A pyrrolopyrimidine derivative and its preparation method, pharmaceutical composition and application

Abstract

The present invention relates to the field of chemical medicine, and specifically to a pyrrolopyrimidine derivative and a preparation method, a pharmaceutical composition and application thereof. The present invention obtains a novel pyrrolopyrimidine derivative, the preparation process is simple and easy, and a variety of pyrrolopyrimidine derivatives can be obtained. The compound has a good effect of treating and preventing cancer, has a selective inhibitory effect on FGFR2, and has good safety; and can be composed of a pharmaceutical composition, which is suitable for the development of drugs for treating various cancers. Formula I.

Description

Technical Field

[0001] The present invention relates to the field of chemical medicines, and in particular to a pyrrolopyrimidine derivative and a preparation method, a pharmaceutical composition and application thereof. Background Art

[0002] Multi-target inhibitors and pan-FGFR inhibitors have achieved impressive results in clinical studies and are still the first choice for the treatment of FGFR abnormalities. However, the driving force for the continuous progress of drug research is to improve drug safety, overcome drug resistance, and increase clinical benefits for patients in response to adverse events of current drugs.

[0003] The FGFR2 gene is located on chromosome 10q26 and encodes two subtypes of proteins (FGFR2b and FGFR2c), which are functional receptors for FGF. In the body, FGFR2 is activated upon binding to the ligand, causing autophosphorylation of the corresponding effector cell intracellular domain. Abnormal expression of FGFR2 is associated with the occurrence and progression of a variety of human cancers, and missense mutations of the FGFR2 gene have been shown to occur in gastric cancer, lung cancer, ovarian cancer, and endometrial cancer. Therefore, the discovery of new, effective, and safe anti-tumor drugs is an important issue that needs to be urgently addressed in the treatment of cancer. Summary of the invention

[0004] The purpose of the present invention is to solve the deficiencies of the prior art and provide a pyrrolopyrimidine derivative and a preparation method, a pharmaceutical composition and application thereof, which specifically adopts the following technical scheme:

[0005] According to the first aspect of the present invention, there is provided a pyrrolopyrimidine derivative, the structure of which is shown in Formula I:

[0006] Formula I,

[0007] In Formula I, Linker is selected from one of an alkyl group, an alkoxy group, a heteroatom substituent, a substituted nitrogen heterocycle, an aryl group, and a substituted aryl structure;

[0008] X can be selected from any of the N and O structures;

[0009] R is selected from alkyl, alkoxy, heteroatom substituent, substituted nitrogen heterocycle, aryl or -Ph-N(R 1 R 2 )One of the N-.

[0010] Preferably, in Formula I, Linker, R, and X are independently selected from one of the following structures 1-16:

[0011] In structure 1, Linker is , R corresponds to , X corresponds to O;

[0012] In structure 2, Linker is , R corresponds to , X corresponds to O;

[0013] In structure 3, Linker is , R corresponds to , X corresponds to N;

[0014] In structure 4, Linker is , R corresponds to , X corresponds to N;

[0015] In structure 5, Linker is , R corresponds to , X corresponds to N;

[0016] In structure 6, Linker is , R corresponds to , X corresponds to N;

[0017] In structure 7, Linker is , R corresponds to , X corresponds to N;

[0018] In structure 8, Linker is , R corresponds to , X corresponds to N;

[0019] In structure 9, Linker is , R corresponds to , X corresponds to N;

[0020] In structure 10, Linker is , R corresponds to , X corresponds to N;

[0021] In structure 11, Linker is , R corresponds to , X corresponds to N;

[0022] In structure 12, Linker is , R corresponds to , X corresponds to N;

[0023] In structure 13, Linker is , R corresponds to , X corresponds to N;

[0024] In structure 14, Linker is , R corresponds to , X corresponds to N;

[0025] In structure 15, Linker is , R corresponds to , X corresponds to N;

[0026] In structure 16, Linker is , R corresponds to , X corresponds to N.

[0027] More preferably, the structure of the pyrrolopyrimidine derivative is shown in Formula II or Formula III:

[0028] Formula II, Formula III.

[0029] In vitro antiproliferation experiments showed that both Formula II and Formula III can exhibit antiproliferative effects on SNU-16 tumor cells with high expression of FGFR2, among which Formula III can effectively inhibit the proliferation of SNU-16 tumor cells with high expression of FGFR2 at low nanomolar concentrations. In in vivo antiproliferation experiments, both Formula II and Formula III can significantly inhibit the growth of SNU-16 tumor cells in mice, among which Formula III has an in vivo tumor growth inhibition rate of 87.3%, showing a strong in vivo tumor inhibition effect, indicating that Formula III is a potential drug molecule for the treatment of cancers with abnormal FGFR2. In the future, it will be used as a lead compound to develop FGFR2 selective small molecule inhibitors.

[0030] According to the second aspect of the present invention, a method for preparing the above-mentioned pyrrolopyrimidine derivative is also provided, and the preparation route thereof is:

[0031] .

[0032] According to the third aspect of the present invention, there is also provided the use of the above-mentioned pyrrolopyrimidine derivative or a pharmaceutically acceptable salt thereof in the preparation of a FGFR2 inhibitor.

[0033] Preferably, the FGFR2 inhibitor can be used to prepare a drug for treating related cancers with FGFR2 abnormalities. Preferably, the related cancers include gastric cancer, lung cancer, ovarian cancer and endometrial cancer.

[0034] According to the fourth aspect of the present invention, there is also provided a pharmaceutical composition comprising the above-mentioned pyrrolopyrimidine derivative or a pharmaceutically acceptable salt thereof.

[0035] Preferably, the pharmaceutical composition includes an excipient. Preferably, the excipient is at least one of gum arabic, syrup, lanolin and starch. The excipient is stable in nature, has no incompatibility with the main drug, does not produce side effects, does not affect the efficacy, is not easy to deform, crack, mildew, or be eaten by insects at room temperature, is harmless to the human body, has no physiological effect, does not produce chemical or physical effects with the main drug, and does not affect the content determination of the main drug.

[0036] The beneficial effects of the present invention are as follows: the present invention obtains a pyrrolopyrimidine derivative, the preparation process is simple and easy, and a variety of pyrrolopyrimidine derivatives can be obtained. The compound has good effects in treating and preventing cancer, has a selective inhibitory effect on FGFR2, and can be composed of a pharmaceutical composition, which is suitable for the development of cancer drugs for treating gastric cancer, lung cancer, ovarian cancer, endometrial cancer and the like. DETAILED DESCRIPTION

[0037] The following will be combined with the embodiments to clearly and completely describe the concept and technical effects of the present invention, so as to fully understand the purpose, scheme and effect of the present invention. It should be noted that the embodiments and features in the embodiments of this application can be combined with each other without conflict.

