, 1H), 7.12–7.01 (m, 1H), 7.00–6.89 (m, 1H), 5.98 (s, 1H), 4.09–3.70 (m, 5H), 3.56 (s, 1H), 3.20 (s, 3H), 2.91–2.64 (m, 5H), 2.46–2.33 (m, 1H), 1.47–1.36 (m, 1H), 1.3–1.23 (m, 1H). Therefore, the structural formula of compound j-1 provided in this embodiment is as shown above.

[0053] Example 2

[0054] This embodiment provides compound j-2, the structural formula of which is:

[0055] The synthesis method of compound j-2 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound j-2 is a white solid with an overall yield of 15.3%. 1 H NMR (400MHz, Deuterium Oxide)δ7.20–7.12(m,1H),7.08–6.99(m,1H),6.96–6.89(m,1H),4.78(br,2H),4.6 0–4.39(m,1H),4.26–4.07(m,1H),4.04(s,2H),3.70–3.48(m,3H),3.30–2.99(m,3H ), 2.99–2.93(m,1H), 2.90(s,3H), 2.58–2.46(m,1H), 1.68–1.47(m,3H), 1.46–1.37(m,1H), 1.36–1.29(m,1H), 0.90–0.76(m,6H); Therefore, the structural formula of compound j-2 provided in this embodiment can be determined as shown above.

[0056] Example 3

[0057] This embodiment provides compound j-3, the structural formula of which is:

[0058] The synthesis method of compound j-3 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound j-3 is a white solid with a yield of 13.3%. 1 H NMR (400MHz, Deuterium) Oxide)δ7.22–7.10(m,1H),7.08–6.99(m,1H),6.97–6.88(m,1H),4.68–4.65(m,1H),4.54(br,1H),4.34(br,1H),4.11–3.98(m,2H),3.57(br,3H),3.11(br,3H),2.97–2.92(m,1H),2.90(s,3H),2.57–2.45(m,1H),2.08–1.93(m,1H),1.56–1.46(m,1H),1.39–1.28(m,1H),1.00–0.75(m,6H); Therefore, the structural formula of compound j-3 provided in this embodiment is as shown above.

[0059] Example 4

[0060] This embodiment provides compound j-4, the structural formula of which is:

[0061] The synthesis method of compound j-4 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the X atom in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is a C atom, and the R2 atom is a C atom. Compound j-4 is a white solid with a yield of 9.7%. 1H NMR (400MHz, Deuterium) Oxide)δ7.21–7.11(m,1H),7.10–7.00(m,1H),6.98–6.90(m,1H),4.98–4.83(m,1H),4.57–4.45(m,1H),4.33–4.13(m,3H),3.69–3.48(m,5H),3.33–3.04(m,3H),3.03–2.97(m,1H),2.91(s,3H),2.59–2.50(m,1H),2.40–2.20(m,1H),2.05–1.82(m,3H),1.58–1.48(m,1H),1.40–1.31(m,1H); Therefore, the structural formula of compound j-4 provided in this embodiment can be determined as shown above.

[0062] Example 5

[0063] This embodiment provides compound j-5, the structural formula of which is:

[0064] The synthesis method of compound j-5 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the X atom in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is a C atom, and the R2 group is a C atom. Compound J-5 is a white solid with a yield of 8.2%. 1 HNMR(400MHz,Deuterium Oxide)δ7.21–7.11(m,1H),7.09–7.01(m,1H),6.97–6.88(m,1H),5.02–4.84(m,1H),4 .57–4.43(m,1H),4.33–4.16(m,3H),3.73–3.49(m,5H),3.33–3.03(m,3H),3.02–2.96 (m,1H),2.91(s,3H),2.62–2.47(m,1H),2.40–2.18(m,1H),2.05–1.93(m,2H),1.91–1.83(m,1H),1.59–1.47(m,1H),1.41–1.31(m,1H); Therefore, the structural formula of compound j-5 provided in this embodiment can be determined as shown above.

[0065] Example 6

[0066] This embodiment provides compound j-6, the structural formula of which is:

[0067] The synthesis method of compound j-6 is basically the same as that of compound j-1 provided in Example 1, the main difference being that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is H, and the corresponding R2 group is H. Compound J-6 is a white solid with a yield of 13.9%. 1 ¹H NMR (400MHz, Methanol-d⁴) δ 7.27–7.14 (m, 2H), 7.09–7.01 (m, 1H), 4.33–4.21 (m, 2H), 4.11 (s, 2H), 3.73–3.42 (m, 4H), 3.31–3.10 (m, 4H), 3.09–3.05 (m, 1H), 2.96 (s, 3H), 2.65–2.56 (m, 1H), 1.65–1.57 (m, 1H), 1.44–1.37 (m, 1H); Therefore, the structural formula of compound j-6 provided in this embodiment can be determined as shown above.

