Pyrrolo [2, 3-d] pyrimidine derivative and application thereof in preparation of anti-inflammatory drugs

Abstract

The invention discloses a pyrrolo [2, 3-d] pyrimidine derivative and application of the pyrrolo [2, 3-d] pyrimidine derivative in preparation of anti-inflammatory drugs, and the pyrrolo [2, 3-d] pyrimidine derivative is shown as a formula (I) or a formula (II). In the formula (I), R1 is selected from C2-C6 chain nitrogen-containing alkyl substituent groups; in the formula (II), R2 is selected from unsubstituted or substituted aryl, aryloxy or arylamino; the substituted aryl group, aryloxy group or arylamino group is substituted by one or more of C1-C6 alkyl group, C1-C6 alkoxy group, halogen (F, Cl, Br), trifluoromethyl group and trifluoromethoxy group; pharmacological results show that the pyrrolo [2, 3-d] pyrimidine derivative disclosed by the invention can effectively inhibit release of IL-6 and IL-8 pro-inflammatory factors, and has good anti-inflammatory activity; # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical chemistry, and specifically relates to a pyrrolo[2,3-d]pyrimidine derivative and an application thereof in the preparation of an anti-inflammatory drug. Background Art

[0002] Acute lung injury (ALI) / acute respiratory distress syndrome (ARDS) is an acute diffuse inflammatory lung injury caused by a variety of lung pathogens, leading to acute respiratory failure. Its pathological features are mainly manifested as increased pulmonary vascular permeability, alveolar exudation of protein-rich fluid, pulmonary edema, and the formation of hyaline membranes. Inflammatory response is a normal physiological response of the body, but when the inflammatory response is unbalanced, it may lead to tissue damage and the occurrence of various diseases. Clinical studies have shown that inflammatory cytokines and chemokines play an important role in the process of lung injury and can be used as good biomarkers to reflect acute lung injury. The core theory of the pathogenesis of ALI / ARDS is that the imbalance of inflammatory response aggravates epithelial or endothelial damage, resulting in protein-rich edema fluid entering the alveoli. During ALI, the increased permeability of alveolar epithelial microvessels will eventually lead to ARDS. Therefore, regulating the overexpression of proinflammatory cytokines and chemokines to regulate inflammation is an effective strategy for the treatment of ALI. At present, the clinical efficacy of drugs for treating ALI has not met expectations, and a new drug is urgently needed to effectively prevent and treat ALI in order to treat the increasing number of patients with acute lung injury. Therefore, the research and development of drugs for treating acute lung injury is a research work with far-reaching significance for people's life and health.

[0003] Pyrrolo[2,3-d]pyrimidine, also known as 7-deazapurine (7-DAP), is a parent nucleus of multiple kinase inhibitors with multiple biological activities. It is clinically used to treat a variety of diseases, especially in anti-inflammatory treatment. For anti-inflammatory activity, pyrrolo[2,3-d]pyrimidine follows multiple mechanisms, including inhibiting key kinases in signaling pathways, such as JAK, Cox-2, NIK and PERK, and has shown good therapeutic effects on a variety of inflammatory-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] The present invention provides a pyrrolo[2,3-d]pyrimidine derivative and its use in the preparation of anti-inflammatory drugs, wherein the compound has a highly effective anti-inflammatory effect. The present invention synthesizes a series of pyrrolo[2,3-d]pyrimidine derivatives and evaluates their anti-inflammatory activity, wherein compounds 1qi-1rl exhibit anti-inflammatory activity against HBE, and compound 1rf in particular has a better anti-inflammatory effect.

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

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

[0007]

[0008] In formula (I), R 1 Selected from C 2 -C 6 The chain contains nitrogen-containing alkyl substituents;

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

[0010] R 1 Any one of the following groups is preferred:

[0011]

[0012]

[0013] in, Indicates the substitution position. 2 Any one of the following groups is preferred:

[0014]

[0015] in, Indicates a replacement position.