[0038] Example 1

[0039] A pyrrolopyrimidine derivative (denoted as compound 1), compound A1, compound A2, compound A3, compound A4, and compound A5, whose structures are shown below:

[0040] Compound 1, Compound A1,

[0041] Compound A2, Compound A3,

[0042] Compound A4, Compound A5.

[0043] The specific preparation method is:

[0044] 1) Preparation of compound A1:

[0045] 2-Chloro-7H-pyrrolo[2,3-d]pyrimidine (3.00 g, 19.5 mmol) was dissolved in acetonitrile (60 mL), and N-iodosuccinimide (5.28 g, 23.5 mmol) was added under ice bath and argon protection, and the temperature was slowly raised to room temperature to continue the reaction for 1 hour. The reaction solution was concentrated, a small amount of acetonitrile was added for suction filtration, the filter cake was collected, and dried under vacuum to obtain a white solid compound (4.75 g, 85.7%).

[0046] Detection of compound A1: 1 H NMR (400 MHz, DMSO- d 6 ) d 12.74 (s, 1H), 8.63 (s, 1H), 7.83 (s, 1H). 13 C NMR (100 MHz, DMSO- d 6 ) d 153.6, 153.3, 151.7, 151.4, 133.3,120.3,54.2. HRMS (ESI): calculated for C 6 H 4 CIN 3 + [M+H] + : 279.9133, found279.9138.

[0047] 2) Preparation of Compound A2

[0048] Compound A1 (4.75 g, 17.0 mmol), triethylamine (4.31 mL, 17.0 mmol), and 4-dimethylaminopyridine (146 mg, 1.19 mmol) were dissolved in 50 mL of THF. Di-tert-butyl dicarbonate (4.31 mL, 18.7 mmol) was added dropwise under ice bath and argon protection. The temperature was slowly raised to room temperature and the reaction was continued for 0.5 h. The reaction solution was quenched with saturated sodium chloride solution (100 mL), extracted with ethyl acetate (300 mL), and the organic phase was collected and dried over anhydrous sodium sulfate. The crude product was concentrated under reduced pressure to obtain a crude product. The crude product was purified by silica gel column chromatography (PE:EA = 8:1) to obtain a white solid compound A2 (5.20 g, 95.3%).

[0049] Detection of compound A2: 1 H NMR (400 MHz, CDCl 3 ) d 8.59 (s, 1H), 7.77 (s, 1H), 1.66 (s, 9H). 13 C NMR (100 MHz, CDCl 3 ) d 157.0, 152.7, 152.5, 145.9, 132.1, 122.0,86.5,58.4, 28.1, 27.9, 27.9. HRMS (ESI): calculated for C11 H 12 CIN 3 O 2 + [M+H] + :379.9657, found 379.9658.

[0050] 3) Preparation of Compound A3

[0051] Compound A2 (1.00 g, 2.64 mmol) and 3,5-dimethoxyphenylboronic acid (528 mg, 2.90 mmol) were dissolved in a mixed solution of 1,4-dioxane: water (10.0 mL: 5.00 mL = 2:1), and then potassium carbonate (730 mg, 5.28 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium (II) (193 mg, 0.260 mmol) were added. The system was replaced with argon three times, the oil bath was heated to 75 °C, and the reaction was carried out for 4 h. After the reaction was completed, the reaction was quenched with saturated sodium chloride, extracted twice with ethyl acetate, the organic phase was dried and concentrated, and purified by column chromatography (PE:EA = 5:1 to 2:1) to obtain compound A3 (white solid powder, 450 mg, 64.2%).

[0052] Detection of compound A3: 1 H NMR (400 MHz, DMSO- d 6 ) d 12.63 (s, 1H), 9.23 (s, 1H), 8.07 (d, J = 2.2 Hz, 1H), 6.89 (d, J = 2.3 Hz, 2H),6.46 (t, J = 2.2 Hz, 1H),3.83 (s,6H). 13 C NMR (100 MHz, DMSO- d6 ) d 161.4, 153.7, 152.8, 151.3, 135.5,126.3,115.6, 115.5, 105.0, 99.2, 55.7. HRMS (ESI): calculated for C 14 H 13 CIN 3 O 2 + [M+H] + : 290.0691, found 290.0690.

[0053] 4) Preparation of Compound A4

[0054] Compound A3 (500 mg, 1.73 mmol), triphenylphosphine (815 mg, 3.11 mmol), tert-butyl-4-(5-hydroxypentyl)piperazine-1-carboxylate (597 mg, 2.60 mmol) were dissolved in dry dichloromethane (17 mL). Di-tert-butyl azodicarboxylate (716 mg, 3.11 mmol) was slowly added dropwise under ice bath and argon protection. Subsequently, the system was slowly warmed to room temperature and the reaction was continued for 1 h. The raw material was detected by TLC. The reaction was stopped after the raw material disappeared. The reaction solution was then concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (CH 2 Cl 2 : MeOH = 45: 1 to 30: 1) to give white solid compound A4 (460 mg, 53%).

[0055] Detection of compound A4: 1 H NMR (400 MHz, CDCl 3 ) d 9.05 (s,1H), 7.37 (s, 1H),6.71 (s, 2H), 6.46 (s, 1H), 4.27 (t, J = 7.2 Hz, 2H),3.85 (s, 6H), 3.41 (t, J =5.1 Hz, 4H), 2.34 (dt, J = 18.4, 6.3Hz, 6H), 1.92 (q, J = 7.5 Hz, 2H), 1.59 –1.53 (m, 2H), 1.45 (s, 9H), 1.35 (t, J = 7.7 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) d 161.4, 161.4, 154.7, 153.8, 152.4, 150.7, 134.7, 126.2, 116.3, 115.9,105.3,105.3, 98.9, 79.6, 58.3, 55.4, 55.4, 53.0, 53.0, 44.5, 44.5, 30.0, 30.0,28.4,28.4, 28.4, 26.3, 24.5. HRMS (ESI): calculated for C 28 H39 C1N 5 O 4 + [M+H] + : 545.0930, found 545.0933.

[0056] 5) Preparation of Compound A5

[0057] Compound A4 (250 mg, 0.46 mmol) was dissolved in 1,4-dioxane (5 mL), and then N,N-dimethylethanolamine (1.63 mL, 13.78 mmol) and N,N-diisopropylethylamine (400 μL, 2.3 mmol) were added to the reaction system, and the temperature was raised to 110 °C for 5 h. The reaction solution was heated with H 2 O (10 mL), and then extracted with ethyl acetate (30 mL). The organic phase was collected, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The crude product was separated and purified by silica gel column chromatography (CH 2 Cl 2 :MeOH =20:1), to give white solid compound A5 (102 mg, 41 %).

