Pyrrolo[2,3-d]pyrimidine derivatives and their use in the preparation of anti-inflammatory medicaments

Abstract

This invention discloses a pyrrolo[2,3-d]pyrimidine derivative and its application in the preparation of anti-inflammatory drugs, wherein the pyrrolo[2,3-d]pyrimidine derivative is shown in formula (I) or formula (II); in formula (I), R 1 Selected from nitrogen-containing alkyl substituents in C2-C6 chains; in formula (II), R 2 The derivatives are selected from unsubstituted or substituted aryl, aryloxy, or arylamino groups; the substituted aryl, aryloxy, or arylamino groups are substituted by one or more of C1-C6 alkyl, C1-C6 alkoxy, halogen (F, Cl, Br), trifluoromethyl, and trifluoromethoxy groups; pharmacological results show that the pyrrolo[2,3-d]pyrimidine derivatives of the present invention can effectively inhibit the release of IL-6 and IL-8 inflammatory factors and have good anti-inflammatory activity.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry, specifically relating to a pyrrolo[2,3-d]pyrimidine derivative and its application in the preparation of anti-inflammatory drugs. Background Technology

[0002] Acute lung injury (ALI) / acute respiratory distress syndrome (ARDS) is an acute, diffuse inflammatory lung injury caused by various pulmonary pathogenic factors, leading to acute respiratory failure. Its pathological features mainly include increased pulmonary vascular permeability, alveolar exudation of protein-rich fluid, pulmonary edema, and hyaline membrane formation. Inflammation is a normal physiological response, but when the inflammatory response is imbalanced, it can lead to tissue damage and various diseases. Clinical studies have shown that inflammatory cytokines and chemokines play important roles in lung injury and can serve as good biomarkers reflecting acute lung injury. The core theory of ALI / ARDS pathogenesis is that an imbalance in the inflammatory response exacerbates epithelial or endothelial damage, leading to the entry of protein-rich edema fluid into the alveoli. During ALI, increased permeability of alveolar epithelial microvessels ultimately leads to ARDS. Therefore, regulating inflammation by overexpressing pro-inflammatory cytokines and chemokines is an effective strategy for treating ALI. Currently, the clinical efficacy of drugs for treating ALI has not met expectations, and there is an urgent need for a new drug to effectively prevent and treat ALI in order to treat the increasing number of patients with acute lung injury. Therefore, the development of drugs for treating acute lung injury is a research endeavor with far-reaching significance for people's health and well-being.

[0003] Pyrrolo[2,3-d]pyrimidine, abbreviated as 7-dehydropurine (7-DAP), serves as the core of various kinase inhibitors and possesses diverse biological activities. Clinically, it is used to treat a variety of diseases, particularly demonstrating good therapeutic effects in anti-inflammation. The anti-inflammatory activity of pyrrolo[2,3-d]pyrimidine follows multiple mechanisms, including inhibiting key kinases in signaling pathways such as JAK, Cox-2, NIK, and PERK, showing good therapeutic effects on various inflammation-related diseases (Bioorg. Med. Chem., 2018, 26, 1495-1510; J. Enzyme. Inhib. Med. Chem., 2022, 37, 1821-1837; J. Med. Chem., 2020, 63, 6748-6773; Cell Death Differ., 2017, 24, 1100-1110.). Summary of the Invention

[0004] This invention provides a pyrrolo[2,3-d]pyrimidine derivative and its application in the preparation of anti-inflammatory drugs. This class of compounds exhibits highly effective anti-inflammatory activity. A series of pyrrolo[2,3-d]pyrimidine derivatives were synthesized and their anti-inflammatory activity was evaluated. Compounds 1qi-1rl showed anti-inflammatory activity against HBE, with compound 1rf showing particularly good anti-inflammatory effects.

[0005] The technical solution of the present invention is as follows:

[0006] A pyrrolo[2,3-d]pyrimidine derivative of formula (I) or formula (II), and a pharmaceutically acceptable salt thereof:

[0007]

[0008] In equation (I), R 1 Selected from nitrogen-containing alkyl substituents in C2-C6 chains;

[0009] In equation (II), R 2 Selected from unsubstituted or substituted aryl, aryloxy, or arylamino groups; wherein the substituted aryl, aryloxy, or arylamino group is substituted by one or more of C1-C6 alkyl, C1-C6 alkoxy, halogen (F, Cl, Br), trifluoromethyl, or trifluoromethoxy.

[0010] R 1 Preferably, any one of the following groups is selected:

[0011]

[0012]

[0013] in, Indicates the replacement position. R 2 Preferably, any one of the following groups is selected:

[0014]

[0015] in, Indicates a replacement position.

