Acetal pantothenic acid derivative as well as preparation method and application thereof

Abstract

The invention relates to the field of medicinal chemistry, and discloses an acetal pantothenic acid derivative as well as a preparation method and application thereof. According to the preparation method, calcium pantothenate is taken as a raw material and is subjected to a condensation reaction with various aldehyde compounds under the catalysis of acid, an amino-containing structure is introduced through amidation, and the acetal pantothenic acid derivative with a novel structure is synthesized. The synthesis route has the advantages of cheap and easily available raw materials, mild conditions and simple operation. The acetal pantothenic acid derivative disclosed by the invention can be used for remarkably promoting the response of an STING signal channel. When the compound is used for treating cells at the concentration of 10 mu M, IFN beta 1 mRNA expression induced by STING agonist can be remarkably enhanced, and the enhancement multiple can reach 4715.8. The acetal pantothenic acid derivative disclosed by the invention has a good immune excitation synergistic effect, and is suitable for development of related medicines such as tumor immunotherapy, virus resistance and vaccine adjuvants.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and more specifically, to an acetal pantothenic acid derivative, its preparation method, and its application. Background Technology

[0002] The cGAS-STING pathway is an innate immune signaling pathway that has attracted much attention in the field of tumor immunotherapy in recent years. When tumors develop or external viral invasion leads to abnormal accumulation of nucleic acids in the cytoplasm, cGAS can recognize dsDNA and catalyze the production of endogenous STING agonists such as cGAMP, thereby inducing a conformational change in STING, which is then transported from the endoplasmic reticulum to the Golgi apparatus. During this process, STING recruits and activates TBK1, which then phosphorylates IRF3, allowing it to enter the nucleus and induce the expression of type I interferon and various inflammatory cytokines, further promoting innate and tumor adaptive immune responses, and achieving anti-tumor and antiviral immune effects.

[0003] The development of direct agonists of the STING pathway has made progress, including both nucleic acid and non-nucleic acid molecules such as S-cddA, diABZI, and MSA-2, all of which have shown potential for antitumor or antiviral activity. However, the clinical application of direct agonists remains significantly limited: on the one hand, systemic administration can easily induce a systemic increase in type I interferon, leading to significant immune side effects; on the other hand, many patients with solid tumors or viral infections have various immunosuppressive factors that make it difficult to fully activate STING signaling, thus weakening the therapeutic effect of direct agonists.

[0004] Therefore, removing the inhibitory factors that activate cGAS-STING signaling under pathological conditions can effectively activate cGAS-STING signaling under pathological conditions, or enhance the signal response generated by direct STING agonists, thereby achieving anti-tumor or antiviral immunotherapeutic effects. Although some studies have attempted to improve STING pathway activation from an indirect regulatory perspective, for example, patent CN118903428A can enhance the type I interferon response of immune cells to dsDNA or STING agonist stimulation to some extent by inhibiting the deubiquitinating enzyme USP1, overall, there are still few reported related studies.

[0005] Therefore, current technologies still lack small molecule promoters that can directly trigger the STING signaling pathway under pathological conditions or enhance the activation efficiency of the cGAS-STING pathway mediated by direct STING agonists, thereby enhancing anti-tumor or antiviral immune effects. Summary of the Invention

[0006] To overcome the shortcomings of the prior art, which lacks small molecule co-agonists that can be directly combined with STING direct agonists and significantly improve their activation efficiency of the cGAS-STING pathway, thereby enhancing anti-tumor and antiviral immune effects, the present invention provides an acetal pantothenic acid derivative. Another objective of this application is to provide a method for preparing acetal pantothenic acid derivatives; Another objective of this application is to provide an application of an acetal pantothenic acid derivative.

[0007] To solve the above-mentioned technical problems, the technical solution of the present invention is as follows: An acetal pantothenic acid derivative, the structural formula of which is shown in Formula I and Formula II:

[0008] In Formula I, R1 is selected from phenyl, 2-pyrrole, 2-thienyl, 3-indolyl, 5-fluoro-3-indolyl, 5-methoxy-3-indolyl, 4-quinolinyl, 2-aminophenyl, 2-halophenyl, 3-halophenyl, 4-halophenyl, 4-acetylphenyl, 4-nitrophenyl, 4-aminophenyl, 5-oxo-5,6,7,8-tetrahydronaphth-2-yl, and 3,4-diiodophenyl; X is selected from , , , , ; In Formula II, R3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, phenyl, 4-halophenyl, 3-halophenyl, 2-halophenyl, 4-nitrophenyl, 4-alkynylphenyl, and 4-methoxyphenyl. In Formula I and Formula II, R2 is selected from hydrogen, ethyl, n-butyl, 4-ethylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-methylthiophenyl, 4-halophenyl, 3-halophenyl, 4-cyanophenyl, cyclohexyl, phenyl, pyrroleyl, thiophenyl, and 3,4,5-trimethoxyphenyl.

[0009] Furthermore, in Formula I, R1 is selected from phenyl, 3-iodophenyl, and 4-iodophenyl; X is selected from ethylenediamine or piperazine; and R2 is selected from 4-methoxy, 4-iodophenyl, and 4-cyanophenyl.

[0010] Furthermore, in Formula II, R2 is 4-methoxyphenyl, and R3 is selected from aniline, 3-iodoaniline, and 4-iodoaniline.

[0011] A method for preparing the acetal pantothenic acid derivative includes the following steps: S1. Calcium pantothenate is reacted with an acidic reagent to form an active intermediate, which is then condensed with R2-CHO under catalyst A to obtain intermediate 1. ; S2. R1-COOH is reacted with ethylenediamine or piperazine protected by a single-sided BOC in the presence of catalyst B and an acid-binding agent to undergo an amidation reaction, yielding intermediate 2. Or intermediate 3 ; S3, regarding intermediate 2 Or intermediate 3 After removing the BOC group, intermediate 4 is obtained. Or intermediate 5 ; S4, intermediate 1 With intermediate 4 Or intermediate 5 An amidation reaction was carried out under catalyst B and an acid-binding agent to obtain the acetal pantothenic acid derivative shown in Formula I. S5, intermediate 1 The acetal pantothenic acid derivative shown in Formula II was obtained by amidation reaction with R3-NH2 under catalyst B and acid-binding agent. In S1, R2 in R2-CHO is selected from hydrogen, ethyl, n-butyl, 4-ethylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-methylthiophenyl, 4-halophenyl, 3-halophenyl, 4-cyanophenyl, cyclohexyl, phenyl, pyrrole, thiophene, 3,4,5-trimethoxyphenyl; In S2, R1 in R1-COOH is selected from phenyl, 2-pyrrole, 2-thienyl, 3-indolyl, 5-fluoro-3-indolyl, 5-methoxy-3-indolyl, 4-quinolinyl, 2-aminophenyl, 2-halophenyl, 3-halophenyl, 4-halophenyl, 4-acetylphenyl, 4-nitrophenyl, 4-aminophenyl, 5-oxo-5,6,7,8-tetrahydronaphth-2-yl, and 3,4-diiodophenyl; In S5, R3 in R3-NH2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, phenyl, 4-halophenyl, 3-halophenyl, 2-halophenyl, 4-nitrophenyl, 4-ynylphenyl, and 4-methoxyphenyl.