[0058] Detection of compound A5: 1 H NMR (400 MHz, CDCl 3 ) d 8.94 (s, 1H), 7.20 (s, 1H), 6.72 (s, 2H), 6.42 (s, 1H), 4.50 (t, J = 5.4Hz, 2H), 4.18 (t, J = 6.6 Hz, 2H),3.84 (s, 6H), 3.40 (t, J = 4.8Hz, 4H), 2.90 (d, J = 7.5 Hz, 2H), 2.55 (s, 6H),2.37 - 2.30 (m, 6H),2.24 (d, J = 8.0 Hz, 2H), 1.88 (t, J = 7.8 Hz, 2H), 1.53 (t, J = 7.8 Hz, 2H), 1.44 (d, J = 2.6 Hz, 12H), 1.35 (d, J = 7.9 Hz,2H). 13 C NMR (100MHz, CDCl 3 ) d 161.7, 161.3,161.3, 154.7, 153.3, 150.7, 135.7, 123.9, 116.0,112.9, 105.0, 105.0, 98.7,79.6, 65.8, 65.8, 60.0, 58.4, 56.5, 55.4, 55.4,53.0, 53.0, 45.4, 45.4, 44.1,30.0, 29.7, 28.5, 28.4, 28.4, 27.2, 26.4, 24.7.HRMS (ESI): calculated for C 33 H 51 N 6 O 5 + [M+H] + : 610.8000, found 610.8004.

[0059] 6) Preparation of compound 1

[0060] Add trifluoroacetic acid (0.5 mL) to a dichloromethane (0.7 mL) solution of compound A5 (80 mg, 0.14 mmol), react at room temperature for 0.5 h, and concentrate under reduced pressure to obtain a crude product. Add the crude intermediate compound obtained in the above experiment to a dry dichloromethane (1.5 mL) solution, add triethylamine (36 μL, 0.26 mmol) to the system, and then slowly add acryloyl chloride (11 μL, 0.14 mmol) dropwise at 0 °C. Stir the reaction solution at room temperature for 0.5 h. After the reaction is complete by TLC, add H 2 O (1.4 mL) to quench the reaction, and extract with dichloromethane (4.2 mL). Collect the organic phase, dry it with anhydrous sodium sulfate and concentrate it under reduced pressure to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (CH 2 Cl 2 :MeOH =15:1), to give yellow solid compound 1 (50 mg, 56%).

[0061] Detection of compound 1: Mp116.1-116.9 °C; IR (KBr): 3412, 3378, 2716,1537, 1072, 1067, 960 cm -1 . 1 H NMR (400 MHz, CDCl 3 ) d8.80 (s, 1H), 7.08 (s,1H),6.71 (s, 2H), 6.59 – 6.49 (m, 1H), 6.40 (s, 1H), 6.26 (dd, J = 18.5Hz, 1H),5.67 (dd, J = 8.9 Hz, 1H), 4.26 (d, J = 6.3 Hz, 2H),3.83 (s, 6H), 3.65 (s, 2H),3.51 (s, 2H), 3.04 (d, J = 4.4 Hz, 3H), 2.83– 2.76 (m, 2H), 2.54 (d, J = 15.0 Hz,4H). 13 C NMR (100 MHz, CDCl 3 ) d 165.3, 161.2, 161.2, 159.7, 153.7, 150.0, 136.1,127.9, 127.4, 122.2, 116.1, 109.7, 104.8, 104.8, 98.5, 57.4, 55.4, 55.4,53.5,52.7, 45.8, 41.9, 41.1, 28.7. HRMS (ESI): calculated for C 24 H 31 N 6 O 3 + [M+H] + :451.5430, found 451.5433.

[0062] Example 2

[0063] A pyrrolopyrimidine derivative (denoted as compound 2) has the following structure:

[0064] Compound 2,

[0065] The specific preparation method is similar to the preparation method of compound 1, except that the N,N-dimethylethanolamine used in the preparation of compound A5 is replaced by N,N-dimethylpropanolamine to obtain a yellow solid with a yield of 60%.

[0066] Detection of compound 2: Mp161.3-162.3 °C; IR (KBr): 3148, 2834, 1680,1532, 1435, 1302, 1234, 1170, 859, 802cm -1 . 1 H NMR (400 MHz, CDCl3) d 8.96 (s,1H), 7.21 (s, 1H), 6.73 (s, 2H), 6.54 (dd, J = 16.8, 10.5 Hz, 1H), 6.43(t, J =2.1 Hz, 1H), 6.27 (dt, J = 16.9, 1.7 Hz, 1H), 5.68 (dt, J = 10.6, 1.6 Hz, 1H),4.51 (t, J = 6.1 Hz, 2H), 4.20 (t, J = 7.1Hz, 2H), 3.85 (s, 6H), 3.67 (t, J = 4.9Hz, 2H), 3.53 (t, J = 4.9Hz, 2H), 2.91 (d, J = 8.7 Hz, 2H), 2.56 (s, 6H), 2.40(t, J = 5.0Hz, 5H), 2.30 (dt, J = 21.3, 7.5 Hz, 4H), 1.89 (p, J = 7.3 Hz,2H), 1.54(p, J = 7.6 Hz, 2H), 1.35 (p, J = 7.9 Hz, 2H). 13 CNMR (100 MHz, CDCl 3 ) d165.3,161.3, 161.3, 153.2, 150.8,135.6, 127.8, 127.4, 124.1, 116.0, 113.0, 105.0,105.0, 98.6, 98.6, 65.0, 58.1,58.1, 56.3, 55.4, 55.4, 53.5, 52.7, 45.7, 44.3,44.2, 41.9, 29.9, 26.4, 25.8,24.6. HRMS (ESI): calculated for C 31 H 45 N 6 O 4 + [M+H] + :565.7310, found 565.7314.

[0067] Example 3

[0068] A pyrrolopyrimidine derivative (denoted as compound 3) has the following structure:

[0069] Compound 3,

[0070] The specific preparation method is similar to the preparation method of compound 1, except that the N,N-dimethylethanolamine used in the preparation of compound A5 is replaced by aniline to obtain a yellow solid with a yield of 63%.