[0016] The pyrrolo[2,3-d]pyrimidine derivatives of the present invention are more preferably any one of the following structural formulas:

[0017]

[0018] The pyrrolo[2,3-d]pyrimidine derivatives described in this invention can be used to prepare drugs for treating inflammation-related diseases, especially drugs that treat inflammation-related diseases by inhibiting the release of IL-6 or IL-8.

[0019] The causes of the inflammation-related diseases mentioned above are at least partly caused by inflammation, including but not limited to: sepsis, pneumonia, hepatitis, rheumatoid arthritis, systemic lupus erythematosus, asthma, chronic obstructive pulmonary disease, viral myocarditis, acute respiratory distress syndrome, pancreatitis, systemic inflammatory response syndrome, sepsis, ulcerative colitis, bronchitis, infective endocarditis, and autoimmune diseases.

[0020] In particular: sepsis, pneumonia, hepatitis, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, acute respiratory distress syndrome, pancreatitis, systemic inflammatory response syndrome, sepsis, and autoimmune diseases.

[0021] The preparation method of the pyrrolo[2,3-d]pyrimidine derivative shown in formula (I) is as follows:

[0022]

[0023] Compound 1ae (600 g, 3 mmol, 1 equiv.) was dissolved in 15 mL of N,N-dimethylformamide. Potassium carbonate (414 mg, 3 mmol, 1 equiv.) was added in portions with stirring. The mixture was stirred for 5 min, and then dibromoalkanes (5 mmol, 2 equiv.) were added dropwise. The mixture was stirred at room temperature for 6 h. The reaction was monitored by TLC with a petroleum ether:ethyl acetate ratio of 2:1 (v / v). After the reaction was completed, the reaction solution was diluted with water, extracted three times with ethyl acetate, and concentrated. The solution was then purified by column chromatography with a petroleum ether:ethyl acetate ratio of 4:1 (v / v) to obtain a pale yellow viscous liquid 1oa-1oe. The dibromoalkanes were 1,2-dibromoethane, 1,3-dibromopropane, 1,4-dibromobutane, 1,5-dibromopentane, or 1,6-dibromohexane.

[0024] Compound 1oa-1oe (0.85 mmol), dimethylamine hydrochloride or diethylamine (0.94 mmol, 1.1 equiv.), triethylamine (454 mg, 4.3 mmol, 5 equiv.) and 5 mL of acetonitrile were added to a sealed tube and stirred at 80 °C for 5 h. The reaction was monitored by TLC with a PE:EA ratio of 4:1 (v / v). After the reaction was completed, the mixture was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, concentrated, and purified by column chromatography with a petroleum ether:ethyl acetate ratio of 4:1 (v / v) to obtain a pale yellow viscous liquid 1pa-1pf.

[0025] Compound 1od (100 mg, 0.3 mmol, 1 equiv.) was dissolved in 5 mL of ethanol, and sodium iodide (27 mg, 0.18 mmol, 0.6 equiv.) and nitrogen-containing compounds were added. The mixture was stirred at 80 °C for 12 h and monitored by TLC with a PE:EA ratio of 4:1 (v / v). After the reaction was completed, the mixture was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, concentrated, and purified by column chromatography with a petroleum ether:ethyl acetate ratio of 2:1 (v / v) to obtain a pale yellow viscous liquid of 1 pg-1 ps. The nitrogen-containing compounds were piperidine, cyclohexylimine, piperazine, morpholine, tetrahydropyrrole, N-methylpiperazine, N-ethylpiperazine, N,N′-dimethylethylenediamine, N,N,N′-trimethylethylenediamine, diethanolamine, N-benzyl tert-butylamine, 1,2,3,4-tetrahydroquinoline, or phthalimide.

[0026]

[0027] 1 of compound (70 mg, 0.25 mmol, 1 equiv.), 2 mL of tetrahydrofuran, and triethylamine (77 mg, 1.08 mmol) were added to a sealed tube. The mixture was stirred at room temperature for 10 min, and then an acylation reagent (0.25 mmol, 1.2 equiv.) was added while stirring. The reaction was carried out at room temperature for 12 h. The reaction was monitored by TLC with a PE:EA (v / v) ratio of 1:1. After the reaction was completed, the mixture was diluted with water, extracted three times with ethyl acetate, concentrated, and then column-sected with a PE:EA (v / v) ratio of 2:1 to obtain a pale yellow viscous liquid 1qa-1qm. The acylation reagent was p-methylbenzenesulfonyl chloride, p-methoxybenzenesulfonyl chloride, p-fluorobenzenesulfonyl chloride, o-trifluoromethylbenzenesulfonyl chloride, 3-pyridinesulfonyl chloride, 2-thiophenesulfonyl chloride, benzoyl chloride, p-methoxybenzenesulfonyl chloride, p-fluorobenzenesulfonyl chloride, m-fluorobenzenesulfonyl chloride, p-methoxyphenyl isocyanate, p-trifluoromethylphenyl isocyanate, or p-methoxyphenyl isothiocyanate.