[0068] Example 7

[0069] This embodiment provides compound j-7, the structural formula of which is:

[0070] The synthesis method of compound 7 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-7 is a white solid with a yield of 12.3%. 1 ¹H NMR (400MHz, Methanol-d⁴) δ 7.29–7.11 (m, 2H), 7.09–7.00 (m, 1H), 4.97–4.89 (m, 1H), 4.65 (br, 1H), 4.26 (br, 1H), 4.04 (s, 2H), 3.86–3.46 (m, 3H), 3.33–3.11 (m, 3H), 3.08–3.01 (m, 1H), 2.97 (s, 3H), 2.69–2.56 (m, 1H), 1.67–1.53 (m, 1H), 1.50–1.32 (m, 4H); Therefore, the structural formula of compound j-7 provided in this embodiment can be determined as shown above.

[0071] Example 8

[0072] This embodiment provides compound j-8, the structural formula of which is:

[0073] The synthesis method of compound j-8 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-8 is a white solid with a yield of 11.6%. 1 ¹H NMR (400MHz, Deuterium Oxide) δ 7.21–7.11 (m, 1H), 7.08–6.99 (m, 1H), 6.97–6.88 (m, 1H), 4.95 (br, 1H), 4.55–4.44 (m, 1H), 4.34–4.19 (m, 1H), 4.05 (s, 2H), 3.65–3.52 (m, 3H), 3.24–3.02 (m, 3H), 2.98–2.88 (m, 4H), 2.57–2.40 (m, 3H), 2.02 (s, 3H), 1.99–1.82 (m, 2H), 1.57–1.48 (m, 1H), 1.39–1.29 (m, 1H); Therefore, the structural formula of compound j-8 provided in this embodiment is as shown above.

[0074] Example 9

[0075] This embodiment provides compound j-9, the structural formula of which is:

[0076] The synthesis method of compound j-9 is basically the same as that of compound j-1 provided in Example 1, the main difference being that: in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-9 is a white solid with a yield of 10.4%. 1H NMR (400MHz, Deuterium Oxide)δ7.20–7.11(m,1H),7.07–6.98(m,1H),6.95–6.88(m,1H),4.68–4.63(m,1H),4.60 –4.46(m,1H),4.43–4.27(m,1H),4.11–3.96(m,2H),3.65–3.51(m,3H),3.22–2.92(m,4H), 2.92–2.83(m,3H), 2.57–2.47(m,1H), 1.76(br,1H), 1.55–1.46(m,1H), 1.43–1.29(m,2H), 1.14–1.00(m,1H), 0.81(dq,J=22.8,7.7,7.2Hz,6H); Therefore, the structural formula of compound j-9 provided in this embodiment can be determined as shown above.

[0077] Example 10

[0078] This embodiment provides compound j-10, the structural formula of which is:

[0079] The synthesis method of compound j-10 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-10 is a white solid with a yield of 16.7%. 1 ¹H NMR (400MHz, Methanol-d⁴) δ 7.46–7.10 (m, 7H), 7.08–6.99 (m, 1H), 5.19–5.08 (m, 1H), 4.72–4.52 (m, 1H), 4.20 (dd, J=52.3, 15.0Hz, 1H), 4.08–3.93 (m, 2H), 3.57–3.37 (m, 2H), 3.32–3.16 (m, 1H), 3.11–2.88 (m, 6H), 2.76 (s, 1H), 2.60 (s, 1H), 1.59 (s, 1H), 1.43–1.32 (m, 1H); Therefore, the structural formula of compound j-10 provided in this embodiment can be determined as shown above.

[0080] Example 11

[0081] This embodiment provides compound j-11, the structural formula of which is:

[0082] The synthesis method of compound j-11 is basically the same as that of compound j-1 provided in Example 1, the main difference being that: in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-11 is a white solid with a yield of 13.1%. 1 ¹H NMR (400MHz, Methanol-d⁴) δ 7.30–7.14 (m, 2H), 7.08–7.01 (m, 1H), 4.97–4.90 (m, 1H), 4.65 (br, 1H), 4.26 (br, 1H), 4.03 (s, 2H), 3.87–3.45 (m, 3H), 3.34–3.10 (m, 3H), 3.08–3.00 (m, 1H), 2.96 (s, 3H), 2.70–2.57 (m, 1H), 1.68–1.52 (m, 1H), 1.49–1.31 (m, 4H); Therefore, the structural formula of compound j-11 provided in this embodiment can be determined as shown above.