[0071] Detection of compound 3: Mp161.3-162.6 °C; IR (KBr): 2948, 2833, 1679,1531, 1434.8, 1301, 1233, 1169, 869,801 cm -1 . 1 H NMR (400 MHz, CDCl 3 ) d 8.94 (s,1H), 7.79 – 7.72 (m, 2H), 7.36 (d, J = 7.4 Hz, 2H), 7.13 (s,1H), 7.01 (t, J = 7.3Hz, 1H), 6.75 (d, J = 2.2 Hz, 2H), 6.51(dd, J = 16.8, 10.5 Hz, 1H), 6.43 (t, J =2.3 Hz, 1H), 6.27 (dd, J= 16.9, 1.9 Hz, 1H), 5.68 (dd, J = 10.5, 2.0 Hz, 1H),4.22 (t, J = 6.9 Hz, 2H), 3.86 (s, 6H), 3.73 – 3.61 (m, 2H), 3.59 – 3.47 (m,2H), 2.42 (s,4H), 2.35 (t, J = 7.6 Hz, 2H), 1.93 (q, J = 7.2 Hz, 2H), 1.59 (q, J =8.1, 7.1 Hz, 2H), 1.37 (p, J = 7.8 Hz, 2H). 13 CNMR (100 MHz, CDCl 3 ) d 165.3, 161.4,161.3, 155.9, 152.6,150.3, 140.4, 135.9, 128.9, 128.9, 127.9, 127.4, 122.99,121.7, 118.3, 118.3,116.3, 111.1, 104.9, 104.9, 98.6, 58.1, 55.4, 55.4, 53.2,52.7, 45.4, 43.9,41.5, 29.8, 25.9, 24.4. HRMS (ESI): calculated for 32 H 39 N 6 O 3 + [M+H] + : 555.6950, found 555.6953.

[0072] Example 4

[0073] A pyrrolopyrimidine derivative (denoted as compound 4) has the following structure:

[0074] Compound 4,

[0075] The specific preparation method is similar to the preparation method of compound 1, except that the N,N-dimethylethanolamine used in the preparation of compound A5 is replaced by 3-amino-9-ethylcarbazole. Yellow solid, yield 60%.

[0076] Detection of compound 4: Mp181.3-182.1 °C; IR (KBr): 3248, 2813, 1639,1551, 1424,1302,1253, 1159, 849, 791 cm -1 . 1 H NMR (400 MHz, CDCl 3 ) d 8.97 (s,1H), 8.66 (d, J = 2.1 Hz, 1H), 8.05 (d, J = 7.7 Hz, 1H),7.62 (dd, J = 8.7, 2.1 Hz,1H), 7.49 – 7.42 (m, 1H), 7.38 (dd, J = 11.6, 8.4 Hz, 2H), 7.22 – 7.16 (m, 1H), 7.11 (s, 1H), 6.77 (d, J = 2.3Hz, 2H), 6.47 – 6.36 (m, 2H), 6.24 (dd, J = 16.8,2.1 Hz, 1H), 5.63 (dd, J = 10.5, 2.0 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 4.22 (t, J = 6.9 Hz, 2H), 3.85 (s, 6H), 3.61 (s, 2H), 3.39 (t, J = 5.1 Hz, 2H),2.30 (dt, J =15.2, 7.2 Hz, 6H), 1.96 (p, J = 7.1 Hz, 2H), 1.57(p, J = 7.6 Hz, 2H), 1.42 (t, J =7.2 Hz, 3H), 1.40 – 1.34 (m,2H). 13 C NMR (100 MHz, CDCl 3 ) d165.2, 161.3,161.3,156.7, 152.9, 150.3, 140.4, 136.1, 136.0, 132.5, 127.9, 127.3, 125.6,123.0,122.9, 122.7, 120.3, 119.1, 118.4, 116.2, 111.2, 110.7, 108.6, 108.5,104.8,104.8, 98.6, 58.0, 55.4, 55.4, 53.0, 52.6, 45.2, 44.0, 41.4, 37.6, 29.8,25.8,24.5, 13.9. HRMS (ESI): calculated for C 40 H 46 N 7 O 3 + [M+H] + : 672.8460, found672.8462.

[0077] Example 5

[0078] A pyrrolopyrimidine derivative (denoted as compound 5) has the following structure:

[0079] Compound 5,

[0080] The specific preparation method is similar to the preparation method of compound 1, except that the N,N-dimethylethanolamine used in the preparation of compound A5 is replaced with 4-(4-ethylpiperazine-1-yl)aniline to obtain a yellow solid with a yield of 63%.

[0081] Detection of compound 5: Mp174.2-174.9 °C; IR (KBr): 3251, 2832, 1676,1531, 1435, 1322, 1231, 1163, 879, 802cm -1 . 1 H NMR (400 MHz, CDCl 3 ) d 8.89 (s,1H), 7.63 (dd, J = 8.8, 2.2 Hz, 2H), 7.09 (d, J = 2.0Hz, 1H), 6.94 (dd, J = 8.9,2.2 Hz, 2H), 6.73 (d, J = 2.2 Hz,2H), 6.51 (dd,J = 16.8, 10.6, 2.0 Hz, 1H), 6.40(q, J = 2.3 Hz,1H), 6.24 (dt, J = 16.9, 2.1 Hz, 1H), 5.66 (dt, J = 10.4, 2.1 Hz,1H), 4.17 (dt, J = 7.0, 3.5 Hz, 2H), 3.83 (d, J = 2.1 Hz, 6H),3.70 – 3.61 (m,2H), 3.55 – 3.45 (m, 2H), 3.36 (t, J = 4.7 Hz, 4H), 2.94(d, J = 5.3 Hz, 4H), 2.79(q, J = 7.6 Hz, 2H), 2.38 (t, J = 4.8 Hz, 4H), 2.34 – 2.28 (m, 2H), 1.91 (q, J =7.5 Hz, 2H), 1.55 (p, J = 7.8 Hz, 2H), 1.37 – 1.28 (m, 5H). 13 C NMR (100 MHz,CDCl 3 ) d 165.2, 161.3, 161.3, 156.2, 152.7, 150.3, 145.5, 135.9, 134.3, 127.8,127.4, 122.7, 119.8, 119.8, 117.9, 117.9, 116.1, 110.8, 104.8, 104.8, 98.5,58.1, 55.4, 55.4, 53.4, 52.6, 52.3, 52.1, 52.1, 49.0, 49.0, 45.5, 43.9, 41.7,29.8, 26.1, 24.5, 10.6. HRMS (ESI): calculated for C 38 H 51 N 8 O 3 + [M+H] + : 667.8710,found 667.8711。

[0082] Example 6

[0083] A pyrrolopyrimidine derivative (denoted as compound 6) has the following structure:

[0084] Compound 6,

[0085] The specific preparation method is similar to the preparation method of compound 1, except that the N,N-dimethylethanolamine used in the preparation of compound A5 is replaced by 4-(4-methylpiperazine-1-yl)aniline to obtain a yellow solid with a yield of 60%.