[0028] The preparation method of the pyrrolo[2,3-d]pyrimidine derivative shown in formula (II) is as follows:

[0029]

[0030] Compound 1oh (1.0 g, 6.5 mmol) was dissolved in 10 mL of toluene. Potassium carbonate (1.01 mg, 7.8 mmol, 1.3 equiv.), PdCl2(PPh3)2 (210 mg, 0.30 mmol, 0.05 equiv.), and arylboronic acid (9 mmol, 1.5 equiv.) were added with stirring. The reaction was carried out at 120 °C for 6 h, monitored by TLC (PE:EA v:v = 4:1). After the reaction was complete, the mixture was cooled to room temperature, quenched with water, and extracted three times with ethyl acetate (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (PE:EA v:v = 4:1) to give compound 1ra-1re; wherein the arylboronic acid was 2-thiopheneboronic acid, 2-methylphenylboronic acid, 3-methylphenylboronic acid, 4-methylphenylboronic acid, or 3-methoxyphenylboronic acid.

[0031]

[0032] Compound 1OH (70 mg, 0.2 mmol, 1 equiv.), 2 mL of DMF solvent, potassium carbonate (55 mg, 0.4 mmol), and a phenolic compound (0.22 mmol, 1.1 equiv.) were added to a sealed tube. The mixture was stirred at 110 °C for 8 h. The reaction was monitored by TLC with a PE:EA (v / v) ratio of 1:1. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, concentrated, and column-sected with a PE:EA (v / v) ratio of 2:1 to obtain a viscous product 1rf-1rl. The phenolic compound was phenol, p-methylphenol, p-trifluoromethoxyphenol, m-methoxyphenol, o-methoxyphenol, 3,4-dimethoxyphenol, or 3,5-dimethoxyphenol.

[0033]

[0034] Compound 1OH (70 mg, 0.2 mmol, 1 equiv.), isopropanol (2 mL), concentrated hydrochloric acid (0.1 mL, three drops), and aniline compound (0.22 mmol, 1.1 equiv.) were added to a sealed tube. The mixture was stirred at 100 °C for 8 h and monitored by TLC PE:EA (v / v) 1:1. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, concentrated, and column-sected with DCM:CH3OH (v / v) 40:1 to obtain product 1rm-1rt. The aniline compound was aniline, p-methoxyaniline, p-trifluoromethylaniline, m-trifluoromethylaniline, m-trifluoromethoxyaniline, p-fluoroaniline, p-chloroaniline, or p-bromoaniline.

[0035] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0036] This invention utilizes pyrrolo[2,3-d]pyrimidine as a backbone and employs computer-aided drug design to prepare a series of pyrrolo[2,3-d]pyrimidine derivatives. In vitro anti-inflammatory activity tests showed that most compounds of this invention exhibited good inhibitory activity against the pro-inflammatory cytokines IL-6 and IL-8, with compound 1rf showing particularly strong anti-inflammatory effects, inhibiting IL-6 and IL-8 by 66% and 70%, respectively. In vivo anti-inflammatory experiments demonstrated that compound 1rf significantly improved the pathological features of pneumonia in mice, with a marked reduction in the number of inflammatory cells and basophils, and the disappearance of edema. Therefore, compound 1rf can be used as an anti-inflammatory lead compound for further structural optimization, with the expectation of becoming a clinical candidate compound for the treatment of acute lung injury. Attached Figure Description

[0037] Figure 1 : The hydrogen NMR spectrum of compound 1qi obtained in Example 6.

[0038] Figure 2 : Carbon NMR spectrum of compound 1qi obtained in Example 6.

[0039] Figure 3 : The hydrogen NMR spectrum of compound 1rf obtained in Example 8.

[0040] Figure 4 : Carbon NMR spectrum of compound 1rf obtained in Example 8.

[0041] Figure 5 Example 10: Inhibitory activity of compound 1pg-1qp against the release of IL-6 and IL-8.

[0042] Figure 6 Example 11: Inhibitory activity of compound 1qi-1rt against the release of IL-6 and IL-8. Detailed Implementation

[0043] To better illustrate the present invention, specific synthetic routes for the pyrrolo[2,3-d]pyrimidine derivatives described herein are given in the following detailed embodiments. Those skilled in the art should understand that the present invention claims protection of the compound structure, and that the present invention can also be implemented using certain other synthetic routes.