[0083] Example 12

[0084] This embodiment provides compound j-12, the structural formula of which is:

[0085] The synthesis method of compound j-12 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-12 is a white solid with a yield of 17.8%. 1H NMR(400MHz, Methanol-d4)7.63(d,J=7.6Hz,1H),7.33(d,J=8.0Hz,1H),7.20–7.15(m,1H),7.14–7.08 (m,1H),7.08–6.98(m,2H),6.96–6.78(m,3H),5.27–5.17(m,1H),3.99–3.82(m,2H),3.54–3.40(m,2H) ,3.28–3.11(m,3H),2.92–2.78(m,2H),2.29–2.21(m,1H),2.18–2.11(m,1H),2.09(s,3H),2.07–2.00(m,2H),1.99–1.90(m,1H),1.29–1.22(m,1H),1.10–1.02(m,1H); Therefore, the structural formula of compound j-12 provided in this embodiment can be determined as shown above.

[0086] Example 13

[0087] This embodiment provides compound j-13, the structural formula of which is:

[0088] The synthesis method of compound j-13 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the X atom in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is an S atom, and the R2 atom is an S atom. Compound J-13 is a white solid with a yield of 8.4%. 1 H NMR(400MHz, Methanol-d4)δ7.27–7.14(m,2H),7.08–7.01(m,1H),5.44–5.31(m,1H),4.86–4 .82(m,1H),4.71–4.62(m,1H),4.42(d,J=16.2Hz,1H),4.30(d,J=16.3Hz,1H),4.21–3.74(m,4 The sH of the compound j-13 provided in this embodiment is 3.61–3.51 (m, 1H), 3.50–3.35 (m, 4H), 3.21–3.12 (m, 1H), 3.07–3.00 (m, 1H), 2.96 (s, 3H), 2.64–2.54 (m, 1H), 1.64–1.54 (m, 1H), 1.43–1.34 (m, 1H). Therefore, the structural formula of the compound j-13 provided in this embodiment is as shown above.

[0089] Example 14

[0090] This embodiment provides compound j-14, the structural formula of which is:

[0091] The synthesis method of compound j-14 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-14 is a white solid with a yield of 16.3%. 1 H NMR(400MHz, DMSO-d6)δ9.67(s,2H),9.23(dd,J=8.1,2.5Hz,1H),8.53(dd,J=11.4,7.6Hz,1H),7.4 7–7.20(m,7H),7.11–6.98(m,1H),5.53(dd,J=8.1,3.2Hz,1H),4.06–3.91(m,2H),3.87–3.79(m,1H ), 3.78–3.66(m,2H), 3.34–3.26(m,2H), 2.95–2.83(m,1H), 2.58–2.52(m,1H), 1.71(d,J=12.7Hz,1H), 1.61–1.51(m,2H), 1.51–1.40(m,1H), 1.38–1.27(m,2H); Therefore, the structural formula of compound j-14 provided in this embodiment can be determined as shown above.

[0092] Example 15

[0093] This embodiment provides compound j-15, the structural formula of which is:

[0094] The synthesis method of compound 15 is basically the same as that of compound 1 provided in Example 1, the main difference being that: in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-15 is a white solid with a yield of 15.7%. 1H NMR(400MHz,DMSO-d6)δ9.88(brs,1H),9.79–9.62(m,1H),9.29–9.21(m,1H),7.47–7.22(m, 11H),7.08–7.00(m,2H),6.00(d,J=7.4Hz,1H),3.97–3.91(m,2H),3.91–3.79(m,2H),3.77– 3.70(m,1H), 3.65–3.55(m,1H), 3.36–3.24(m,2H), 3.23–3.16(m,1H), 2.95–2.82(m,2H), 2.60–2.53(m,1H), 1.62–1.55(m,1H), 1.33–1.26(m,1H); Therefore, the structural formula of compound j-15 provided in this embodiment can be determined as shown above.

[0095] Example 16

[0096] This embodiment provides compound j-16, the structural formula of which is:

[0097] The synthesis method of compound j-16 is basically the same as that of compound 1 provided in Example 1, the main difference being that: in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-16 is a white solid with a yield of 16.6%. 1 H NMR(400MHz,DMSO-d6)δ9.73(brs,2H),9.26–9.15(m,1H),7.49–7.43(m,2H),7.41–7.24(m,5H),7.1 9–7.11(m,3H),7.11–7.06(m,1H),7.06–7.00(m,1H),6.09–5.96(m,1H),4.92–4.37(m,2H),3.98–3. 85(m,2H), 3.82–3.71(m,1H), 3.69–3.60(m,1H), 2.94–2.86(m,1H), 2.82–2.69(m,1H), 2.59–2.51(m,2H), 2.39–2.29(m,1H), 1.64–1.51(m,1H), 1.33–1.25(m,1H); Therefore, the structural formula of compound j-16 provided in this embodiment can be determined as shown above.