[0086] Detection of compound 6: Mp163.3-163.9 °C; IR (KBr): 3245, 2823, 1659,1532, 1435, 1302, 1231, 1159, 879, 811cm -1 . 1 H NMR (400 MHz, CDCl 3 ) d 8.89 (s,1H), 7.62 (d, J = 8.9 Hz, 2H), 7.09 (s, 1H), 6.95 (d, J = 8.9 Hz, 2H), 6.73 (d, J =2.3 Hz, 2H), 6.52 (dd, J = 16.8, 10.5Hz, 1H), 6.41 (t, J = 2.3 Hz, 1H), 6.26 (dd, J = 16.9, 2.0 Hz,1H), 5.67 (dd, J = 10.5, 2.0 Hz, 1H), 4.17 (t, J = 6.9 Hz, 2H), 3.84 (s, 6H), 3.65 (d, J = 5.5 Hz, 2H), 3.49 (t, J = 5.0 Hz, 2H),3.24 (t, J = 4.9Hz, 4H), 2.73 (t, J = 4.8 Hz, 4H), 2.45 (s, 3H), 2.37 (q, J = 5.4 Hz, 4H), 2.30(t, J = 7.5 Hz, 2H), 1.91 (p, J= 7.1 Hz, 2H), 1.55 (p, J = 7.6 Hz, 2H), 1.35 (h, J =7.4, 6.5Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) d 165.2, 161.3,161.3, 156.3, 152.8,150.3, 146.1, 136.0, 133.8, 127.8, 127.5, 122.6, 119.9,119.9, 117.5, 117.5,116.1, HRMS (ESI): calculated forC 37 H 49 N 8 O 3 + [M+H] + : 653.8440, found 653.8442.

[0087] Example 7

[0088] A pyrrolopyrimidine derivative (denoted as compound 7) has the following structure:

[0089] Compound 7,

[0090] The specific preparation method is similar to the preparation method of compound 1, except that the tert-butyl-4-(5-hydroxypentyl)piperazine-1-carboxylate used in the preparation of compound A4 is changed to tert-butyl-4-(2-hydroxyethyl)piperazine-1-carboxylate, and the N,N-dimethylethanolamine used in the preparation of compound A5 is changed to 4-(4-methylpiperazin-1-yl)aniline to obtain a yellow solid with a yield of 60%.

[0091] Compound 7 was detected: Mp141.3-142.6 °C; IR (KBr): 3235, 2813, 1649,1512, 1425, 1352, 1232, 1176, 880, 812cm -1 . 1 H NMR (400 MHz, CDCl 3 ) d8.89 (s,1H), 7.65 – 7.47 (m, 2H), 7.15 (s, 1H), 7.00 – 6.86 (m, 2H), 6.73 (d, J = 2.3Hz, 2H), 6.51 (dd, J = 16.8, 10.5 Hz, 1H), 6.42 (t, J = 2.3Hz, 1H), 6.26 (dd, J =16.8, 2.0 Hz, 1H), 5.67 (dd, J = 10.5, 2.0Hz, 1H), 4.28 (t, J = 6.4 Hz, 2H), 3.84(s, 6H), 3.73 – 3.37 (m, 4H), 3.23 (t, J = 5.0 Hz, 4H), 2.81 (t, J = 6.5 Hz, 2H),2.70 (t, J = 4.9 Hz, 4H), 2.53 (dt, J = 10.4, 5.0 Hz, 4H), 2.42 (s, 3H). 13 CNMR (100 MHz, CDCl 3 ) d 165.3, 161.3, 161.3, 156.4, 152.9,150.4, 146.5, 136.0,133.4, 127.9, 127.4, 122.8, 120.4, 120.4, 117.2, 117.2,116.2, HRMS (ESI): calculated for C 34 H 43 N 8 O 3 + [M+H] + : 611.7630, found611.7633.

[0092] Example 8

[0093] A pyrrolopyrimidine derivative (denoted as compound 8) has the following structure:

[0094] Compound 8,

[0095] The specific preparation method is similar to the preparation method of compound 1, except that the tert-butyl-4-(5-hydroxypentyl)piperazine-1-carboxylate used in the preparation of compound A4 is changed to tert-butyl-4-(3-hydroxypropyl)piperazine-1-carboxylate, and the N,N-dimethylethanolamine used in the preparation of compound A5 is changed to 4-(4-methylpiperazin-1-yl)aniline to obtain a yellow solid with a yield of 60%.

[0096] Compound 8 was detected: Mp151.3-152.1 °C; IR (KBr): 3246, 2813, 1661,1542, 1415, 1362, 1232, 1156, 877, 801cm -1 . 1 H NMR (400 MHz, CDCl 3 ) d 8.88 (s,1H), 7.62 (d, J = 8.9 Hz, 2H), 7.12 (s, 1H), 6.95 (d, J = 9.0 Hz, 2H), 6.72 (d, J =2.3 Hz, 2H), 6.53 (dd, J = 16.8, 10.5Hz, 1H), 6.42 (t, J = 2.3 Hz, 1H), 6.26 (dd, J = 16.8, 2.0 Hz,1H), 5.68 (dd, J = 10.5, 1.9 Hz, 1H), 4.25 (t, J = 6.7 Hz, 2H),3.85 (s, 6H), 3.66 (d, J = 6.6 Hz, 2H), 3.49 (s, 2H), 3.33 – 3.19 (m,4H), 2.80(d, J = 5.4 Hz, 4H), 2.49 (s, 3H), 2.40 (q, J = 7.1,5.9 Hz, 6H), 2.08 (p, J = 6.8Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) d165.3, 161.3, 161.3, 156.2, 152.8, 150.2,146.1, 135.9, 127.9, 127.4,123.5, 122.9, 120.1, 120.1, 117.5, 117.5, HRMS (ESI): calculated for C 35 H 44 N 8 O 3 + [M+H] + :625.7900, found 625.7904.

[0097] Example 9

[0098] A pyrrolopyrimidine derivative (denoted as compound 9) has the following structure:

[0099] Compound 9,

[0100] The specific preparation method is similar to the preparation method of compound 1, except that the tert-butyl-4-(5-hydroxypentyl)piperazine-1-carboxylate used in the preparation of compound A4 is changed to tert-butyl-4-(4-hydroxybutyl)piperazine-1-carboxylate, and the N,N-dimethylethanolamine used in the preparation of compound A5 is changed to 4-(4-methylpiperazin-1-yl)aniline to obtain a yellow solid with a yield of 59%.