[0044] Example 1: Synthesis of compound 1pa

[0045]

[0046] 1.0 g (6.5 mmol) of 4-chloro-7-hydropyrrolo[2,3-d]pyrimidine was dissolved in 10 mL of toluene. Potassium carbonate (1.01 mg, 7.8 mmol, 1.3 equiv.), PdCl₂(PPh₃)₂ (210 mg, 0.30 mmol, 0.05 equiv.), and phenylboronic acid (1.01 g, 9 mmol, 1.5 equiv.) were added with stirring. The reaction was carried out at 120 °C for 6 h. The reaction was monitored by TLC (PE:EA v:v = 4:1). After the reaction was complete, the mixture was cooled to room temperature, quenched with water, and extracted three times with ethyl acetate (3 × 100 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (PE:EA v:v = 4:1) to obtain 1ae in 88% yield.

[0047] Compound 1ae (600 g, 3 mmol, 1 equiv.) was dissolved in 15 mL of N,N-dimethylformamide. Potassium carbonate (414 mg, 3 mmol, 1 equiv.) was added in portions with stirring for 5 min. Excess dibromoethane (5 mmol, 2 equiv.) was added dropwise, and the mixture was stirred at room temperature for 6 h. The reaction progress was monitored by TLC with petroleum ether:ethyl acetate (v / v) 2:1. The reaction solution was diluted with water, extracted three times with ethyl acetate, and concentrated. Column chromatography with petroleum ether:ethyl acetate (v / v) 4:1 yielded a pale yellow viscous liquid, 1oa, in 73% yield.

[0048] Compound 1oa (256 mg, 0.85 mmol), dimethylamine hydrochloride (77 mg, 0.94 mmol), triethylamine (454 mg, 4.3 mmol), and 5 mL of acetonitrile were added to a sealed tube and stirred at 80 °C for 5 h. The reaction was monitored by TLC with a PE:EA ratio of 4:1 (v / v). After cooling to room temperature, the reaction solution was diluted with water, extracted three times with ethyl acetate, and concentrated. The solution was then purified by column chromatography with a petroleum ether:ethyl acetate ratio of 4:1 (v / v) to give a pale yellow viscous liquid, 1 Pa, with a yield of 82%.

[0049] N,N-dimethyl-2-(4-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)ethan-1-amine(1pa). Yellow liquid(176mg, 78% yield). 1 H NMR (400MHz, CDCl3) δ8.92 (s, 1H), 8.10-8.03 (m, 2H), 7.52-7.42 (m, 3H), 7.29 (d, J = 3.6H z,1H),6.73(d,J=3.6Hz,1H),4.34(t,J=6.6Hz,2H),2.70(t,J=6.6Hz,2H),2.25(s,6H).13 C NMR (101MHz, CDCl3)δ157.22,151.53,151.26,138.24,129.89,129.38,128.81,128.71,115.68,100.17,58.84,45.48,42.37.HRMS-ESI calculated for C 16 H 18 N4[M+H] + 267.1603, found 267.1605.

[0050] Example 2: Synthesis of compound 1pd

[0051]

[0052] Compound 1ae (600 g, 3 mmol, 1 equiv.) was dissolved in 15 mL of N,N-dimethylformamide. Potassium carbonate (414 mg, 3 mmol, 1 equiv.) was added in portions with stirring for 5 min. Excess dibromopentane (5 mmol, 2 equiv.) was added dropwise, and the mixture was stirred at room temperature for 6 h. The reaction progress was monitored by TLC with petroleum ether:ethyl acetate (v / v) 2:1. The reaction solution was diluted with water, extracted three times with ethyl acetate, and concentrated. Column chromatography with petroleum ether:ethyl acetate (v / v) 4:1 yielded a pale yellow viscous liquid, 1 od, with a yield of 81%.

[0053] Compound 1od (292 mg, 0.85 mmol), dimethylamine hydrochloride (77 mg, 0.94 mmol), triethylamine (454 mg, 4.3 mmol), and 5 mL of acetonitrile were added to a sealed tube and stirred at 80 °C for 5 h. The reaction was monitored by TLC with a PE:EA (v / v) ratio of 4:1. After cooling to room temperature, the reaction solution was diluted with water, extracted three times with ethyl acetate, and concentrated. The solution was then purified by column chromatography with a petroleum ether:ethyl acetate (v / v) ratio of 4:1 to give a pale yellow viscous liquid 1pd, with a yield of 88%.