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

[0017]

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

[0019] The cause of the inflammation-related disease is at least partially caused by inflammation, including but not limited to: sepsis, pneumonia, hepatitis, rheumatoid arthritis, systemic lupus erythematosus, asthma, chronic obstructive pneumonia, viral myocarditis, acute respiratory distress syndrome, pancreatitis, systemic inflammatory response syndrome, sepsis, ulcerative colitis, bronchitis, infective endocarditis, autoimmune disease;

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

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

[0022]

[0023] Compound 1ae (600 g, 3 mmol, 1 equiv.) was dissolved in 15 mL N,N-dimethylformamide, potassium carbonate (414 mg, 3 mmol, 1 equiv.) was added in batches under stirring, and the mixture was stirred for 5 min. Dibromoalkane (5 mmol, 2 equiv.) was added dropwise, and the mixture was stirred at room temperature for 6 h. TLC petroleum ether: ethyl acetate (v / v) was used for monitoring at 2:1. After the reaction was completed, the reaction solution was diluted with water, extracted three times with ethyl acetate, concentrated, and filtered through a column with petroleum ether: ethyl acetate (v / v) at 4:1 to obtain a light yellow viscous liquid 1oa-1oe; wherein the dibromoalkane is 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, stirred at 80°C for 5 h, monitored by TLC PE:EA (v / v) 4:1. After the reaction was completed, it was cooled to room temperature, the reaction solution was diluted with water, extracted three times with ethyl acetate and concentrated, and passed through a column with petroleum ether:ethyl acetate (v / v) 4:1 to obtain a light yellow viscous liquid 1pa-1pf;

[0025] The compound 10d (100 mg, 0.3 mmol, 1 equiv.) was dissolved in 5 mL of ethanol, sodium iodide (27 mg, 0.18 mmol, 0.6 equiv.) and a N-containing compound were added, and the mixture was stirred at 80°C for 12 h and monitored by TLC PE:EA (v / v) 4:1. After the reaction was completed, the mixture was cooled to room temperature, and the reaction solution was diluted with water. The mixture was extracted three times with ethyl acetate and concentrated. The mixture was passed through a column with petroleum ether:ethyl acetate (v / v) 2:1 to obtain a light yellow viscous liquid of 1 pg-1 ps; wherein the N-containing compound is piperidine, cycloheximide, 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] Compound 1of (70 mg, 0.25 mmol, 1 equiv.), 2 mL of tetrahydrofuran and triethylamine (77 mg, 1.08 mmol) were added to a sealed tube and stirred at room temperature for 10 min. An acylating agent (0.25 mmol, 1.2 equiv.) was added under stirring and reacted at room temperature for 12 h. TLC PE:EA (v / v) was used for monitoring at 1:1. After the reaction was completed, the mixture was diluted with water, extracted three times with ethyl acetate and concentrated. The mixture was filtered through a column with PE:EA (v / v) at 2:1 to obtain a light yellow viscous liquid of 1qa-1qm. The acylating agent was p-toluenesulfonyl chloride, p-methoxysulfonyl chloride, p-fluorobenzenesulfonyl chloride, o-trifluoromethylbenzenesulfonyl chloride, 3-pyridinesulfonyl chloride, 2-thiophenesulfonyl chloride, benzoyl chloride, p-methoxybenzoyl chloride, p-fluorobenzoyl chloride, m-fluorobenzoyl chloride, p-methoxyphenyl isocyanate, p-trifluoromethylphenyl isocyanate or p-methoxyphenyl isothiocyanate.

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

[0029]

[0030] Take compound 1oh (1.0 g, 6.5 mmol), dissolve it in 10 mL of toluene, add potassium carbonate (1.01 mg, 7.8 mmol, 1.3 equiv.), PdCl 2 (PPh 3 ) 2(210 mg, 0.30 mmol, 0.05 equiv.) and aryl boronic acid (9 mmol, 1.5 equiv.), react at 120°C for 6 h, monitor by TLC (PE: EA v: v = 4: 1), after the reaction is completed, cool to room temperature, add water to quench the reaction, extract with ethyl acetate three times (3×100 mL), dry the organic layer with anhydrous sodium sulfate, concentrate under reduced pressure, and purify the concentrate with silica gel column chromatography (PE: EA v: v = 4: 1) to obtain compound 1ra-1re; wherein the aryl boronic acid is 2-thiopheneboric acid, 2-methylphenylboric acid, 3-methylphenylboric acid, 4-methylphenylboric acid or 3-methoxyphenylboric acid;