[0101] Compound 9 was detected: Mp171.1-171.9 °C; IR (KBr): 3241, 2822, 1655,1537, 1436, 1301, 1232, 1139, 889, 791cm -1 . 1 H NMR (400 MHz, CDCl 3 ) d 8.89 (s,1H), 7.61 (d, J = 8.5 Hz, 2H), 7.10 (s, 1H), 6.95 (d, J = 8.6 Hz, 2H), 6.73 (s,2H), 6.53 (dd, J= 16.8, 10.5 Hz, 1H), 6.42 (d, J = 2.2 Hz, 1H), 6.27 (dd, J =16.7, 1.9 Hz, 1H), 5.68 (dd, J =10.5, 1.9 Hz, 1H), 4.20 (t, J = 6.9 Hz, 2H), 3.85(s, 6H), 3.64 (s, 2H), 3.49 (d, J = 6.6 Hz, 2H), 3.34 – 3.23 (m, 4H), 2.79 (s,4H), 2.49 (s,3H), 2.38 (dt, J = 12.1, 6.5 Hz, 6H), 1.92 (q, J = 7.3 Hz, 2H),1.54(q, J = 7.7 Hz, 2H). 13 C NMR (100 MHz, CDCl 3 ) d 165.2, 161.3, 161.3, 156.3, 152.8,150.3, 146.1, 136.0, 133.7, 127.8,127.4, 122.5, 120.1, 120.1, 117.5, 117.5,116.3, HRMS (ESI): calculated forC 36 H 47 N 8 O 3 + [M+H] + : 639.8170, found 639.8173.

[0102] Example 10

[0103] A pyrrolopyrimidine derivative (denoted as compound 10) has the following structure:

[0104] Compound 10,

[0105] The specific preparation method is similar to the preparation method of compound 1, except that the tert-butyl-4-(5-hydroxypentyl)piperazine-1-carboxylate used in the preparation of compound A4 is replaced by tert-butyl-4-(6-hydroxyhexyl)piperazine-1-carboxylate, and the N,N-dimethylethanolamine used in the preparation of A5 is replaced by 4-(4-methylpiperazin-1-yl)aniline to obtain a yellow solid with a yield of 61%.

[0106] Compound 10 was detected: Mp171.8-172.3 °C; IR (KBr): 3262, 2925, 1646,1581, 1428, 1316, 1234, 1173, 856, 805cm -1 . 1 H NMR (400 MHz, CDCl 3 ) d 8.90 (s,1H), 7.63 (d, J = 9.0 Hz, 2H), 7.10 (s, 1H), 6.95 (d, J = 9.0 Hz, 2H), 6.74 (d, J =2.3 Hz, 2H), 6.53 (dd, J = 16.8, 10.5Hz, 1H), 6.42 (t, J = 2.3 Hz, 1H), 6.27 (dd, J = 16.8, 2.0 Hz,1H), 5.68 (dd, J = 10.5, 2.0 Hz, 1H), 4.17 (t, J = 7.0 Hz, 2H),3.85 (s, 6H), 3.60 (d, J = 54.8 Hz, 4H), 3.28 (t, J = 5.0 Hz,4H), 2.80 (t, J = 5.0Hz, 4H), 2.50 (s, 3H), 2.39 (t, J = 5.0 Hz,4H), 2.34 – 2.26 (m, 2H), 1.93 –1.84 (m, 2H), 1.47 (s, 2H), 1.39 – 1.29 (m,4H). 13 C NMR (100 MHz, CDCl 3 ) d165.3,161.3,161.3, 156.2, 152.7, 150.3, 145.9, 136.0, 133.9, 127.9, 127.4, 122.7,119.9,119.9, 117.6, 117.6, 116.1, 110.9, 104.8, 104.8, 98.5, 58.33, 58.3,55.4, 55.4,54.8, 54.8, 53.4, 52.7, 49.5, 49.5, 45.5, 44.1, 41.7, 29.9, 26.9,26.6, 26.5. HRMS (ESI): calculated for C 38 H 51 N 8 O 3 + [M+H] + : 667.8710, found667.8713.

[0107] Embodiment 11

[0108] A pyrrolopyrimidine derivative (denoted as compound 11) has the following structure:

[0109] Compound 11,

[0110] The specific preparation method is similar to the preparation method of compound 1, except that the tert-butyl-4-(5-hydroxypentyl)piperazine-1-carboxylate used in the preparation of compound A4 is changed to 1-Boc-3-hydroxymethylpyrrolidine, and the N,N-dimethylethanolamine used in the preparation of compound A5 is changed to 4-(4-methylpiperazin-1-yl)aniline to obtain a yellow solid with a yield of 61%.

[0111] Detection of compound 11: Mp170.3-170.6 °C; IR (KBr): 3256, 2924, 1643,1565, 1422, 1313, 1246, 1175, 865, 811cm -1 . 1 H NMR (400 MHz, CDCl 3 ) d 8.91 (s,1H), 7.57 (d, J = 13.8 Hz, 2H), 7.08 (s, 1H), 6.94 (d, J= 12.7 Hz, 2H), 6.72 (s,2H), 6.45 – 6.37 (m, 2H), 6.32 (s, 1H), 5.74 – 5.56(m, 1H), 4.47 – 4.12 (m,2H), 3.85 (s, 6H), 3.80 – 3.40 (m, 5H), 3.31 (dt, J = 9.8, 4.6 Hz, 4H), 3.05 –2.71 (m, 5H), 2.51 (s, 3H), 2.12 – 2.00 (m, 1H),1.80 (dt, J = 12.4, 6.1 Hz,1H). 13 C NMR (100 MHz, CDCl 3 ) d 164.6, 161.3, 161.3, 156.5, 152.9, 150.6, 146.0,135.7, 133.6, 128.3,127.9, 122.4, 120.4, 120.2, 117.6, 117.5, 116.8, 110.7,104.9, 104.9, 98.8,77.4, 77.2, 77.0, 76.7, 55.4, 55.4, 54.7, 49.9, 49.3,46.0, 45.7, 45.0, 40.3,38.2, 29.6, 27.9. HRMS (ESI): calculated for C 33 H 40 N 7 O 3 + [M+H] + : 582.7210, found 582.7214.

[0112] Example 12

[0113] A pyrrolopyrimidine derivative (denoted as compound 12) has the following structure:

[0114] Compound 12,

[0115] The specific preparation method is similar to the preparation method of compound 1, except that the tert-butyl-4-(5-hydroxypentyl)piperazine-1-carboxylate used in the preparation of compound A4 is changed to N-Boc-4-piperidinemethanol, and the N,N-dimethylethanolamine used in the preparation of compound A5 is changed to 4-(4-methylpiperazin-1-yl)aniline to obtain a yellow solid with a yield of 61%.