[0054] N,N-dimethyl-5-(4-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pentan-1-amine(1pd). Yellow liquid(188mg, 72% yield). 1H NMR (400MHz, CDCl3) δ8.93(s,1H),8.13-8.07(m,2H),7.57-7.51(m,3H),7.28(d,J=3.4Hz,1H),6.81(d,J=3.6Hz,1H) ,4.32(t,J=6.9Hz,2H),2.89-2.76(m,2H),2.65(s,6H),1.94(p,J=7.1Hz,2H),1.85-1.71(m,2H),1.41-1.30(m,2H). 13 C NMR (101MHz, CDCl3) δ157.54,151.52,151.31,138.10,130.06,129.01,128.85 ,128.81,115.76,100.48,57.27,44.14,42.56,29.69,23.95,23.77.HRMS-ESI calculated for C 19 H 24 N4[M+H] + 309.2073, found 309.2083.

[0055] Example 3: Synthesis of compound 1pp

[0056]

[0057] Compound 1od (292 mg, 0.85 mmol), diethanolamine (99 mg, 0.94 mmol), triethylamine (454 mg, 4.3 mmol), and 5 mL of acetonitrile were added to a sealed tube and stirred at 80 °C for 5 h. The reaction was monitored by TLC with a PE:EA (v / v) ratio of 4:1. After cooling to room temperature, the reaction solution was diluted with water, extracted three times with ethyl acetate, and concentrated. The solution was then purified by column chromatography with a petroleum ether:ethyl acetate (v / v) ratio of 4:1 to give a pale yellow viscous liquid 1pp, with a yield of 80%.

[0058] 2,2'-((5-(4-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pentyl)azanediyl)bis(ethan-1-ol)(1pp). Yellow liquid (84mg, 76% yield). 1H NMR (400MHz, CDCl3) δ8.91 (s, 1H), 8.13-8.05 (m, 2H), 7.56-7.45 (m, 3H), 7.26 (d, J = 3.6Hz, 1H), 6.78 (d, J = 3.6Hz, 1H), 4.47 (d, J = 25.4Hz, 2H), 4. 28(t,J=7.1Hz,2H),3.65(t,J=5.2Hz,4H),2.76(t,J=5.2Hz,4H),2.63(t ,J=7.6Hz,2H),1.91-1.83(m,2H),1.58-1.52(m,2H),1.35-1.27(m,2H). 13 C NMR (101MHz, CDCl3) δ157.45,151.37,151.17,138.04,130.03,129.18,128.84,128.77, 115.79,100.32,58.69,56.00,54.37,44.48,29.91,25.50,24.14.HRMS-ESIcalculated for C 21 H 28 N4O2[M+H] + 369.2284, found 369.2291.

[0059] Example 4: Synthesis of compound 1qc

[0060]

[0061] One fraction of compound (70 mg, 0.25 mmol, 1 equiv.) was added to a sealed tube, followed by 2 mL of tetrahydrofuran and triethylamine (77 mg, 1.08 mmol). The mixture was stirred at room temperature for 10 min. Then, p-fluorobenzenesulfonyl chloride (49 mg, 0.25 mmol, 1.2 equiv.) was added while stirring, and the reaction was continued at room temperature for 12 h. The reaction progress was monitored by TLC using a PE:EA (v / v) ratio of 1:1. After the reaction was complete, the mixture was diluted with water. The solution was extracted three times with ethyl acetate and concentrated. The solution was then purified by column chromatography using a PE:EA (v / v) ratio of 2:1 to obtain a pale yellow viscous liquid, yield 1 qc, with a yield of 77%.

[0062] 4-fluoro-N-(5-(4-phenyl-pyrrolo[2,3-d]pyrimidin-7-yl)pentyl)benzenesulfonamide(1qc).Yellow liquid(84mg,77%yield). 1H NMR (400MHz, CDCl3) δ8.97(s,1H),8.13(d,J=7.2Hz,2H),7.87(dd,J=8.7,4.9Hz,2H),7.61-7.49(m,3H),7.26(d,J=3.5Hz,1H),7.18(t,J=8.4Hz ,2H),6.84(d,J=3.7Hz,1H),4.85(s,1H),4.29(t,J=7.1Hz,2H),2.96(t ,J=6.9Hz,2H),1.91-1.85(m,2H),1.60-1.53(m,2H),1.36-1.30(m,2H). 13 C NMR (101MHz, CDCl3) δ166.29,163.76,157.62,151.42,138.17,136.09,130.06(J C-F =3.03Hz),129.76,129.67,128.85(J C-F =7.07Hz), 116.35(J) C-F =23.23Hz),115.77,100.45,44.37,42.88,29.73,29.12,23.53.HRMS-ESI calculated for C 23 H 23 FN4O2S[M+H] + 439.1598, found 439.1587.