[0012] Furthermore, in S1, the molar ratio of calcium pantothenate to R2-CHO is 1:2~6; in S5, the molar ratio of intermediate 1 to R3-NH2 is 1:1~3.

[0013] Preferably, in S1, the molar ratio of calcium pantothenate to R2-CHO is 1:4; in S5, the molar ratio of intermediate 1 to R3-NH2 is 1:1.2.

[0014] Furthermore, in S2, the molar ratio of R1-COOH to ethylenediamine protected by a single-sided BOC is 1:1~3; or the molar ratio of R1-COOH to piperazine protected by a single-sided BOC is 1:1~3.

[0015] Preferably, in S2, the molar ratio of R1-COOH to ethylenediamine protected by a single-sided BOC is 1:1.2; or the molar ratio of R1-COOH to piperazine protected by a single-sided BOC is 1:1.2.

[0016] Furthermore, in S4, the molar ratio of intermediate 1 to intermediate 4 is 1:1~3; or the molar ratio of intermediate 1 to intermediate 5 is 1:1~3.

[0017] Preferably, in S4, the molar ratio of intermediate 1 to intermediate 4 is 1:1.2; or the molar ratio of intermediate 1 to intermediate 5 is 1:1.2.

[0018] Furthermore, the condensation in S1 proceeds at room temperature for 4-6 hours; the amidation reaction in S2 proceeds at room temperature for 1-2 hours.

[0019] Preferably, S1 to S5 are all carried out in an organic solvent, including dichloromethane.

[0020] Preferably, catalyst B comprises at least one of dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 4-dimethylaminopyridine, 1-hydroxybenzotriazole, N,N'-carbonyldiimidazole, O-(7-azabenzotriazole-1-yl)-N,N,N',N'-tetramethylurea, and benzotriazole-1-yl-oxotripyrrolylphosphide; and the acid-absorbing agent is at least one of N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, and pyridine.

[0021] Preferably, S3 uses trifluoroacetic acid to remove the BOC group.

[0022] Preferably, the acidic reagent in S1 is trifluoroacetic acid, and the catalyst A is camphor sulfonic acid.

[0023] Preferably, the catalysts in S2, S4 and S5 are 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1-hydroxybenzotriazole, and the acid-binding agent is N,N-diisopropylethylamine.

[0024] An application of the aforementioned acetal pantothenic acid derivative in the preparation of tumor immunotherapy and antiviral drugs, as well as in vaccine adjuvants.

[0025] Furthermore, the pharmaceutical composition includes the acetal pantothenic acid derivative and its pharmaceutically acceptable salt.

[0026] Compared with the prior art, the beneficial effects of the technical solution of the present invention are: The acetal pantothenic acid derivative of this invention has a novel structure, a simple and mild synthetic route, readily available raw materials, and good reaction yield and industrial feasibility. The synthesized acetal pantothenic acid derivative significantly enhances STING signaling-mediated intracellular IFNβ1 expression, indicating its strong ability to enhance the activity of the STING signaling pathway. In vitro experimental results show that it can significantly upregulate STING agonist-induced IFNβ1 mRNA expression levels, with compounds A23 and A25 showing fold increases of 4715.83 and 4402.59, respectively, significantly superior to the STING agonist-only group, demonstrating good immunomodulatory potential. The acetal pantothenic acid derivative of this invention can be used as a synergistic agent with STING agonists and has wide applications in antitumor and antiviral immunotherapy, vaccine adjuvant development, and other fields. Detailed Implementation

[0027] The present invention will be further described below with reference to specific embodiments in the specification, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field.

[0028] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0029]

[0030]

[0031] The preparation of acetal pantothenic acid derivatives is carried out via the following route:

[0032]

[0033] S1. Calcium pantothenate reacts with an acidic reagent to form an active intermediate, which is then condensed with R2-CHO under catalyst A to obtain intermediate 1: ; S2. R1-COOH is reacted with mono-BOC-ethylenediamine or piperazine-1-carboxylic acid methyl ester in the presence of catalyst B and an acid-binding agent to undergo an amidation reaction, yielding intermediate 2: Or intermediate 3: ; S3, regarding intermediate 2 Or intermediate 3 After removing the BOC group, intermediate 4 is obtained: Or intermediate 5: ; S4, intermediate 1 With intermediate 4 Or intermediate 5 An amidation reaction was carried out under catalyst B and an acid-binding agent to obtain the acetal pantothenic acid derivative shown in Formula I. S5, intermediate 1 The acetal pantothenic acid derivative shown in Formula II was obtained by amidation reaction with R3-NH2 under catalyst B and acid-binding agent. In S1, R2 in R2-CHO is selected from hydrogen, ethyl, n-butyl, 4-ethylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-methylthiophenyl, 4-halophenyl, 3-halophenyl, 4-cyanophenyl, cyclohexyl, phenyl, pyrrole, thiophene, 3,4,5-trimethoxyphenyl; In S2, R1 in R1-COOH is selected from phenyl, 2-pyrrole, 2-thienyl, 3-indolyl, 5-fluoro-3-indolyl, 5-methoxy-3-indolyl, 4-quinolinyl, 2-aminophenyl, 2-halophenyl, 3-halophenyl, 4-halophenyl, 4-bromophenyl, 4-chlorophenyl, 4-acetylphenyl, 4-nitrophenyl, 4-aminophenyl, 5-oxo-5,6,7,8-tetrahydronaphth-2-yl, and 3,4-diiodophenyl; In S5, R3 in R3-NH2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, phenyl, 4-halophenyl, 3-halophenyl, 2-halophenyl, 4-nitrophenyl, 4-ynylphenyl, and 4-methoxyphenyl.

[0034] In S1, the molar ratio of calcium pantothenate to R2-CHO is 1:2~6; in S5, the molar ratio of intermediate 1 to R3-NH2 is 1:1~3.

[0035] In S2, the molar ratio of R1-COOH to ethylenediamine protected by a single-sided BOC is 1:1~3; or the molar ratio of R1-COOH to piperazine protected by a single-sided BOC is 1:1~3.

[0036] In S4, the molar ratio of intermediate 1 to intermediate 4 is 1:1~3; or the molar ratio of intermediate 1 to intermediate 5 is 1:1~3.

[0037] The condensation in S1 proceeds at room temperature for 4-6 hours; the amidation reaction in S2 proceeds at room temperature for 1-2 hours.