[0116] Detection of compound 12: Mp151.3-152.1 °C; IR (KBr): 3228, 2931, 1642,1561, 1438, 1356, 1214, 1163, 852, 803cm -1 . 1 H NMR (400 MHz, CDCl 3 ) d 8.91 (s,1H), 7.60 (d, J = 7.3 Hz, 2H), 7.05 (s, 1H), 6.95 (d, J = 7.5 Hz, 2H), 6.73 (s,2H), 6.55 (ddd, J = 16.9, 10.6, 2.0 Hz, 1H), 6.42 (s, 1H), 6.26 (dd, J = 16.9, 2.1Hz, 1H), 5.66 (dd, J =10.5, 2.0 Hz, 1H), 4.06 (d, J = 6.8 Hz, 2H), 3.85 (s, 6H), 3.22 – 3.14 (m, 4H), 3.02 (d, J = 12.9 Hz, 1H), 2.63 – 2.58 (m, 4H), 2.37 (s, 3H). 13 CNMR (100 MHz, CDCl 3 ) d 165.4, 162.5, 161.3, 161.3, 156.5,152.9, 150.4,146.3, 135.8, 133.5, 127.8, 122.9, 120.1, 120.1, 117.3, 117.3,116.3, HRMS (ESI):calculated for C 34 H 42 N 7 O 3 + [M+H] + : 596.7480, found 596.7484.

[0117] Embodiment 13

[0118] A pyrrolopyrimidine derivative (denoted as compound 13) has the following structure:

[0119] Compound 13,

[0120] The specific preparation method is similar to the preparation method of compound 1, except that the tert-butyl-4-(5-hydroxypentyl)piperazine-1-carboxylate used in the preparation of compound A4 is changed to tert-butyl 3-hydroxymethylazetidine-1-carboxylate, and the N,N-dimethylethanolamine used in the preparation of compound A5 is changed to 4-(4-methylpiperazin-1-yl)aniline to obtain a yellow solid with a yield of 60%.

[0121] Detection of compound 13: Mp142.5-143.1 °C; IR (KBr): 3262, 2915, 1656,1580, 1427, 1326, 1224, 1143, 836, 801cm -1 . 1 H NMR (400 MHz, CDCl 3 ) d 8.90 (s,1H), 7.65 – 7.49 (m, 2H), 7.05 (s, 1H), 6.97 – 6.88 (m, 2H), 6.71 (d, J = 2.3Hz, 2H), 6.43 (t, J = 2.2 Hz, 1H), 6.33 (dd, J = 16.9, 1.9Hz, 1H), 6.13 (dd, J =17.0, 10.3 Hz, 1H), 5.65 (dd, J = 10.3,1.8 Hz, 1H), 4.48 (dd, J = 14.1, 8.5 Hz,1H), 4.39 – 4.09 (m, 4H), 3.97(dd, J = 10.5, 5.2 Hz, 1H), 3.84 (s, 6H), 3.24(q, J = 8.7, 6.8Hz, 5H), 2.73 (t, J = 4.8 Hz, 4H), 2.45 (s, 3H). 13 C NMR (100MHz,CDCl 3 ) d 165.8, 161.3, 161.2, 156.6, 153.0, 150.7,146.4, 135.6, 133.2, 127.6,125.6, 122.0, 120.4, 120.4, 117.3, 117.3, 116.9,110.8, 104.9, 104.9, 98.8,55.4, 55.4, 54.9, 54.9, 53.6, 51.1, 49.4, 49.4,47.3, 45.6, 29.4. HRMS (ESI): calculated for C 32 H 38 N 7 O 3 + [M+H] + : 568.6940, found 568.6943.

[0122] Embodiment 14

[0123] A pyrrolopyrimidine derivative (denoted as compound 14) has the following structure:

[0124] Compound 14

[0125] The specific preparation method is similar to the preparation method of compound 1, except that the tert-butyl-4-(5-hydroxypentyl)piperazine-1-carboxylate used in the preparation of compound A4 is changed to N-Boc-4-hydroxypiperidine, and the N,N-dimethylethanolamine used in the preparation of compound A5 is changed to 4-(4-methylpiperazin-1-yl)aniline to obtain a yellow solid with a yield of 58%.

[0126] Compound 14 was detected: Mp161.3-162.1 °C; IR (KBr): 3232, 2925, 1676,1523, 1426, 1316, 1214, 1134, 846, 802cm -1 . 1 H NMR (400 MHz, CDCl 3 ) d 8.90 (s,1H), 7.58 (d, J = 9.0 Hz, 2H), 7.10 (s, 1H), 6.95 (d, J = 9.0 Hz, 2H), 6.71 (d, J =2.3 Hz, 2H), 6.65 (dd, J= 16.8, 10.6Hz, 1H), 6.42 (t, J = 2.2 Hz, 1H), 6.34 (dd, J = 16.8, 2.0 Hz,1H), 5.75 (dd, J = 10.5, 2.0 Hz, 1H), 4.94 (d, J = 13.4 Hz, 1H),4.77 (tt, J = 10.7, 4.5 Hz, 1H), 4.20 (d, J = 13.7 Hz, 1H), 3.84(s, 6H), 3.27 (t, J = 5.1 Hz, 5H), 2.77 (t, J = 4.9 Hz, 5H), 2.48(s, 3H), 2.23 – 1.97 (m, 4H). 13 CNMR (100 MHz, CDCl 3 ) d 31.36, 32.08, 31.71, 32.58, 31.36. HRMS (ESI): calculated forC 33 H 40 N 7 O 3 + [M+H] + : 582.7210, found 582.7213.

[0127] Embodiment 15

[0128] A pyrrolopyrimidine derivative (denoted as compound 15) has the following structure:

[0129] Compound 15

[0130] The specific preparation method is similar to the preparation method of compound 1, except that the tert-butyl-4-(5-hydroxypentyl)piperazine-1-carboxylate used in the preparation of compound A4 is changed to BOC-3-aminobenzyl alcohol, and the N,N-dimethylethanolamine used in the preparation of compound A5 is changed to 4-(4-methylpiperazin-1-yl)aniline to obtain a yellow solid with a yield of 61%.

[0131] Detection of compound 15: Mp201.3-202.1 °C; IR (KBr): 3247, 2933, 1676,1521, 1435, 1302, 1214, 1167, 872, 805cm -1 . 1 H NMR (400 MHz, CDCl 3 ) d 8.88 (s,1H), 7.83 (s, 1H), 7.59 (s, 1H), 7.53 (d, J = 8.6 Hz, 2H), 7.18(s, 1H), 7.09(s, 1H), 7.00 (d, J = 7.9 Hz, 1H), 6.88 (d, J = 8.7Hz, 2H), 6.71 (d, J = 2.3 Hz,2H), 6.40 (ddd, J = 8.2, 6.9, 1.5Hz, 2H), 6.27 (dd, J = 16.8, 10.1 Hz, 1H), 5.71(dd, J = 10.0,1.5 Hz, 1H), 3.82 (s, 6H), 3.22 (t, J = 4.9 Hz, 4H), 2.75 (t, J =4.9Hz, 4H), 2.46 (s, 3H). 13 C NMR (100 MHz, CDCl 3 ) d163.7, 161.2, 161.2, 156.4,152.8, 150.4, 145.9, 138.4, 137.9, 135.8, 133.7,131.1, 129.5, 127.9, 123.5,122.7, 120.1, HRMS (ESI): calculatedfor C 35 H 38 N 7 O 3 + [M+H] + : 604.7270, found 604.7274.