[0063] Example 5: Synthesis of 1 qg of compound

[0064]

[0065] One fraction of compound (70 mg, 0.25 mmol, 1 equiv.) was added to a sealed tube, followed by 2 mL of tetrahydrofuran and triethylamine (77 mg, 1.08 mmol). The mixture was stirred at room temperature for 10 min. Benzoyl chloride (35 mg, 0.25 mmol, 1.2 equiv.) was then added while stirring, and the reaction was continued at room temperature for 12 h. The reaction progress was monitored by TLC using a PE:EA (v / v) ratio of 1:1. After the reaction was complete, the mixture was diluted with water. The solution was extracted three times with ethyl acetate and then concentrated. The solution was then column-sected at a PE:EA (v / v) ratio of 2:1 to give 1 q g of a pale yellow viscous liquid, with a yield of 84%.

[0066] 1-phenyl-6-(4-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)hexan-1-one(1qg).Yellow liquid(78%yield).1 H NMR (400MHz, CDCl3) δ8.95 (s, 1H), 8.11 (d, J = 7.2Hz, 2H), 7.78-7.72 (m, 3H), 7.57-7.51 (m, 2H), 7.51-7.4 3(m,1H),7.40(t,J=7.0Hz,2H),7.28(d,J=4.1Hz,1H),6.80(d,J=3.7Hz,1H),4.32(t,J=7.1Hz,2H),3.47 -3.41(m,2H),1.95(t,J=7.6Hz,2H),1.68(t,J=7.6Hz,2H),1.45-1.39(m,2H). 13 C NMR (101MHz, CDCl3) δ167.64,157.33,151.55,151.18,137.91,134.64,131.43,130.13,129.08,128. 92,128.82,128.59,126.81,115.73,100.48,44.51,39.69,29.87,29.18,23.99.HRMS-ESIcalculated for C 24 H 24 N4O[M+H] + 385.2022, found 385.2024.

[0067] Example 6: Synthesis of compound 1qi

[0068]

[0069] Compound 1 of (70 mg, 0.25 mmol, 1 equiv.) was added to a sealed tube, followed by 2 mL of tetrahydrofuran and triethylamine (77 mg, 1.08 mmol). The mixture was stirred at room temperature for 10 min. p-fluorobenzoyl chloride (40 mg, 0.25 mmol, 1.2 equiv.) was added while stirring, and the reaction was continued at room temperature for 12 h. The reaction progress was monitored by TLC using a PE:EA (v / v) ratio of 1:1. After the reaction was complete, the mixture was diluted with water. The solution was extracted three times with ethyl acetate and concentrated. The solution was then purified by column chromatography using a PE:EA (v / v) ratio of 2:1 to obtain a pale yellow viscous liquid, 1 qi, in 86% yield.

[0070] 4-fluoro-N-(5-(4-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pentyl)benzamide(1qi). Yellow liquid (79 mg, 79% yield). 1H NMR (400MHz, CDCl3) δ8.96 (s, 1H), 8.12 (d, J = 7.4Hz, 2H), 7.76-7.72 (m, 3H), 7.59-7.53 (m, 3H), 7.30 (s, 1H), 7.09 (t, J = 8.2Hz, 3H), 6 .82(d,J=3.7Hz,1H),6.14(s,1H),4.36(t,J=6.9Hz,2H),3.50-3.43(m,2H),2.00-1.94(m,2H),1.76-1.66(m,2H),1.48-1.42(m,2H). 13 C NMR(101MHz,CDCl3)δ166.57,164.66(J C-F =252Hz),157.56,151.57,151.40,138.21,130.04,129.24(J C-F =8.08Hz),129.17,129.08,128.86,128.80,115.71(J C-F =5.05Hz),115.49,100.38,44.44,39.77,29.87,29.13,23.97.HRMS-ESI calculated for C 24 H 23 FN4O[M+H] + 403.1928, found 403.1937.

[0071] Example 7: Synthesis of compound 1qp

[0072]

[0073] Compound 1od (100 mg, 0.3 mmol, 1 equiv.) was dissolved in 2 mL of DMF, and 35 mg of guanidine hydrochloride (0.36 mmol, 1.2 equiv.) and 207 mg of potassium carbonate (1.5 mmol, 5 equiv.) were added. The mixture was stirred at 80 °C for 12 h, and the reaction was monitored using a DCM:CH3OH (v / v) ratio of 10:1. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the filtrate was concentrated. The filtrate was extracted three times with dichloromethane, the solvent was removed under reduced pressure, and the mixture was washed with ethyl acetate to give 1 qp of a white solid, with a yield of 78%.