[0038] The acidic reagent is trifluoroacetic acid (TFA), and catalyst A is camphor sulfonic acid (CSA); catalyst B includes at least one of dicyclohexylcarbodiimide, diisopropylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, 4-dimethylaminopyridine, 1-hydroxybenzotriazole, N,N'-carbonyldiimidazole, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethylurea, and benzotriazol-1-yl-oxotripyrrolylphosphine hexafluorophosphate; the acid-releasing agent is at least one of N,N-diisopropylethylamine, triethylamine, N-methylmorpholine, and pyridine.

[0039] Example 1 Preparation of acetal pantothenic acid derivatives A1~A28 S1. Add calcium pantothenate (1 eq) to a reaction flask, add 10 mL of trifluoroacetic acid, and stir at room temperature until the calcium pantothenate is completely dissolved. Reduce the trifluoroacetic acid concentration by rotary evaporation to obtain a colorless oil. Add 10 mL of dichloromethane as a solvent, along with R2-CHO (4 eq) and camphorsulfonic acid (0.1 eq) as a catalyst. Stir the reaction at room temperature for 4–6 hours, monitoring the reaction for completeness by TLC. Add 20 mL of sodium carbonate solution (1 M) to the above reaction flask and filter. Extract the filtrate with water / dichloromethane. Retain the aqueous layer, acidify to pH 4–5 with 10% hydrochloric acid solution, and immediately extract with dichloromethane, retaining the organic phase. Reduce the concentration by rotary evaporation, and perform column chromatography to obtain intermediate 1.

[0040] S2. Dissolve R1-COOH (1 eq) and ethylenediamine (or piperazine with a single-sided BOC protection) (1.2 eq) in 10 mL of dichloromethane. Add the catalysts 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2 eq), 1-hydroxybenzotriazole (2 eq), and the acid-containing agent N,N-diisopropylethylamine (3 eq). Stir the mixture at room temperature for 1–2 hours, and monitor the reaction until complete by TLC. Quench the reaction with a large amount of water, extract with water / dichloromethane, and retain the organic layer to obtain intermediate 2 (intermediate 3). The crude product can be used directly in the next reaction.

[0041] S3. Dissolve crude intermediate 2 (intermediate 3) in 10 mL of dichloromethane, add 1 mL of trifluoroacetic acid, stir at room temperature, and monitor the reaction until complete by TLC. Dry the dichloromethane and trifluoroacetic acid by rotary evaporation to obtain intermediate 4 (intermediate 5).

[0042] S4. Intermediate 1 (1 eq) and Intermediate 4 (Intermediate 5) (1.2 eq) were dissolved in 10 mL of dichloromethane. Catalysts 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2 eq) and 1-hydroxybenzotriazole (2 eq) were added, along with the acid-setting agent N,N-diisopropylethylamine (3 eq). The reaction was stirred at room temperature and monitored by TLC until complete. The reaction was quenched with a large amount of water, extracted with water / dichloromethane, and the organic layer was retained. The solution was evaporated to dryness, and column chromatography was used to obtain the acetal pantothenic acid derivatives A1~A26 as shown in Formula I.

[0043] S5. Intermediate 1 (1 eq) and R3-NH2 (1.2 eq) were dissolved in 10 mL of dichloromethane. Catalysts 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (2 eq) and 1-hydroxybenzotriazole (2 eq) were added, along with the acid-setting agent N,N-diisopropylethylamine (3 eq). The mixture was stirred at room temperature, and the reaction was monitored by TLC until complete. The reaction was quenched with a large amount of water, extracted with water / dichloromethane, and the organic layer was retained. The solution was evaporated to dryness, and column chromatography was used to precipitate the acetal pantothenic acid derivatives A27~A28 as shown in Formula II.

[0044] In S1, R2 of R2-CHO is 4-methoxy, 4-iodophenyl, or 4-cyanophenyl; in S2, R1 of R1-COOH is phenyl, 3-iodophenyl, or 4-iodophenyl; X is selected from ethylenediamine or piperazine; in S5, R3 of R3-NH2 is aniline, 3-iodoaniline, or 4-iodoaniline.

[0045] Example 2 Determination of the enhancing effect of acetal pantothenic acid derivatives on the STING signaling pathway This embodiment uses a STING direct agonist model to evaluate its enhancing effect on the STING signaling pathway by measuring the effect of the acetal pantothenic acid derivative on the expression of type I interferon mRNA mediated by the STING direct agonist S-cddA in RAW264.7 cells. 1–2 mg of each sample was weighed into a 1.5 mL EP tube, and DMSO was added to prepare a 10 mM solution as a stock solution. The experiment included a blank group, a control group, and an experimental group (cell density: 1 × 10⁻⁶). 6 In the blank control group, an equal volume of DMSO was added as to the drugs added to the control and experimental groups, and incubation was carried out for 2 hours. In the control group, only the STING direct agonist S-cddA was added, bringing the S-cddA concentration in the system to 50 nM, and incubation was carried out for 2 hours. In the experimental group, the acetal pantothenic acid derivative stock solution was diluted with DMSO and added to the cell lines to be tested along with the STING direct agonist ScddA, bringing the total S-cddA concentration in the system to 50 nM and the acetal pantothenic acid derivative concentration to 10 μM. Both were incubated for 2 hours. The structural formula of S-cddA is as follows:

[0046] Detection methods 1. Chemical structure characterization The compounds were characterized by nuclear magnetic resonance (NMR) and high-resolution mass spectrometry (HRMS). The NMR spectrometer was a Bruker AVANCE II NMR spectrometer from Switzerland, with tetramethylsilane (TMS) as an internal standard; the HRMS spectrometer was an AB SCIEXX500R quadrupole time-of-flight high-resolution mass spectrometer.

[0047] 2. Assay of the co-agonistic activity of STING direct agonists Total RNA was collected from cells, and the mRNA expression of IFNβ1 was quantitatively tested using qPCR. The enhancing activity of each compound on the STING signaling pathway is expressed by the following formula: The relative mRNA expression of IFNβ1 in the combination of the compound and S-cddA / the relative mRNA expression of IFNβ1 in the S-cddA alone group.

[0048] Analysis and Explanation 1. Compound Characterization The structural formulas of the acetal pantothenic acid derivatives A1~A28 are as follows:

[0049] Compounds A1 to A14 are all compounds of Formula I, where R1 is, in order, phenyl, 2-pyrrole, 3-indolyl, 5-fluoro-3-indolyl, 2-aminophenyl, 2-iodophenyl, 3-iodophenyl, 4-iodophenyl, 4-bromophenyl, 4-chlorophenyl, 4-acetylphenyl, 4-nitrophenyl, 5-oxo-5,6,7,8-tetrahydronaphth-2-yl, and 4-aminophenyl; R2 is 4-methoxyphenyl; and X is ethylenediamine.