[0098] Example 17

[0099] This embodiment provides compound j-17, the structural formula of which is:

[0100] The synthesis method of compound j-17 is basically the same as that of compound 1 provided in Example 1, the main difference being that: in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound j-17 is a white solid with a yield of 8.9%. ¹H NMR (400 MHz, DMSO-d6) δ 9.67 (s, 2H), 9.16–9.08 (m, 2H), 7.43–7.22 (m, 7H), 7.08–7.00 (m, 1H), 5.87 (dd, J = 7.5, 3.0 Hz, 1H), 3.98–3.84 (m, 2H), 2.94 (d, J = 3.5 Hz, 3H), 2.92–2.87 (m, 2H), 2.87 (s, 3H), 2.86 (s, 3H), 2.58–2.51 (m, 1H), 1.61–1.51 (m, 1H), 1.35–1.24 (m, 1H); therefore, the structural formula of compound j-17 provided in this embodiment is as shown above.

[0101] Example 18

[0102] This embodiment provides compound j-18, the structural formula of which is:

[0103] The synthesis method of compound j-18 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-18 is a white solid with a yield of 14.3%. 1H NMR(400MHz, DMSO-d6)δ9.60(brs,1H),9.10(dd,J=8.0,2.2Hz,1H),8.53–8.43(m,1H),7.36–7.27 (m,2H),7.29–7.10(m,5H),6.98–6.88(m,1H),5.41(dd,J=8.0,2.7Hz,1H),3.94–3.79(m,2H),2.9 4–2.83(m,1H), 2.84–2.72(m,2H), 2.49–2.36(m,1H), 1.51–1.41(m,1H), 1.24–1.14(m,1H), 0.80–0.67(m,1H), 0.24(dd,J=8.1,2.0Hz,2H), 0.04–0.00(m,2H); Therefore, the structural formula of compound j-18 provided in this embodiment can be determined as shown above.

[0104] Example 19

[0105] This embodiment provides compound j-19, the structural formula of which is:

[0106] The synthesis method of compound j-19 is basically the same as that of compound 1 provided in Example 1, the main difference being that: in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-19 is a white solid with a yield of 13.4%. 1 HNMR(400MHz,DMSO-d6)δ9.72(brs,2H),9.25–9.14(m,1H),7.45–7.23(m,7H),7.08–7.01( m,1H),5.67(dd,J=7.6,2.5Hz,1H),3.99–3.85(m,2H),3.69–3.60(m,1H),3.35(d,J=6.4Hz ,1H),3.32–3.21(m,1H),3.17–3.06(m,1H),2.96–2.86(m,1H),2.60–2.51(m,2H),1.94–1.63(m,4H),1.63–1.53(m,1H),1.30(h,J=6.8Hz,1H); Therefore, the structural formula of compound j-20 provided in this embodiment can be determined as shown above.

[0107] Example 20

[0108] This embodiment provides compound j-20, the structural formula of which is:

[0109] The synthesis method of compound j-20 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-20 is a white solid with a yield of 12.8%. 1 H NMR(400MHz, DMSO-d6)δ9.76(brs,1H),9.24(dd,J=7.9,2.2Hz,1H),8.56–8.46(m,1H),7.48–7.40(m, 2H),7.40–7.22(m,5H),7.10–7.01(m,1H),5.50(dd,J=7.9,3.4Hz,1H),4.05–3.91(m,2H),3.46–3.35( The stoichiometric coefficients are: m, 1H), 3.29–3.21 (m, 2H), 3.18–3.01 (m, 2H), 2.95–2.84 (m, 1H), 2.61–2.51 (m, 1H), 1.63–1.51 (m, 3H), 1.36–1.26 (m, 1H), 1.02 (d, J = 1.9 Hz, 3H), 1.01 (d, J = 1.9 Hz, 3H); Therefore, the structural formula of compound j-20 provided in this embodiment can be determined as shown above.

[0110] Example 21

[0111] This embodiment provides compound j-21, the structural formula of which is:

[0112] The synthesis method of compound j-21 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-21 is a white solid with a yield of 13.5%. 1H NMR(400MHz,DMSO-d6)δ9.74(br,2H),9.25–9.13(m,1H),8.64–8.51(m,1H),7.48–7.41(m, 2H),7.39–7.24(m,5H),7.08–7.02(m,1H),5.60–5.52(m,1H),4.03–3.91(m,2H),3.84–3.76 (m, 1H), 3.74–3.64(m, 1H), 3.60–3.53(m, 1H), 3.13(t, J = 5.7 Hz, 2H), 2.94–2.84(m, 1H), 2.61–2.50(m, 1H), 1.85–1.55(m, 4H), 1.51–1.25(m, 2H); Therefore, the structural formula of compound j-21 provided in this embodiment can be determined as shown above.