[0031]

[0032] Add compound 1OH (70 mg, 0.2 mmol, 1 equiv.), solvent DMF 2 mL, potassium carbonate (55 mg, 0.4 mmol) and phenol compound (0.22 mmol, 1.1 equiv.) into a sealed tube, stir at 110°C for 8 h, monitor with TLC PE:EA (v / v) 1:1, cool to room temperature after the reaction, dilute with water, extract three times with ethyl acetate and concentrate, pass through a column with PE:EA (v / v) 2:1 to obtain a viscous product 1RF-1RL; wherein the phenol compound is 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.), solvent isopropanol 2 mL, concentrated hydrochloric acid (0.1 mL, three drops) and aniline compound (0.22 mmol, 1.1 equiv.) were added to the sealed tube, stirred at 100 °C for 8 h, monitored by TLC PE:EA (v / v) 1:1, cooled to room temperature after the reaction, diluted with water, extracted three times with ethyl acetate and concentrated, DCM:CH 3 OH (v / v) 40:1 is passed through the column to obtain the product 1rm-1rt; wherein the aniline compound is 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 as follows:

[0036] The present invention uses pyrrolo[2,3-d]pyrimidine as the skeleton and prepares a series of pyrrolo[2,3-d]pyrimidine derivatives by computer-aided drug design. The results of in vitro anti-inflammatory activity tests show that most of the compounds of the present invention have good inhibitory ability against proinflammatory cytokines IL-6 and IL-8, especially compound 1rf, which has a better anti-inflammatory effect, with an inhibition rate of 66% and 70% for IL-6 and IL-8. In vivo anti-inflammatory experiments showed that the pathological characteristics of lung inflammation in mice were significantly improved after administration of compound 1rf, among which the number of inflammatory cells and basophils was significantly reduced, and edema disappeared. Therefore, compound 1rf can be used as an anti-inflammatory lead compound for subsequent structural optimization, and it is expected to become a clinical candidate compound for the treatment of acute lung injury. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 : H NMR image of compound 1qi obtained in Example 6.

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

[0039] Figure 3 : H NMR image of compound 1rf obtained in Example 8.

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

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

[0042] Figure 6 : Example 11 Compound 1qi-1rt has inhibitory activity on the release of IL-6 and IL-8. DETAILED DESCRIPTION

[0043] In order to better illustrate the present invention, the specific synthesis route of the pyrrolo[2,3-d]pyrimidine derivatives of the present invention is given in the following specific embodiments. Those skilled in the art should understand that the present invention claims to protect the compound structure, and the present invention can also be implemented using certain other synthesis routes.

[0044] Example 1: Synthesis of Compound 1pa

[0045]

[0046] Take 1.0 g (6.5 mmol) of 4-chloro-7-hydropyrrolo[2,3-d]pyrimidine, dissolve it in 10 mL of toluene, add potassium carbonate (1.01 mg, 7.8 mmol, 1.3 equiv.), PdCl 2(PPh 3 ) 2 (210 mg, 0.30 mmol, 0.05 equiv.) and phenylboronic acid (1.01 g, 9 mmol, 1.5 equiv.), reacted at 120 ° C for 6 h. TLC detected the reaction (PE: EA v: v = 4: 1). After the reaction was completed, it was cooled to room temperature, water was added to quench the reaction, and ethyl acetate was extracted three times (3×100 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (PE: EA v: v = 4: 1) to obtain 1ae with a yield of 88%.