[0074] 1-(5-(4-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pentyl)guanidine(1qp).White soild(75mg,78%yield).Mp:113-115℃. 1H NMR (400MHz, CDCl3) δ8.87(s,1H),8.07-8.01(m,2H),7.49-7.46(m,3H),7.25(d,J=3.7Hz,1H),6.72(dd,J=3.6 ,1.0Hz,1H),4.20(t,J=7.2Hz,2H),3.34-3.14(m,2H),1.86-1.77(m,2H),1.68-1.57(m,2H),1.38-1.21(m,2H). 13 C NMR (101MHz, CDCl3) δ162.61,156.21,157.38,151.31,151.01,130.06,129.32,128.75,115.78,100.34,44.26,41.65,29.58,28.08,23.60.HRMS-ESI calculated forC 18 H 22 N6[M+H] + 323.1978, found 323.1990.

[0075] Example 8: Synthesis of compound 1rf

[0076]

[0077] Compound 1OH (70 mg, 0.2 mmol, 1 equiv.) was added to a sealed tube along with 2 mL of DMF as solvent, potassium carbonate (55 mg, 0.4 mmol), and phenol (21 mg, 0.22 mmol, 1.1 equiv.). The mixture was stirred at 110 °C for 8 h. The reaction was monitored by TLC with a PE:EA (v / v) ratio of 1:1. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, concentrated, and then column-sected with a PE:EA (v / v) ratio of 2:1 to give a pale red viscous product 1rf, with a yield of 69%.

[0078] 4-fluoro-N-(5-(4-phenoxy-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pentyl)benzamide(1rf). Yellow liquid (59 mg, 71% yield). 1H NMR (400MHz, CDCl3) δ8.45(s,1H),7.75(dd,J=8.8,5.3Hz,2H),7.47(t,J=7.9Hz,2H),7.31(d,J=7.4Hz,1H),7.27(d,J=1.1Hz,1H),7.25(s,1H),7.14 -7.09(m,3H),6.46(d,J=3.5Hz,1H),6.16(s,1H),4.30(t,J=7.1Hz,2H),3 .49-3.41(m,2H),1.97-1.93(m,2H),1.72-1.65(m,2H),1.46-1.38(m,2H). 13 C NMR(101MHz,CDCl3)δ166.56,164.66(J C-F =252.5Hz),162.46,152.95,152.69,150.84,130.80,129.69,129.14(J C-F =8.08Hz),126.62,125.58,121.84,115.60(J C-F =22.2Hz),105.71,98.63,44.73,39.80,30.01,29.14,23.96.HRMS-ESI calculated forC 24 H 23 FN4O2[M+H] + 419.1877, found 419.1869.

[0079] Example 9: Synthesis of compound 1ro

[0080]

[0081] Compound 1OH (70 mg, 0.2 mmol, 1 equiv.) was added to a sealed tube, along with 2 mL of isopropanol as solvent, 0.1 mL of concentrated hydrochloric acid (three drops), and p-trifluoromethylaniline (35 mg, 0.22 mmol, 1.1 equiv.). The mixture was stirred at 100 °C for 8 h. TLC analysis was performed using PE:EA (v / v) at a 1:1 ratio. After the reaction was complete, the mixture was cooled to room temperature, diluted with water, extracted three times with ethyl acetate, concentrated, and then column-sected using DCM:CH3OH (v / v) at a 40:1 ratio to obtain the target product 1RO, with a yield of 62%.

[0082] 4-fluoro-N-(5-(4-((4-(trifluoromethyl)phenyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)p entyl)benzamide(1ro). Yellow liquid (65mg, 67% yield). 1 H NMR (400MHz, CDCl3) δ8.52(s,1H),7.85(d,J=8.4Hz,2H),7.78-7.72(m,2H),7.65(d,J=8.4Hz,2H),7.12(d,J=8.6Hz,1H),7.10-7.06(m,1H),6.98 (s,1H),6.38(d,J=3.5Hz,1H),6.08(s,1H),4.28(t,J=7.1Hz,2H),3.45( q,J=6.9Hz,2H),1.98-1.91(m,2H),1.73-1.66(m,2H),1.46-1.38(m,2H). 13 C NMR(101MHz,CDCl3)δ168.47,164.86(J C-F =2.02Hz),153.36,150.87,149.68,141.54,130.86(J C-F =3.03Hz), 130.19(J) C-F =6.06Hz), 126.52(J) C-F =6.06Hz), 125.36, 125.04 (J) C-F =10.1Hz)122.84,115.89(J) C-F =16.16Hz),106.33,97.09,45.31,39.76,28.62,28.40,24.14.HRMS-ESI calculated for C 25 H 23 F4N5O[M+H] + 486.1911, found 486.1922.