[0050] The characterization results of the acetal pantothenic acid derivatives A1~A14 in the examples are as follows: Compound A1: N-(3-((2-benzamidoethyl)amino)-3-oxopropyl)-2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane-4-carboxamide. White solid, yield 67%. 1 H NMR (400 MHz, CDCl3) δ7.83 – 7.77 (m, 2H), 7.50 – 7.45 (m, 1H), 7.43 – 7.38 (m, 4H), 7.34 (t, 1H), 7.00 (t, J = 11.9, 5.5 Hz, 1H), 6.97 (t, J= 5.6 Hz, 1H), 6.92 – 6.87 (d, 2H), 5.42 (s, 1H), 4.04 (s, 1H), 3.79 (s, 3H), 3.66 (m, J = 26.0, 11.4 Hz, 2H), 3.57 – 3.41 (m, 6H), 2.44 (m, J = 6.3 Hz, 2H), 1.08 (s, 3H), 1.06 (s, 3H). HRMS ESI-MS for C26H33N3O6 [M+Na] + found:506.2262 m / z;Calc.Mass:483.2369. Compound A2: N-(2-(3-(2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane-4-carbamoyl)propamido)ethyl)-1H-pyrrole-2-carboxamide. Yellow solid, yield 54%. 1 H NMR (400 MHz, CDCl3) δ 9.74 (s, 1H), 7.44 – 7.38 (d, 2H), 6.99 (m, J = 10.9, 4.7 Hz, 2H), 6.93 –6.87 (m, 4H), 6.65 (m, J = 3.7, 2.5, 1.3 Hz, 1H), 6.21 (m, J = 3.6, 2.6 Hz,1H), 5.42 (s, 1H), 4.05 (s, 1H), 3.80 (s, 3H), 3.71 – 3.59 (m, 2H), 3.56 –3.37 (m, 6H), 2.41 (m, J = 13.8, 7.6 Hz, 2H), 1.09 (s, 3H), 1.06 (s, 3H).HRMS ESI-MS for C24H32N4O6 Calc.Mass: 472.2322 Compound A3: N-(2-(3-(2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane-4-formamido)propamido)ethyl)-1H-indole-3-formamide. White solid, 60% yield. 1 HNMR (400 MHz, DMSO) δ 11.52 (s, 1H), 8.13 (d,J = 7.7 Hz, 1H), 8.04 (t, J =5.5 Hz, 1H), 7.97 (d, J = 2.9 Hz, 1H), 7.93 (t, J = 5.5 Hz, 1H), 7.48 (t, J =11.9, 5.9 Hz, 1H), 7.45 – 7.42 (d, 2H), 7.41 (m, J = 5.7 Hz, 1H), 7.17 – 7.05 (m, 2H), 6.92 (d, J = 8.7 Hz, 2H), 5.50 (s, 1H), 4.08 (s, J = 6.5 Hz, 1H), 3.74 (s, 3H), 3.66 – 3.57 (q, 2H), 3.40 – 3.15 (m, 6H), 2.30 (m, J = 6.9 Hz, 2H), 1.01 (s, 3H), 0.95 (s, 3H).HRMS ESI-MS for C28H34N4O6 [M+Na] + found:545.2331 m / z;Calc.Mass: 522.2478. Compound A4: 5-fluoro-N-(2-(3-(2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane-4-formamido)propamido)ethyl)-1H-indole-3-formamide. White solid, 60% yield. 1 H NMR (400 MHz, DMSO) δ 8.06 (m, J = 7.3 Hz, 2H), 8.01 (t, J = 5.6 Hz, 1H), 7.82 (dd, J = 10.3, 2.6 Hz, 1H), 7.48 (t, J = 5.9 Hz, 1H), 7.43 (d, J =8.6 Hz, 3H), 6.99 (m, J = 9.1, 2.6 Hz, 1H), 6.92 (d, J= 8.7 Hz, 2H), 5.51 (s, 1H), 4.07 (s, 1H), 3.74 (s, 3H), 3.61 (q, J = 11.2 Hz, 2H), 3.40- 3.19 (m, 6H), 2.30 (m, J = 6.9 Hz, 2H), 1.01 (s, 3H), 0.94 (s, 3H). HRMS ESI-MS forC28H33FN4O6 [M+Na] + found:563.2247 m / z;Calc.Mass:540.2384 Compound A5: N-(3-((2-aminobenzamido)ethyl)amino)-3-oxopropyl)-2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane-4-carboxamide. White solid, 58% yield. 1 H NMR (400 MHz, CDCl3) δ 7.43 – 7.38 (m, 2H), 7.35 (dd, J = 7.9, 1.4 Hz, 1H),7.19 (ddd, J = 8.5, 7.2, 1.5 Hz, 1H), 6.99 (m, J = 4.7 Hz, 2H), 6.93 – 6.88 (m, 2H), 6.81 (t, 1H), 6.67 – 6.61 (m, 2H), 5.40 (s, 1H), 4.04 (s, 1H), 3.80 (s, 3H), 3.72 – 3.60 (m, 2H), 3.56 – 3.40 (m, 6H), 2.43 (m, J = 6.3 Hz, 2H), 1.08 (s, 3H), 1.06 (s, 3H). HRMS ESI-MS for C26H34N4O6 [M+Na] + found:521.2332m / z;Calc.Mass: 498.2478 Compound A6: N-(3-((2-iodobenzoamido)ethyl)amino)-3-oxopropyl)-2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane-4-formamide. White solid, yield 57%. 1HNMR (400 MHz, CDCl3) δ 7.85 (d, J = 7.9 Hz, 1H), 7.43 – 7.39 (m, 2H), 7.37 –7.35 (m, 1H), 7.35 (d, J = 0.5 Hz, 1H), 7.13 – 7.06 (m, 1H), 6.99 (t, J = 6.0Hz, 1H), 6.93 – 6.88 (m, 2H), 6.77 (t, J = 5.3 Hz, 1H), 6.66 (t, 1H), 5.41 (s, 1H), 3.98 (s, J = 4.1 Hz, 1H), 3.81 (s, 3H), 3.70 – 3.59 (m, 2H), 3.58 –3.43 (m, 6H), 2.43 (m, J = 6.6, 2.3 Hz, 2H), 1.07 (s, 3H), 1.00 (s, 3H). HRMS ESI-MS for C26H32IN3O6 [M+Na] + found:632.1195 m / z;Calc.Mass:609.1336 Compound A7: N-(3-((3-iodobenzoamido)ethyl)amino)-3-oxopropyl)-2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane-4-carboxamide. White solid, 55% yield. 1 HNMR (400 MHz, CDCl3) δ 8.19 (t, J = 1.7 Hz, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 7.8 Hz, 1H), 7.40 (d, J = 8.7 Hz, 2H), 7.14 (t, J = 7.8 Hz, 1H), 6.98 (t, J = 6.6 Hz, 1H), 6.90 (d, J= 8.8 Hz, 2H), 6.74 (t, 1H), 5.44 (s, 1H), 4.07 (s, 1H), 3.81 (s, 3H), 3.72 – 3.62 (m, 2H), 3.60 – 3.45 (m, 6H), 2.50 – 2.42 (m, 2H), 1.09 (s, 3H), 1.07 (s, 3H). HRMS ESI-MS for C26H32IN3O6[M+Na] + found:632.1182 m / z;Calc.Mass: 609.1336 Compound A8: N-(3-((4-iodobenzoamido)ethyl)amino)-3-oxopropyl)-2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane-4-carboxamide. White solid, yield 67%. 1 HNMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 7.50 (t, 1H), 7.40 (d, J = 8.7 Hz, 2H), 7.00 (t, J = 6.2 Hz, 1H), 6.97 – 6.91 (t, 1H), 6.90 (d, J = 8.7 Hz, 2H), 5.43 (s, 1H), 4.04 (s, 1H), 3.80 (s, 3H), 3.67 (m, J = 26.1, 11.5 Hz, 2H), 3.56 – 3.42 (m, 6H), 2.44 (t, J = 6.2 Hz, 2H), 1.08 (s, 3H), 1.06 (s, 3H). HRMS ESI-MS for C26H32IN3O6 [M+Na] + found:632.1176 m / z;Calc.Mass: 609.1336 Compound A9: N-(3-((4-bromobenzamido)ethyl)amino)-3-oxopropyl)-2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane-4-carboxamide. White solid, yield 68%. 1HNMR (400 MHz, CDCl3) δ 7.70 – 7.66 (d, 2H), 7.59 (t, 1H), 7.54 – 7.50 (d, 2H), 7.42 – 7.38 (d, 2H), 7.07 – 7.03 (t, 1H), 7.01 (t, J = 6.4 Hz, 1H), 6.92– 6.87 (d, 2H), 5.43 (s, 1H), 4.04 (s, 1H), 3.79 (s, 3H), 3.66 (m, J = 26.0,11.4 Hz, 2H), 3.55 – 3.42 (m, 6H), 2.44 (m, J = 6.3 Hz, 2H), 1.08 (s, 3H), 1.05 (s, 3H). HRMS ESI-MS for C26H32BrN3O6 [M+Na] + found:584.1342 m / z;Calc.Mass: 561.1474 Compound A10: N-(3-((4-chlorobenzamido)ethyl)amino)-3-oxopropyl)-2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane-4-formamide. White solid, yield 68%. 1 HNMR (400 MHz, CDCl3) δ 7.78 – 7.72 (d, 2H), 7.46 (t, 1H), 7.41 (d, J = 5.7Hz, 2H), 7.38 – 7.34 (d, 2H), 6.99 (t, J = 6.1 Hz, 1H), 6.92 – 6.88 (d, 2H), 6.88 (t, J = 2.9 Hz, 1H), 5.43 (s, 1H), 4.06 (s, 1H), 3.81 (s, J = 6.6 Hz, 3H), 3.73 – 3.62 (m, 2H), 3.57 – 3.41 (m, 6H), 2.45 (m, J = 6.2 Hz, 2H), 1.08 (s, 3H), 1.06 (s, 3H). HRMS ESI-MS for C26H32ClN3O6 [M+Na] +found:540.1827m / z;Calc.Mass: 517.1980 Compound A11: N-(3-((4-acetylbenzamido)ethyl)amino)-3-oxopropyl)-2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane-4-formamide. White solid, yield 54%. 1 H NMR (500 MHz, CDCl3) δ 7.98 (d, J = 8.2 Hz, 2H), 7.90 (d, J = 8.2 Hz, 2H), 7.58 (t, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.00 (t, 1H), 6.89 (d, J = 8.4Hz, 2H), 6.82 (t, 1H), 5.44 (s, 1H), 4.08 (s, 1H), 3.80 (s, 3H), 3.67 (dd, J = 29.6, 11.4 Hz, 2H), 3.53 (m, J = 16.7 Hz, 6H), 2.62 (s, 3H), 2.48 (m, J =6.1 Hz, 2H), 1.09 (s, 3H), 1.07 (s, 3H). HRMS ESI-MS for C28H35N3O7 [M+Na] + found:548.2339 m / z;Calc.Mass: 525.2475 Compound A12: 2-(4-methoxyphenyl)-5,5-dimethyl-N-(3-((2-(4-nitrobenzamide)ethyl)amino)-3-oxopropyl)-1,3-dioxane-4-carboxamide. White solid, 50% yield. 1 H NMR (400 MHz, CDCl3) δ 8.26 – 8.22 (d, 2H), 8.02 – 7.97 (d, 2H), 7.90 (t, 1H), 7.40 (d, J =8.7 Hz, 2H), 6.98 (t, J = 6.4 Hz, 1H), 6.89 (m, J= 6.8, 4.8 Hz, 3H), 5.45 (s, 1H), 4.09 (s, 1H), 3.80 (s, 3H), 3.68 (dd, J = 25.8, 11.4 Hz, 2H), 3.60 –3.47 (m, 6H), 2.52 – 2.46 (m, 2H), 1.09 (s, 3H), 1.07 (s, 3H). HRMS ESI-MS for C26H32N4O8 [M+Na] + found:551.2083 m / z;Calc.Mass: 528.2220 Compound A13: 2-(4-methoxyphenyl)-5,5-dimethyl-N-(3-oxo-3-((2-(5-oxo-5,6,7,8-tetrahydronaphthalene-2-formamido)ethyl)amino)propyl)-1,3-dioxane-4-carboxamide. White solid, yield 47%. 1 H NMR (400 MHz, CDCl3) δ 8.04 (d, J = 8.1 Hz, 1H), 7.74 (s, 1H), 7.67 (dd, J = 8.1, 1.7 Hz, 1H), 7.51 (t, 1H), 7.42 – 7.37 (d, 2H), 7.00 (t, J = 6.3 Hz, 1H), 6.91 – 6.86 (m, 3H), 5.43 (s, 1H), 4.05 (s, 1H), 3.80 (s, 3H), 3.66 (dd, J = 25.7, 11.4 Hz, 2H), 3.58 – 3.43 (m, 6H), 2.98 (t, J = 6.1 Hz, 2H), 2.71 – 2.62 (m, 2H), 2.50 – 2.42 (m, 2H), 2.18 –2.07 (m, 2H), 1.08 (s, 3H), 1.06 (s, 3H). HRMS ESI-MS for C30H37N3O7 [M+Na] + found:574.2486 m / z;Calc.Mass: 551.2632 Compound A14: N-(3-((4-aminobenzamido)ethyl)amino)-3-oxopropyl)-2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane-4-formamide. White solid, yield 46%. 1 H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.6 Hz, 2H), 7.42 (d, J = 5.7 Hz, 2H), 7.04 (m, J = 5.8 Hz, 2H), 6.99 (t, J = 5.5 Hz, 1H), 6.92 – 6.87 (d, 2H), 6.61 (d, J = 8.6 Hz, 2H), 5.42 (s, 1H), 4.04 (s, 1H), 3.79 (s, 3H), 3.65 (m, J =24.3, 11.3 Hz, 2H), 3.54 – 3.39 (m, 6H), 2.41 (t, J = 6.3 Hz, 2H), 1.08 (s,3H), 1.06 (s, 3H). HRMS ESI-MS for C26H34N4O6 [M+Na] + found:521.2338 m / z;Calc.Mass:498.2478 Examples of acetal pantothenic acid derivatives A15~A19 are all compounds having formula I, where R1 is 4-iodophenyl; R2 is halogen, methylthio, and cyano in sequence; and X is ethylenediamine.