[0113] Example 22

[0114] This embodiment provides compound j-22, the structural formula of which is:

[0115] The synthesis method of compound j-22 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-22 is a white solid with a yield of 7.4%. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.86 (brs, ¹H), 9.50–9.29 (m, ¹H), 7.50–7.20 (m, 7H), 7.10–7.01 (m, ¹H), 5.53–5.37 (m, ¹H), 3.97 (d, J = 3.2Hz, 2H), 3.63 (s, 2H), 2.99–2.89 (m, ¹H), 2.63–2.53 (m, ¹H), 1.67–1.53 (m, ¹H), 1.36–1.21 (m, ¹H); Therefore, the structural formula of compound j-22 provided in this embodiment can be determined as shown above.

[0116] Example 23

[0117] This embodiment provides compound j-23, the structural formula of which is:

[0118] The synthesis method of compound j-23 is basically the same as that of compound 1 provided in Example 1, the main difference being that: in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-23 is a white solid with a yield of 16.9%. 1 H NMR(400MHz,DMSO-d6)δ9.75(brs,2H),9.27(dd,J=7.8,2.3Hz,1H),9.12–8.96(m,1H) ,7.50–7.42(m,2H),7.40–7.20(m,8H),7.19–7.14(m,2H),7.09–7.01(m,1H),5.57(dd J = 7.7, 2.5 Hz, 1H), 4.37–4.19 (m, 2H), 4.08–3.85 (m, 2H), 2.97–2.82 (m, 1H), 2.60–2.52 (m, 1H), 1.67–1.51 (m, 1H), 1.37–1.25 (m, 1H); Therefore, the structural formula of the compound j-23 provided in this embodiment can be determined as shown above.

[0119] Example 24

[0120] This embodiment provides compound j-24, the structural formula of which is:

[0121] The synthesis method of compound j-24 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-24 is a white solid with a yield of 17.1%. 1H NMR(400MHz,DMSO-d6)δ9.79(br,2H),9.22–9.08(m,1H),7.49–7.21(m,7H),7.04(d,J=8.1Hz,1H),5 .94(dd,J=51.2,7.4Hz,1H),4.26(d,J=12.9Hz,1H),4.02–3.82(m,3H),3.48–3.39(m,1H),3.23–3.1 1(m,1H), 2.94–2.86(m,1H), 2.78–2.69(m,1H), 2.61–2.52(m,1H), 2.38–2.19(m,2H), 1.64–1.53(m,1H), 1.34–1.24(m,1H), 1.13–0.98(m,4H), 0.91–0.86(m,2H); Therefore, the structural formula of compound j-24 provided in this embodiment can be determined as shown above.

[0122] Example 25

[0123] This embodiment provides compound j-25, the structural formula of which is: The synthesis method of compound j-25 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-25 is a white solid with a yield of 14.7%. 1 ¹H NMR (400MHz, DMSO-d₆) δ 9.65 (s, 1H), 9.25 (dd, J = 7.8, 3.0Hz, 1H), 9.11 (dd, J = 12.8, 6.7Hz, 1H), 7.45–7.24 (m, 7H), 7.05 (dtt, J = 7.3, 5.3, 2.7Hz, 1H), 5.46 (dd, J = 7.8, 3.6Hz, 1H), 4.12–3.90 (m, 3H), 2.98–2.78 (m, 3H), 2.69–2.50 (m, 3H), 1.63–1.50 (m, 1H), 1.34–1.28 (m, 1H); Therefore, the structural formula of compound j-25 provided in this embodiment can be determined as shown above.

[0124] Example 26

[0125] This embodiment provides compound j-26, the structural formula of which is: The synthesis method of compound j-26 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-26 is a white solid with a yield of 17.8%. 1 H NMR(400MHz, DMSO-d6)δ9.67(s,2H),9.23(dd,J=8.1,2.5Hz,1H),8.53(dd,J=11.4,7.6Hz ,1H),7.47–7.20(m,7H),7.11–6.98(m,1H),5.53(dd,J=8.1,3.2Hz,1H),4.06–3.91(m,2H ), 3.87–3.79(m,1H), 3.78–3.66(m,2H), 3.34–3.26(m,2H), 2.95–2.83(m,1H), 2.58–2.52(m,1H), 1.71(d,J=12.7Hz,1H), 1.61–1.51(m,2H), 1.51–1.40(m,1H), 1.38–1.27(m,2H). Therefore, the structural formula of compound j-26 provided in this embodiment can be determined as shown above.