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

[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 into a sealed tube and stirred at 80°C for 5 h. The reaction was monitored by TLC PE:EA (v / v) 4:1. The mixture was cooled to room temperature, diluted with water, extracted three times with ethyl acetate and concentrated. The mixture was filtered through a column with petroleum ether:ethyl acetate (v / v) 4:1 to obtain a light yellow viscous liquid 1pa 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 (400 MHz, CDCl 3 )δ8.92(s,1H),8.10-8.03(m,2H),7.52-7.42(m,3H),7.29(d,J=3.6Hz,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 (101 MHz, CDCl 3)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 N 4 [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 N,N-dimethylformamide, and potassium carbonate (414 mg, 3 mmol, 1 equiv.) was added in batches under stirring, and stirred for 5 min. Excess dibromopentane (5 mmol, 2 equiv.) was added dropwise, and stirred at room temperature for 6 h. The reaction progress was monitored by TLC petroleum ether: ethyl acetate (v / v) 2:1. The reaction solution was diluted with water, extracted three times with ethyl acetate, and concentrated. The light yellow viscous liquid 1 od was obtained by column with petroleum ether: ethyl acetate (v / v) 4:1, and the yield was 81%.

[0053] Compound 10d (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 into a sealed tube and stirred at 80°C for 5 h. The reaction was monitored by TLC PE:EA (v / v) 4:1. The mixture was cooled to room temperature, diluted with water, extracted three times with ethyl acetate and concentrated. The mixture was filtered through a column with petroleum ether:ethyl acetate (v / v) 4:1 to obtain 1pd of a light yellow viscous liquid 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). 1 H NMR (400 MHz, CDCl 3)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 (101 MHz, CDCl 3 )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 N 4 [M+H] + 309.2073, found 309.2083.

[0055] Example 3: Synthesis of Compound 1pp

[0056]

[0057] Compound 10d (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 PE:EA (v / v) 4:1. The mixture was cooled to room temperature, diluted with water, extracted three times with ethyl acetate and concentrated. The mixture was filtered through a column with petroleum ether:ethyl acetate (v / v) 4:1 to obtain 1 pp of a light yellow viscous liquid 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). 1 H NMR (400 MHz, CDCl 3)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 (101 MHz, CDCl 3 )δ157.45,151.37,151.17,138.04,130.03,129.18,128.84,128.77,115.79,1 00.32,58.69,56.00,54.37,44.48,29.91,25.50,24.14.HRMS-ESIcalculated for C 21 H 28 N 4 O 2 [M+H] + 369.2284, found 369.2291.

[0059] Example 4: Synthesis of Compound 1qc

[0060]

[0061] Add compound 1of (70 mg, 0.25 mmol, 1 equiv.) to a sealed tube, add 2 mL of tetrahydrofuran and triethylamine (77 mg, 1.08 mmol), and stir at room temperature for 10 min. Add p-fluorobenzenesulfonyl chloride (49 mg, 0.25 mmol, 1.2 equiv.) under stirring, react at room temperature for 12 h, monitor the reaction progress with TLC PE:EA (v / v) 1:1, and dilute with water after the reaction is completed. Extract with ethyl acetate three times and concentrate, pass through a column with PE:EA (v / v) 2:1, and obtain 1qc of light yellow viscous liquid 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). 1 H NMR (400 MHz, CDCl 3)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),6.8 4(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 (101 MHz, CDCl 3 )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 FN 4 O 2 S[M+H] + 439.1598, found 439.1587.

[0063] Example 5: Synthesis of Compound 1qg

[0064]

[0065] Add compound 1of (70 mg, 0.25 mmol, 1 equiv.) to a sealed tube, add 2 mL of tetrahydrofuran and triethylamine (77 mg, 1.08 mmol), and stir at room temperature for 10 min. Add benzoyl chloride (35 mg, 0.25 mmol, 1.2 equiv.) under stirring, react at room temperature for 12 h, monitor the progress of the reaction by TLC PE: EA (v / v) 1:1, and dilute with water after the reaction is completed. Extract with ethyl acetate three times and concentrate, pass through a column with PE: EA (v / v) 2:1, and obtain 1 qg of a light 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 (400 MHz, CDCl 3 )δ8.95(s,1H),8.11(d,J=7.2Hz,2H),7.78-7.72(m,3H),7.57-7.51(m,2H),7.51-7.43(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 (101 MHz, CDCl 3 )δ167.64,157.33,151.55,151.18,137.91,134.64,131.43,130.13,129.08,128.92,128.8 2,128.59,126.81,115.73,100.48,44.51,39.69,29.87,29.18,23.99.HRMS-ESIcalculated for C 24 H 24 N 4 O[M+H] + 385.2022, found 385.2024.