[0051] The characterization results of the acetal pantothenic acid derivatives A15~A19 in the examples are as follows: Compound A15: 2-(4-fluorophenyl)-N-(3-((2-(4-iodobenzamide)ethyl)amino)-3-oxopropyl)-5,5-dimethyl-1,3-dioxane-4-carboxamide. White solid, 60% yield. 1 H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.3 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.50 – 7.44 (m, 3H), 7.09 – 7.03 (d, 2H), 7.02 (t, J= 6.3 Hz, 1H), 6.96 (t, 1H), 5.46 (s, 1H), 4.05 (s, 1H), 3.68 (m, J = 26.6, 11.4 Hz, 2H), 3.57 – 3.39 (m, 6H), 2.44 (m, J = 6.3 Hz, 2H), 1.07 (s, 3H), 1.06 (s, 3H). HRMS ESI-MS for C25H29FIN3O5 [M+Na] + found:620.0984 m / z;Calc.Mass: 597.1136 Compound A16: 2-(4-iodophenyl)-N-(3-((2-(4-iodobenzamide)ethyl)amino)-3-oxopropyl)-5,5-dimethyl-1,3-dioxane-4-carboxamide. White solid, yield 66%. 1 H NMR (400 MHz, CDCl3) δ 7.71 (m, J = 8.4 Hz, 4H), 7.61 (t, J = 4.8 Hz, 1H), 7.51 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 7.15 (t, J = 5.1 Hz, 1H), 7.05 (t, J = 6.2 Hz, 1H), 5.42 (s, 1H), 4.03 (s, 1H), 3.66 (m, J = 29.4, 11.5 Hz, 2H), 3.55 – 3.43 (m, 6H), 2.42 (m, J = 6.3 Hz, 2H), 1.05 (s, 3H), 1.04 (s, 3H). HRMS ESI-MS for C25H29I2N3O5 [M+Na] + found:728.0042 m / z;Calc.Mass: 705.0197 Compound A17: 2-(4-bromophenyl)-N-(3-((2-(4-iodobenzamide)ethyl)amino)-3-oxopropyl)-5,5-dimethyl-1,3-dioxane-4-carboxamide. White solid, yield 66%. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.5 Hz, 2H), 7.55 – 7.51 (d, 2H), 7.50 (d, J = 4.3 Hz, 2H), 7.46 (t, 1H), 7.36 (d, J = 8.4 Hz, 2H), 7.02 (t, J = 6.1 Hz, 1H), 6.93 (t, J = 5.5 Hz, 1H), 5.44 (s, 1H), 4.05 (s, 1H), 3.68 (m, J = 28.5, 11.4 Hz, 2H), 3.57 – 3.41 (m, 6H), 2.44 (m, J = 6.2 Hz, 2H), 1.06 (s, 6H). HRMS ESI-MS forC25H29BrIN3O5 [M+Na] + found:680.0188 m / z;Calc.Mass:657.0335 Compound A18: 2-(4-cyanophenyl)-N-(3-((2-(4-iodobenzamide)ethyl)amino)-3-oxopropyl)-5,5-dimethyl-1,3-dioxane-4-carboxamide. White solid, yield 68%. 1 H NMR (400 MHz, CDCl3) δ 7.75 – 7.71 (d, 2H), 7.66 (d, J = 8.5 Hz, 2H), 7.61 (d, J = 8.3 Hz, 2H), 7.54 – 7.50 (d, 2H), 7.49 (t, J = 5.4 Hz, 1H), 7.10 (t, J = 6.1 Hz, 1H), 7.01 (t, J = 5.5 Hz, 1H), 5.52 (s, 1H), 4.08 (s, 1H), 3.70 (m, J = 28.3, 11.5Hz, 2H), 3.50 (m, J = 12.5, 9.1, 5.8 Hz, 6H), 2.45 (m, J= 6.2 Hz, 2H), 1.07 (s, 3H), 1.07 (s, 3H). HRMS ESI-MS for C26H29IN4O5 [M+Na] + found:627.1053 m / z;Calc.Mass:604.1183 Compound A19: 2-(4-methylthiophenyl)-N-(3-((2-(4-iodobenzamide)ethyl)amino)-3-oxopropyl)-5,5-dimethyl-1,3-dioxane-4-carboxamide. White solid, yield 54%. 1 H NMR (400 MHz, CDCl3) δ 7.75 – 7.71 (d, 2H), 7.56 (t, J = 4.7 Hz, 1H), 7.54 – 7.50 (d, 2H), 7.39 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 6.7 Hz, 2H), 7.07 (t, J = 5.6 Hz, 1H), 7.02 (t, J = 6.4 Hz, 1H), 5.43 (s, 1H), 4.04 (s, 1H), 3.67 (m, J = 27.5, 11.4Hz, 2H), 3.54 – 3.40 (m, 6H), 2.46 (s, 3H), 2.43 (m, J = 6.3 Hz, 2H), 1.07 (s, 3H), 1.05 (s, 3H). HRMS ESI-MS for C26H32IN3O5S [M+Na] + found:648.0962 m / z;Calc.Mass:625.1107 The acetal pantothenic acid derivatives A20~A26 in the examples are all compounds having general formula I, where R2 is methoxy; X is piperazine; and R1 is 4-iodophenyl, 4-chlorophenyl, 4-fluorophenyl, 3-iodophenyl, 3-bromophenyl, 3-chlorophenyl, and 3-fluorophenyl, respectively.