[0126] Example 27

[0127] This embodiment provides compound j-27, the structural formula of which is:

[0128] The synthesis method of compound j-27 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-27 is a white solid with a yield of 12.4%. 1H NMR(400MHz,DMSO-d6)δ10.79(brs,1H),9.78(brs,2H),9.40–9.27(m,1H),9.01–8.84(m ,1H),7.49–7.41(m,2H),7.39–7.24(m,5H),7.06(s,1H),5.47(d,J=7.0Hz,1H),4.08–3. 89(m,2H), 3.58–3.48(m,1H), 3.46–3.40(m,1H), 3.20–3.07(m,2H), 2.91(br,1H), 2.73(s,6H), 2.57(br,1H), 1.59(br,1H), 1.31(br,1H); Therefore, the structural formula of compound j-27 provided in this embodiment can be determined as shown above.

[0129] Example 28

[0130] This embodiment provides compound j-28, the structural formula of which is:

[0131] The synthesis method of compound j-28 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-28 is a white solid with a yield of 13.6%. 1 H NMR(400MHz, Deuterium Oxide)δ7.46–7.37(m,3H),7.36–7.25(m,2H),7.17–7.08(m,1H),7.03–6.94(m,1H),6.90–6 .82(m,1H),5.90–5.79(m,1H),4.28–4.17(m,1H),4.12–3.92(m,2H),3.78–3.65(m,1H),3.36 –3.19(m,1H),3.14–2.98(m,1H),2.96–2.86(m,1H),2.56–2.43(m,1H),1.85–1.70(m,2H),1.58–1.45(m,2H),1.37–1.24(m,4H),0.87–0.71(m,1H); Therefore, the structural formula of compound j-28 provided in this embodiment can be determined as shown above.

[0132] Example 29

[0133] This embodiment provides compound j-29, the structural formula of which is:

[0134] The synthesis method of compound j-29 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-29 is a white solid with a yield of 15.7%. 1 ¹H NMR (400MHz, DMSO-d⁶) δ 9.94–9.44 (m, 4H), 9.26–9.16 (m, 1H), 7.44–7.25 (m, 7H), 7.07–7.01 (m, 1H), 5.96 (d, J = 7.2Hz, 1H), 3.99–3.79 (m, 4H), 3.64–3.55 (m, 1H), 3.54–3.46 (m, 2H), 3.08–2.95 (m, 3H), 2.92–2.86 (m, 1H), 2.65 (br, 1H), 2.58–2.52 (m, 1H), 1.60–1.51 (m, 1H), 1.34–1.26 (m, 1H); Therefore, the structural formula of compound j-29 provided in this embodiment can be determined as shown above.

[0135] Example 30

[0136] This embodiment provides compound j-30, the structural formula of which is:

[0137] The synthesis method of compound j-30 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-30 is a white solid with a yield of 14.8%. 1H NMR (400MHz, Deuterium Oxide)δ7.47–7.34(m,3H),7.37–7.23(m,2H),7.19–7.06(m,1H),7.04–6.92(m,1H),6.86(p,J=5. 8Hz,1H),5.92–5.77(m,1H),4.52–4.39(m,1H),4.12–3.84(m,3H),3.41–3.26(m,1H),3.19–3.06(m ,1H),2.97–2.84(m,1H),2.82–2.70(m,1H),2.54–2.41(m,1H),2.10–1.88(m,2H),1.73–1.60(m,1H),1.53–1.43(m,1H),1.37–1.18(m,2H),0.49–0.30(m,1H); Therefore, the structural formula of compound j-30 provided in this embodiment can be determined as shown above.

[0138] Example 31

[0139] This embodiment provides compound j-31, the structural formula of which is:

[0140] The synthesis method of compound j-31 is basically the same as that of compound 1 provided in Example j-1, the main difference being that: in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is The compound J-31 is a white solid with a yield of 12.3%. 1 H NMR (400MHz, DMSO-d6) δ10.79 (s, 1H), 8.64–8.54 (m, 1H), 8.46 (br, 1H), 7.51 (dd, J = 8. 0,3.0Hz,1H),7.42–7.23(m,7H),7.17(br,1H),7.10–7.01(m,2H),7.00–6.90(m,2H),5 .47(br,1H),3.99–3.81(m,2H),3.34–3.29(m,2H),2.86–2.77(m,2H),2.73(s,1H),2.19–2.08(m,1H),1.30(s,10H),1.19–1.08(m,1H); Therefore, the structural formula of compound j-31 provided in this embodiment can be determined as shown above.