[0083] The above detailed description is a specific description of feasible embodiments of the invention. These embodiments are not intended to limit the scope of protection of the invention. All equivalent implementations or modifications that do not depart from the invention should be included within the scope of protection of the invention.

[0084] Example 10:

[0085] This embodiment investigates the inhibitory activity of the pyrrolo[2,3-d]pyrimidine core structure compounds prepared in Examples 1-7 above against the release of inflammatory factors from human respiratory tract epithelial (HBE) cells stimulated by lipopolysaccharide (LPS). The preliminary in vitro anti-inflammatory activity of the compounds was tested using a method that inhibits the release of the inflammatory factor IL-6 from HBE cells stimulated by LPS. The specific method is as follows: 3.5 × 10⁻⁶ 5 HBE cells were cultured in 1640 medium containing 15% FBS at 37°C for 24 hours. The medium was then replaced, and the test compound (final concentration 5 μM) was added for pretreatment for 30 minutes. The cells were then treated with 100 μg / mL LPS for another 22 hours. The culture medium was collected, and IL-6 and IL-8 levels were detected by ELISA. Total protein concentration was also measured from the collected cells. ELISA results were calibrated by dividing the corresponding total protein concentration, with the IL-6 or IL-8 level of the LPS control group set as 100. Each compound was tested three times, and the average value and error were calculated.

[0086] The inhibitory activity of compound 1pg-1qp on the release of IL-6 and IL-8 is shown in the figure. Figure 5 Most of the effective compounds inhibited the release of IL-6 stimulated by LPS. Among them, compound 1qi showed better inhibitory effects and has the potential to become a new anti-inflammatory drug.

[0087] Example 11:

[0088] This embodiment demonstrates the inhibitory activity of the pyrrolo[2,3-d]pyrimidine core structure compounds prepared in Examples 8-9 above on the release of inflammatory factors IL-6 and IL-8 from human respiratory epithelial (HBE) cells stimulated by lipopolysaccharide (LPS).

[0089] The preliminary in vitro anti-inflammatory activity of the compound was tested by inhibiting the release of the inflammatory factor IL-8 from HBE cells stimulated by LPS. The specific method is as follows: 3.5 × 10 5 HBE cells were cultured in 1640 medium containing 15% FBS at 37°C for 24 hours. The medium was then replaced, and the test compound (final concentration 5 μM) was added for pretreatment for 30 minutes. The cells were then treated with 100 μg / mL LPS for another 22 hours. The culture medium was collected, and IL-6 and IL-8 levels were detected by ELISA. Total protein concentration was also measured from the collected cells. ELISA results were calibrated by dividing the corresponding total protein concentration, with the IL-6 or IL-8 level of the LPS control group as 100. Each compound was tested three times, and the average value and error were calculated. Inhibitory activity is described in [see section on inhibitory activity]. Figure 6 .

[0090] The inhibitory activity of compound 1qi-1rt on the release of IL-6 and IL-8 is shown in the figure. Figure 6Most of the effective compounds inhibit the release of IL-6 stimulated by LPS. Among them, compound 1rf has a better inhibitory effect and has the potential to become a new anti-inflammatory drug.

[0091] The above detailed description is a specific description of feasible embodiments of the invention. These embodiments are not intended to limit the scope of protection of the invention. All equivalent implementations or modifications that do not depart from the invention should be included within the scope of protection of the invention.

Claims

1. A pyrrolo[2,3-d]pyrimidine derivative and a pharmaceutically acceptable salt thereof; The structural formula of the pyrrolo[2,3-d]pyrimidine derivative is any one of the following: 。 2. The use of the pyrrolo[2,3-d]pyrimidine derivatives as described in claim 1 and pharmaceutically acceptable salts thereof in the preparation of medicaments for treating inflammation-related diseases.

3. Use according to claim 2, wherein the compound is ###0002### The drug is a medication that treats inflammation-related diseases by inhibiting the release of IL-6 or IL-8.

4. Use according to claim 2 or 3, wherein the compound is ###0002### The inflammation-related diseases mentioned are: pneumonia, hepatitis, asthma, viral myocarditis, acute respiratory distress syndrome, pancreatitis, systemic inflammatory response syndrome, sepsis, ulcerative colitis, bronchitis, infective endocarditis, and autoimmune diseases.

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