[0052] The characterization results of the acetal pantothenic acid derivatives A20~A26 in the examples are as follows: Compound A20: N-(3-(4-(4-iodobenzoyl)piperazin-1-yl)-3-oxopropyl)-2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane-4-formamide. White solid, yield 48%. 1 H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.4 Hz, 2H), 7.45 – 7.40 (d, 2H), 7.13 (d, J = 8.6, 1.9 Hz, 2H), 7.09 (t, J = 6.2 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 5.46 (s, 1H), 4.07 (s, 1H), 3.81 (s, 3H), 3.72 – 3.42 (m, 12H), 2.56 (m, 2H), 1.10 (s, 6H). HRMS ESI-MS for C28H34IN3O6 [M+Na] + found:658.1349 m / z;Calc.Mass: 635.1492 Compound A21: N-(3-(4-(4-bromobenzoyl)piperazin-1-yl)-3-oxopropyl)-2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane-4-formamide. White solid, 45% yield. 1 H NMR (400 MHz, CDCl3) δ 7.60 – 7.54 (d, 2H), 7.46 – 7.39 (d, 2H), 7.31 –7.25 (d, 2H), 7.12 (t, J = 6.2 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 5.46 (s,1H), 4.07 (s, 1H), 3.81 (s, 3H), 3.73 – 3.37 (m, 12H), 2.56 (m, 2H), 1.09 (s,6H). HRMS ESI-MS for C28H34BrN3O6 [M+Na] + found:610.1487 m / z;Calc.Mass:587.1631 Compound A22: N-(3-(4-(4-fluorobenzoyl)piperazin-1-yl)-3-oxopropyl)-2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane-4-formamide. White solid, yield 46%. 1 H NMR (400 MHz, CDCl3) δ 7.46 – 7.39 (m, 4H), 7.12 (d, J = 6.6 Hz, 2H), 7.09 (d, J = 3.1 Hz, 1H), 6.91 (d, J = 8.7 Hz, 2H), 5.46 (s, 1H), 4.07 (s, 1H), 3.81 (s, 3H), 3.74 – 3.43 (m, 12H), 2.57 (m, J = 5.7 Hz, 2H), 1.10 (s, 6H). HRMS ESI-MS for C28H34FN3O6 [M+Na] + found: m / z;Calc.Mass: 527.2432 Compound A23: N-(3-(4-(3-iodobenzoyl)piperazin-1-yl)-3-oxopropyl)-2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane-4-formamide. White solid, yield 47%. 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 8.1 Hz, 1H), 7.75 (s, 1H), 7.43 (d, J = 5.7 Hz, 2H), 7.35 (d, J = 7.7 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.11 (t, J = 6.2 Hz, 1H), 6.92 (d, J = 8.5 Hz, 2H), 5.46 (s, 1H), 4.04 (s, 1H), 3.82 (s, 3H), 3.75 – 3.36 (m, 12H), 2.57 (m, 2H), 1.10 (s, 6H). HRMS ESI-MS for C28H34IN3O6 [M+Na] + found:658.1366 m / z;Calc.Mass: 635.1492 Compound A24: N-(3-(4-(3-bromobenzoyl)piperazin-1-yl)-3-oxopropyl)-2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane-4-formamide. White solid, yield 42%. 1 H NMR (400 MHz, CDCl3) δ 7.60 – 7.57 (m, 1H), 7.55 (d, J = 0.9 Hz, 1H), 7.45 – 7.41 (d, 2H), 7.32 (m, J = 4.3, 1.1 Hz, 1H), 7.31 – 7.30 (m, 1H), 7.10 (t, J = 6.2 Hz, 1H), 6.92 (d, J = 8.7 Hz, 2H), 5.46 (s, 1H), 4.07 (s, 1H), 3.81 (s, 3H), 3.74 – 3.41 (m, 12H), 2.57 (m, 2H), 1.10 (s, 6H). HRMS ESI-MSfor C28H34BrN3O6 [M+Na] + found: m / z;Calc.Mass: 587.1631 Compound A25: N-(3-(4-(3-chlorobenzoyl)piperazin-1-yl)-3-oxopropyl)-2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane-4-formamide. White solid, yield 41%. 1 H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 7.4 Hz, 2H), 7.38 (m, J = 11.4, 3.5Hz, 2H), 7.27 (d, J = 5.2 Hz, 2H), 7.09 (t, J = 6.1 Hz, 1H), 6.92 (d, J= 8.6Hz, 2H), 5.46 (s, 1H), 4.07 (s, 1H), 3.82 (s, 3H), 3.74 – 3.42 (m, 12H), 2.58 (s, 2H), 1.10 (s, 6H). HRMS ESI-MS for C28H34ClN3O6 [M+Na] + found:566.2007 m / z;Calc.Mass: 543.2136 Compound A26: N-(3-(4-(3-fluorobenzoyl)piperazin-1-yl)-3-oxopropyl)-2-(4-methoxyphenyl)-5,5-dimethyl-1,3-dioxane-4-formamide. White solid, 40% yield. 1 H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 8.6 Hz, 2H), 7.41 – 7.37 (m, 1H), 7.19-7.08 (m, 4H), 6.91 (d, J = 8.6 Hz, 2H), 5.46 (s, 1H), 4.07 (s, 1H), 3.81 (s, 3H), 3.74 – 3.33 (m, 12H), 2.57 (m, 2H), 1.10 (s, 6H). HRMS ESI-MS forC28H34FN3O6 [M+Na] + found:550.2298 m / z;Calc.Mass: 527.2432.