[0141] Example 32

[0142] This embodiment provides compound j-32, the structural formula of which is: The synthesis method of compound j-32 is basically the same as that of compound j-1 provided in Example 1. The main difference is that in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is Compound J-32 is a white solid with a yield of 13.7%. 1 ¹H NMR (400MHz, DMSO-d6) δ 7.44–7.23 (m, 5H), 7.16 (br, 1H), 7.05–6.71 (m, 2H), 4.37 (t, J = 15.7Hz, 1H), 3.98–3.73 (m, 3H), 3.03–2.66 (m, 3H), 2.64–2.53 (m, 2H), 2.12 (br, 1H), 1.64–1.45 (m, 3H), 1.20–1.16 (m, 1H), 1.07–0.92 (m, 1H); Therefore, the structural formula of compound j-32 provided in this embodiment can be determined as shown above.

[0143] Example 33

[0144] This embodiment provides compound j-33, the structural formula of which is:

[0145] The synthesis method of compound j-33 is basically the same as that of compound 1 provided in Example 1, the main difference being that: in this example, the corresponding R1 group in the structural formulas of raw material a, raw material fatty amine R2H, intermediate b, intermediate c, intermediate i, and the target compound is... Group R2 is The compound J-33 is a white solid with a yield of 7.7%. 1 ¹H NMR (400MHz, Methanol-d⁴) δ 7.51–7.29 (m, 5H), 7.06–6.95 (m, 1H), 6.94–6.70 (m, 2H), 5.90–5.72 (m, 1H), 4.43–4.08 (m, 2H), 4.02–3.66 (m, 3H), 3.64–3.14 (m, 3H), 2.83–2.69 (m, 1H), 2.21–2.07 (m, 1H), 1.25–1.16 (m, 1H), 1.10–0.99 (m, 1H); Therefore, the structural formula of compound j-33 provided in this embodiment can be determined as shown above.

[0146] Example 34

[0147] This embodiment provides compound j-34, the structural formula of which is:

[0148] Compound J-1 was extracted with ethyl acetate / saturated sodium bicarbonate aqueous solution, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and evaporated to dryness to obtain compound J-34, which was a pale yellow liquid.

[0149] Example 35

[0150] This embodiment provides compound j-35, the structural formula of which is:

[0151] Compound J-2 was extracted with ethyl acetate / saturated sodium bicarbonate aqueous solution, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and evaporated to dryness to give compound J-35, which was a pale yellow liquid.

[0152] Example 36

[0153] This embodiment provides compound j-36, the structural formula of which is:

[0154] Compound J-3 was extracted with ethyl acetate / saturated sodium bicarbonate aqueous solution, the organic phases were combined, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and evaporated to dryness to give compound J-36, which was a pale yellow liquid.

[0155] Example 37

[0156] This embodiment provides compound j-37, the structural formula of which is:

[0157] Compound J-34 (0.1 g, 0.23 mmol) was dissolved in ethyl acetate (5 ml), and trifluoroacetic acid (0.05 g, 0.45 mmol) was added. The mixture was stirred at room temperature for 2 h, and then evaporated to dryness to obtain compound J-37, which was a white solid.

[0158] Example 38

[0159] This embodiment provides compound j-38, the structural formula of which is:

[0160] Compound J-34 (0.1 g, 0.23 mmol) was dissolved in ethyl acetate (5 ml) solution, and methanesulfonic acid (0.04 g, 0.45 mmol) was added. The mixture was stirred at room temperature for 2 h, and then evaporated to dryness to obtain compound J-38, which was white.

[0161] LSD1 inhibitory activity assay

[0162] Experimental Methods: The samples were compounds j-1 to j-33 and ORY-1001 synthesized in the above examples (purchased from MedChemExpress). Sample Stock Solution: Weigh 1-2 mg of each sample and dissolve them in DMSO (dimethyl sulfoxide) to prepare a 10 mM stock solution. Dilute with DMSO to the required concentration for the experiment. Incubate the samples with the human complex protein LSD1 / CoREST purified from the *E. coli* expression system, followed by incubation with the substrate H3K4me2 synthesized by Jier Biochemical (Shanghai) Co., Ltd. for 30 min. After incubation, add the fluorescent dye Amplex Red and horseradish peroxidase HRP and react for 5 min. Then, measure the fluorescence signal (E) using an EnVision microplate reader (PerkinElmer, Waltham, MA, USA). X =535nm, E m =595nm), and its inhibition rate was calculated. The results are shown in Table 1. Specifically, the inhibition rate is calculated using the following formula:

[0163]

[0164] In the above inhibition rate calculation formula, the "sample group fluorescence intensity," "standard group fluorescence intensity," and "blank group fluorescence intensity" are all fluorescence intensity values ​​measured using the experimental method described above. The difference lies in that, under the same conditions, the "sample group fluorescence intensity" is measured on a sample solution containing the compound to be tested, while the "standard group fluorescence intensity" is measured on a standard solution that does not contain the sample compared to the sample solution. The "blank group fluorescence intensity" is measured on a blank sample that does not contain LSD1 / CoREST complex protein and H3K4me2 peptide. The IC50 of the above sample compounds was processed using Graphpad Prism 8.0. 50 The data and results are shown in Table 1.