[0067] Example 6: Synthesis of Compound 1qi

[0068]

[0069] Add compound 1of (70 mg, 0.25 mmol, 1 equiv.) to a sealed tube, add 2 mL of tetrahydrofuran and triethylamine (77 mg, 1.08 mmol), and stir at room temperature for 10 min. Add p-fluorobenzoyl chloride (40 mg, 0.25 mmol, 1.2 equiv.) under stirring, react at room temperature for 12 h, monitor the reaction progress with TLC PE: EA (v / v) 1:1, and dilute with water after the reaction is completed. Extract with ethyl acetate three times and concentrate, pass through a column with PE: EA (v / v) 2:1 to obtain a light yellow viscous liquid 1qi with a yield of 86%.

[0070] 4-fluoro-N-(5-(4-phenyl-7H-pyrrolo[2,3-d]pyrimidin-7-yl)pentyl)benzamide(1qi). Yellow liquid (79 mg, 79% yield). 1 H NMR (400 MHz, CDCl 3 )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 (101 MHz, CDCl 3 )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 FN 4 O[M+H] + 403.1928, found 403.1937.

[0071] Example 7: Synthesis of Compound 1qp

[0072]

[0073] Compound 10d (100 mg, 0.3 mmol, 1 equiv.) was dissolved in 2 mL DMF, 35 mg guanidine hydrochloride (0.36 mmol, 1.2 equiv.) and 207 mg potassium carbonate (1.5 mmol, 5 equiv.) were added, and stirred at 80 °C for 12 h. DCM:CH 3OH (v / v) 10:1 detection reaction. After the reaction is completed, cool to room temperature, filter, and concentrate the filtrate. The filtrate is extracted three times with dichloromethane, the solvent is removed under reduced pressure, and washed with ethyl acetate to obtain 1qp of 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℃. 1 H NMR (400 MHz, CDCl 3 )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,1 H), 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 (101 MHz, CDCl 3 )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 N 6 [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.), 2 mL of DMF as solvent, potassium carbonate (55 mg, 0.4 mmol) and phenol (21 mg, 0.22 mmol, 1.1 equiv.) were added to the sealed tube and stirred at 110°C for 8 h. The reaction was detected by TLC PE:EA (v / v) 1:1. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate three times, concentrated, and filtered through a column with PE:EA (v / v) 2:1 to obtain a light 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). 1 H NMR (400 MHz, CDCl 3 )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 (101 MHz, CDCl 3 )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 FN 4 O 2 [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.), 2 mL of isopropanol as solvent, concentrated hydrochloric acid (0.1 mL, three drops) and p-trifluoromethylaniline (35 mg, 0.22 mmol, 1.1 equiv.) were added to the sealed tube and stirred at 100 °C for 8 h. TLC PE:EA (v / v) 1:1 was used for detection. After the reaction was completed, the mixture was cooled to room temperature, diluted with water, extracted three times with ethyl acetate and concentrated, and then the mixture was concentrated with DCM:CH 3 OH (v / v) 40:1 was passed through the column 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 (400 MHz, CDCl 3 )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 (101 MHz, CDCl 3 )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 23F 4 N 5 O[M+H] + 486.1911, found 486.1922.

[0083] The above detailed description is a specific description of a feasible embodiment of the invention, which is not intended to limit the protection scope of the invention. Any equivalent implementation or modification that does not deviate from the invention should be included in the protection scope of the invention.