[0053] In the examples, the acetal pantothenic acid derivatives A27~A28 are all compounds having formula II, where R2 is methoxy and R3 are 4-iodophenyl and 3-iodophenyl, respectively.

[0054] The characterization results of the acetal pantothenic acid derivatives A27~A28 in the examples are as follows: Compound A27: 2-(4-methoxyphenyl)-5,5-dimethyl-N-(3-oxo-3-(4-iodophenylamino)propyl)-1,3-dioxane-4-formamide. White solid, yield 49%. 1 H NMR (400 MHz, CDCl3) δ 8.63 (t, 1H), 7.58 (d, J = 8.6 Hz, 2H), 7.38 (d, J= 9.6 Hz, 2H), 7.33 (d, J = 8.5 Hz, 2H), 7.12 (t, J = 6.1 Hz, 1H), 6.88 (d, J = 8.6 Hz, 2H), 5.44 (s, 1H), 4.08 (s, 1H), 3.81 (s, 3H), 3.71 – 3.62 (m, 2H), 3.63 – 3.49 (m, 2H), 2.67 – 2.54 (m, 2H), 1.07 (s, 3H), 1.06 (s, 3H). HRMS ESI-MS forC23H27IN2O [M+Na] + found:561.0830 m / z;Calc.Mass: 538.0965.

[0055] Compound A28: 2-(4-methoxyphenyl)-5,5-dimethyl-N-(3-oxo-3-(3-iodophenylamino)propyl)-1,3-dioxane-4-formamide. White solid, yield 44%. 1 H NMR (400 MHz, CDCl3) δ 8.50 (t, 1H), 8.00 (s, 1H), 7.51 (d, J = 8.1 Hz, 1H), 7.43 (d, J =3.9 Hz, 1H), 7.40 (d, J = 5.7, 3.7 Hz, 2H), 7.14 (t, J = 6.2 Hz, 1H), 7.02 (dd, J = 10.4, 5.6 Hz, 1H), 6.94 – 6.88 (d, 2H), 5.46 (s, 1H), 4.10 (s, 1H), 3.82 (s, 3H), 3.73 – 3.64 (m, 2H), 3.60 (m, J = 20.3, 10.0, 4.2 Hz, 2H), 2.66– 2.59 (m, 2H), 1.08 (s, 6H). HRMS ESI-MS for C23H27IN2O [M+Na] + found:561.0839 m / z; Calc.Mass: 538.0965.