[0165] Table 1. Results of the inhibitory activity of the compounds provided in the embodiments of the present invention against LSD1.

[0166]

[0167]

[0168] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them; although the present invention has been described in detail with reference to preferred embodiments, those skilled in the art should understand that modifications can still be made to the specific implementation of the present invention or equivalent substitutions can be made to some technical features without departing from the spirit of the technical solutions of the present invention, and all such modifications and substitutions should be covered within the scope of the technical solutions claimed in the present invention.

Claims

1. A dipeptide compound, characterized in that: This includes dipeptide compounds or their pharmaceutically acceptable salts with the following general structural formula: or Wherein, group R1 is , , , , , , , or The group R2 is , , , , , , , , , , , , , , , , , , , or The group X is an atom C or S.

2. A dipeptide compound, characterized in that, The structural formula is: , , or .

3. A method for preparing the dipeptide compound according to claim 1, comprising the steps of: Preparation of intermediate i: Intermediate i is synthesized by an amidation reaction using intermediate h and intermediate c as raw materials; wherein, The structural formula of the intermediate h is as follows: The general structural formula of the intermediate c is as follows: or Furthermore, groups R1, R2, and X are as described in claim 1; the general structural formula of intermediate i is: or ; The target compound j was prepared by removing the tert-butyloxycarbonyl group protecting group from intermediate i under acidic conditions to synthesize the target compound j, i.e., the aforementioned dipeptide compound. The general structural formula of the target compound j is as follows: or .

4. The preparation method according to claim 3, characterized in that, The preparation steps of intermediate i include: adding intermediate h, intermediate c, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, and 1-hydroxybenzotriazole to a first organic solvent in a molar ratio of 1:1-3:1-3:0.1-1.5, and stirring at room temperature for 6-24 h; monitoring the reaction by thin-layer chromatography (TLC), and separating intermediate i after the reaction is completed; wherein, the first organic solvent is N,N-dimethylformamide or dichloromethane.

5. The preparation method according to claim 3 or 4, characterized in that, The steps for preparing the target compound j include: first, adding the intermediate i and the first acidic substance to a second organic solvent at a ratio of 1:5 to 30, and stirring at room temperature for 0.5 to 6 h, wherein the first acidic substance is hydrochloric acid or trifluoroacetic acid, and the second organic solvent is dichloromethane, ethyl acetate, methanol, ethanol, or 1,4-dioxane.

6. The preparation method according to claim 3 or 4, characterized in that, The preparation method of intermediate c includes: hydrolyzing intermediate b under acidic conditions and adjusting the pH to alkaline to obtain intermediate c, wherein the general structural formula of intermediate b is as follows: or .

7. The preparation method according to claim 6, characterized in that, The preparation method of the intermediate b includes: using raw material a and aliphatic amine R2H as raw materials, an amidation reaction is carried out to synthesize intermediate b, wherein the general structural formula of raw material a is: or .

8. The preparation method according to claim 3 or 4, characterized in that, The preparation method of intermediate h includes: reacting intermediate g in a mixed solvent of methanol and water under the action of lithium hydroxide for 2–24 h, adjusting the pH to 3–4 with citric acid, and then separating the intermediate to obtain intermediate h. The structural formula of intermediate g is as follows: .

9. The preparation method according to claim 8, characterized in that, The preparation method of intermediate g includes: reacting intermediate f with di-tert-butyl dicarbonate under the action of an alkaline substance for 2–24 h, followed by separation to obtain intermediate g, wherein the structural formula of intermediate f is as follows: The alkaline substance is triethylamine, diisopropylethylamine, ethylenediamine, potassium carbonate, or sodium bicarbonate.

10. The preparation method according to claim 9, characterized in that, The preparation method of intermediate f includes: dissolving intermediate e and ethyl glyoxylate in an ethanol solution, forming an imine intermediate under the catalysis of acetic acid, followed by reduction with sodium cyanoborohydride, separation, and obtaining intermediate f, wherein the structural formula of intermediate e is as follows: .

11. The preparation method according to claim 10, characterized in that, The preparation method of intermediate e includes: stirring compound d in an alkaline environment at room temperature for 0.5–6 h; followed by extraction and vacuum concentration to obtain intermediate e, wherein the structural formula of compound d is as follows: .

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