[0084] Embodiment 10:

[0085] In this example, the pyrrolo[2,3-d]pyrimidine core structure compound prepared in the above examples 1 to 7 was used to test the inhibitory activity of lipopolysaccharide (LPS)-stimulated human respiratory epithelial (HBE) cells in releasing inflammatory factors. The initial in vitro anti-inflammatory activity of the compound was tested by inhibiting the release of inflammatory factor IL-6 from HBE cells stimulated by LPS. The specific method is as follows: 3.5×10 5 HBE cells / mL were cultured in 1640 culture medium containing 15% FBS at 37°C. After 24 hours, the culture medium was renewed and the tested compound (final concentration was 5μM) was added for pretreatment for 30 minutes. Then 100μg / mL LPS was used for further treatment for 22 hours, and the culture medium was collected to detect the IL-6 and IL-8 content by ELISA. The cells were collected to detect the total protein concentration, and the ELISA results were calibrated by dividing the corresponding total protein concentration, with the IL-6 or IL-8 content of the LPS control group as 100; each compound was tested 3 times, and the average value and error value were calculated.

[0086] The inhibitory activity of compound 1pg-1qp on IL-6 and IL-8 release is shown in Figure 5 Most of the effective compounds have an inhibitory effect on LPS-stimulated IL-6 release, among which compound 1qi has a better inhibitory effect and has the potential to become a new anti-inflammatory drug.

[0087] Embodiment 11:

[0088] In this example, the pyrrolo[2,3-d]pyrimidine core structure compound prepared in Examples 8 to 9 above was used to investigate the inhibitory activity of the inflammatory factors IL-6 and IL-8 released by 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 inflammatory factor IL-8 from HBE cells stimulated by LPS. The specific method is as follows: 3.5×10 5HBE cells / mL were cultured in 1640 medium containing 15% FBS at 37°C. After 24 hours, the medium was renewed and the test compound (final concentration was 5 μM) was added for pretreatment for 30 minutes. Then 100 μg / mL LPS was used for further treatment for 22 hours, and the culture medium was collected to detect the IL-6 and IL-8 content by ELISA. The cells were collected to detect the total protein concentration, and the ELISA results were calibrated by dividing the corresponding total protein concentration, with the IL-6 or IL-8 content of the LPS control group as 100. Each compound was tested 3 times, and the average and error values ​​were calculated. The inhibitory activity was shown in Table 1. Figure 6 .

[0090] The inhibitory activity of compound 1qi-1rt on IL-6 and IL-8 release is shown in Figure 6 Most of the effective compounds have an inhibitory effect on LPS-stimulated IL-6 release, among which 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 a feasible embodiment of the invention, which is not intended to limit the protection scope of the invention. Any equivalent implementation or modification that does not deviate from the invention should be included in the protection scope of the invention.

Claims

1. A pyrrolo[2,3-d]pyrimidine derivative represented by formula (I) or formula (II), and a pharmaceutically acceptable salt thereof: In formula (I), R 1 Selected from C2-C6 chain nitrogen-containing alkyl substituents; In formula (II), R 2 Selected from unsubstituted or substituted aryl, aryloxy or arylamino; the substituted aryl, aryloxy or arylamino is substituted by one or more of C1-C6 alkyl, C1-C6 alkoxy, halogen, trifluoromethyl, trifluoromethoxy.

2. The pyrrolo[2,3-d]pyrimidine derivative according to claim 1, characterized in that R 1 Any one selected from the following groups:

3. The pyrrolo[2,3-d]pyrimidine derivative according to claim 1, characterized in that R 2 Any one selected from the following groups:

4. Use of the pyrrolo[2,3-d]pyrimidine derivative and a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3 in the preparation of a drug for treating inflammation-related diseases.

5. The use according to claim 4, characterized in that The drug is a drug for treating inflammation-related diseases by inhibiting the release of IL-6 or IL-8.

6. The use according to claim 4 or 5, characterized in that The inflammation-related diseases are: sepsis, pneumonia, hepatitis, rheumatoid arthritis, systemic lupus erythematosus, asthma, chronic obstructive pneumonia, viral myocarditis, acute respiratory distress syndrome, pancreatitis, systemic inflammatory response syndrome, sepsis, ulcerative colitis, bronchitis, infective endocarditis, and autoimmune diseases.

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