[0056] 2. Determination of the enhancing effect of acetal pantothenic acid derivatives on the STING signaling pathway Table 1. Enhancement effect of the acetal pantothenic acid derivatives of the present invention on the STING signaling pathway.

[0057] As shown in Table 1, the acetal pantothenic acid derivative provided by this invention, when used in combination with a direct STING agonist, significantly enhances the cGAS-STING signaling pathway, as evidenced by increased expression of the pathway signaling marker IFNβ1 mRNA. Among these, A23 showed the best enhancing effect.

[0058] In summary, the compounds provided by this invention can significantly enhance the STING signaling pathway, demonstrating good potential for drug development and providing a new direction for the development of related anti-tumor and antiviral immunotherapies, as well as immune adjuvants.

[0059] Obviously, the above embodiments of the present invention are merely examples for clearly illustrating the present invention, and are not intended to limit the implementation of the present invention. Those skilled in the art can make other variations or modifications based on the above description. It is neither necessary nor possible to exhaustively describe all embodiments here. Any modifications, equivalent substitutions, and improvements made within the spirit and principles of the present invention should be included within the scope of protection of the claims of the present invention.

Claims

1. An acetal pantothenic acid derivative, characterized in that, The structural formula of the pantoic acid derivative is shown in formula I and formula II. ； In formula I, R1 is selected from phenyl, 2-pyrrolyl, 2-thienyl, 3-indolyl, 5-fluoro-3-indolyl, 5-methoxy-3-indolyl, 4-quinolyl, 2-aminophenyl, 2-halophenyl, 3-halophenyl, 4-halophenyl, 4-acetylphenyl, 4-nitrophenyl, 4-aminophenyl, 5-oxo-5, 6, 7, 8-tetrahydronaphthalen-2-yl, 3, 4-diiodophenyl; X is selected from , , , , ; In formula II, R3 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, phenyl, 4-halophenyl, 3-halophenyl, 2-halophenyl, 4-nitrophenyl, 4-alkynylphenyl, 4-methoxyphenyl; In formula I and formula II, R2 is selected from hydrogen, ethyl, n-butyl, 4-ethylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-methylthiophenyl, 4-halophenyl, 3-halophenyl, 4-cyanophenyl, cyclohexyl, phenyl, pyrrolyl, thienyl, 3, 4, 5-trimethoxyphenyl.

2. Further preferred pantoic acid derivatives according to claim 1, characterized in that In formula I, R1 is selected from phenyl, 3-iodophenyl, 4-iodophenyl; X is selected from ethylenediamine group, piperazine group; R2 is selected from 4-methoxy, 4-iodophenyl, 4-cyanophenyl.

3. Further preferred pantoic acid derivatives according to claim 1, characterized in that In formula II, R2 is 4-methoxyphenyl, and R3 is selected from anilino, 3-iodoanilino, 4-iodoanilino.

4. A process for the preparation of the pantoic acid derivative according to any one of claims 1 to 3, characterized in that, The method comprises the following steps: S1, calcium pantothenate is reacted with an acidic reagent to form an active intermediate, which is condensed with R2-CHO in the presence of catalyst A to give intermediate 1: ​ S2, amidation of R1-COOH with mono-N-BOC protected ethylenediamine or piperazine in the presence of catalyst B and an acid binding agent to give intermediate 2: or intermediate 3: ​ S3, intermediate 2 or intermediate 3 After removal of the BOC group, intermediate 4 is obtained: or intermediate 5: ​ S4, intermediate 1 with intermediate 4 or intermediate 5 The amidation reaction is carried out in the presence of catalyst B and an acid binding agent to obtain the pantoic acid derivative shown in formula I. S5, intermediate 1 amide reaction with R3-NH2 in the presence of catalyst B and an acid binding agent to obtain the pantoic acid derivative shown in formula II; In S1, R2 of R2-CHO is selected from hydrogen, ethyl, n-butyl, 4-ethylphenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-methylthiophenyl, 4-halophenyl, 3-halophenyl, 4-cyanophenyl, cyclohexyl, phenyl, pyrrolyl, thienyl, 3, 4, 5-trimethoxyphenyl; In S2, R1 of R1-COOH is selected from phenyl, 2-pyrrolyl, 2-thienyl, 3-indolyl, 5-fluoro-3-indolyl, 5-methoxy-3-indolyl, 4-quinolyl, 2-aminophenyl, 2-halophenyl, 3-halophenyl, 4-halophenyl, 4-acetylphenyl, 4-nitrophenyl, 4-aminophenyl, 5-oxo-5, 6, 7, 8-tetrahydronaphthalen-2-yl, 3, 4-diiodophenyl; In S5, R3 of R3-NH2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, phenyl, 4-halophenyl, 3-halophenyl, 2-halophenyl, 4-nitrophenyl, 4-alkynylphenyl, 4-methoxyphenyl.

5. The process for the preparation of the pantothenic acid derivative according to claim 4, characterized in that, In S1, the molar ratio of calcium pantothenate to R2-CHO is 1:2-6; in S5, the molar ratio of intermediate 1 to R3-NH2 is 1:1-3.

6. The method for preparing the acetal pantothenic acid derivative according to claim 4, characterized in that, In S2, the molar ratio of R1-COOH to one-side BOC-protected ethylenediamine is 1:1-3; or the molar ratio of R1-COOH to one-side BOC-protected piperazine is 1:1-3; In S4, the molar ratio of intermediate 1 to intermediate 4 is 1:1-3; or the molar ratio of intermediate 1 to intermediate 5 is 1:1-3.

7. The process for the preparation of the pantothenic acid derivative according to claim 4, characterized in that, The catalyst B includes one or more of dicyclohexyl carbodiimide, diisopropyl carbodiimide, 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride, 4-dimethylaminopyridine, 1-hydroxybenzotriazole, N,N'-carbonyldiimidazole, O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate, benzotriazol-1-yl-oxyltrispyrrolidinophosphonium hexafluorophosphate; the base is one or more of N,N-diisopropyl ethylamine, triethylamine, N-methyl morpholine, pyridine.

8. The process for the preparation of the pantoic acid derivative according to claim 4, characterized in that, The condensation in S1 is reacted at room temperature for 4-6 hours; the amidation reaction in S2 is reacted at room temperature for 1-2 hours.

9. Use of a pantoic acid derivative according to any one of claims 1 to 2, characterized in that, The application in preparing tumor immunotherapy drugs, antiviral drugs and vaccine adjuvants.

10. Use of a pantothenic acid derivative according to claim 9, characterized in that, The pharmaceutical composition includes the pantoic acid derivative and pharmaceutically acceptable salts thereof.

Images