[0132] Example 16

[0133] A pyrrolopyrimidine derivative (denoted as compound 16) has the following structure:

[0134] Compound 16

[0135] The specific preparation method is similar to the preparation method of compound 1, except that the tert-butyl-4-(5-hydroxypentyl)piperazine-1-carboxylate used in the preparation of compound A4 is changed to BOC-3-aminobenzyl alcohol, and the N,N-dimethylethanolamine used in the preparation of compound A5 is changed to N-BOC-2-(4-aminophenyl)ethanol to obtain a yellow solid with a yield of 60%.

[0136] Compound 16 was detected: Mp213.3-213.9 °C; IR (KBr): 3238, 2865, 1673,1535, 1436, 1302, 1231, 1168, 870, 792cm -1 . 1 H NMR (400 MHz, CDCl 3 ) d 8.88 (s,1H), 7.61 (t, J = 9.2 Hz, 4H), 7.24 – 7.09 (m, 4H), 7.03 – 6.94(m, 3H), 6.69(d, J = 2.2 Hz, 2H), 6.52 – 6.25 (m, 4H), 5.75 (d,J = 10.1 Hz, 1H), 4.40 – 4.30(m, 2H), 3.84 (s, 6H), 3.28 (t, J = 4.8 Hz,4H), 3.12 (s, 2H), 2.82 (d, J = 5.6Hz, 4H), 2.50 (s, 3H). 13 CNMR (100 MHz, CDCl 3 ) d 163.6, 161.2, 161.2, 156.4,152.8,150.3, 145.9, 138.4, 137.9, 135.8, 133.7, 131.1, 129.5,127.9, 123.5,122.7,120.1, 120.1, 119.4, 119.1, 117.5, 117.5, 116.6, 110.8, 104.8, 104.8,98.7,55.4, 55.4, 54.7, 54.7, 49.3, 49.3, 47.7, 47.7,45.3.HRMS (ESI):calculated for C 36 H 40 N 7 O 3 + [M+H] + : 618.7540, found 618.7543.

[0137] Embodiment 17

[0138] In this example, the compounds prepared in Examples 1-16 were subjected to enzyme activity test experiments.

[0139] The present invention uses AZD4547 as a positive control and adopts homogeneous time-resolved fluorescence (HIRF) to evaluate the kinase inhibitory activity of compounds 1-16 on three subtypes of FGFR1, 2, and 3.

[0140] Table 1 Structure-activity relationship study based on enzyme activity results

[0141]

[0142] The results are shown in Table 1. Compounds 1-16 can inhibit the protein activity of FGFR1 / 2 / 3 to varying degrees. Among them, compound 6 and compound 10 have the best inhibitory effects on FGFR1 and FGFR2. Therefore, a series of tests were carried out on these two compounds.

[0143] Embodiment 18

[0144] In this example, the antiproliferative activities of Compound 6 and Compound 10 against specific cancer cell lines were tested.

[0145] Detection method: Take cells in the logarithmic growth phase, inoculate SNU-16 cells at a density of 8000 cells / well, 90 uL per well in a 96-well plate, add the test compound 6 and compound 10 to the required concentrations, and place in a 5% CO 2 , incubated in a 37 ℃ incubator for 48 h. 10 μL CCK-8 solution was added to each well and cultured in the incubator for another 6 h. The OD value at 450 nm was measured using an ELISA reader, and the corresponding IC was calculated using GraphPad Prizm7. 50 value.

[0146] Table 2 In vitro antiproliferative activity assay

[0147] compound number SNU-16 / IC50(μM) 6 0.255 10 0.097

[0148] As shown in the in vitro antiproliferation experiment in Table 2, both compound 6 and compound 10 can exhibit antiproliferative effects on SNU-16 tumor cells with high expression of FGFR2, among which compound 10 can effectively inhibit the proliferation of SNU-16 tumor cells with high expression of FGFR2 at a low nanomolar concentration.

[0149] Embodiment 19

[0150] This example tests the ability of Compound 6 and Compound 10 to inhibit tumor growth in mice.

[0151] To evaluate the antitumor efficacy of compounds 6 and 10 in vivo, a mouse subcutaneous xenograft tumor model was established using human gastric cancer cell SNU-16 cells with high FGFR2 expression.

[0152] Detection method: Cells in the logarithmic growth phase were collected by trypsin digestion, washed three times with 1× PBS, and the cell pellet was diluted to 1×10 with resuspension buffer (1640 culture medium: Matrigel = 1:1). 8 / mL, according to 5×10 6 The cells were inoculated into the axilla of the forelimb of 5-week-old female Balb / c Nude mice. 3 At the same time, the mice were randomly divided into three groups (control group, 100 mg / kg compound 6 group, 100 mg / kg compound 10 group), with 6 mice in each group. Compound 6 and compound 10 were orally administered daily, and the tumor volume and mouse body weight were measured. After 17 days of administration, the mice were treated, the tumor tissues were dissected, and fixed in formalin solution for later use.

[0153] Table 3 Tumor growth inhibition effect determination

[0154] compound number Tumor growth inhibition rate(TGI%) 6 60.6% 10 87.3%

[0155] As shown in the in vivo antiproliferation test results in Table 3, both compound 6 and compound 10 can significantly inhibit the growth of SNU-16 tumor cells in mice, among which the in vivo tumor growth inhibition rate of compound 10 reached 87.3%, showing a strong in vivo tumor inhibition effect, indicating that compound 10 is a potential drug molecule for the treatment of FGFR2 abnormal cancers. In the future, it will be used as a lead compound for the development of FGFR2 selective small molecule inhibitors.

[0156] In summary, the novel derivatives of 7H-pyrrolo[2,3-d]pyrimidine synthesized in the present invention can be used as effective and selective inhibitors of FGFR2.

[0157] The above is only a preferred embodiment of the present invention. The present invention is not limited to the above implementation. As long as the technical effect of the present invention is achieved by the same means, it should belong to the protection scope of the present invention. Within the protection scope of the present invention, its technical scheme and / or implementation method can have various modifications and changes.

Claims

1. A pyrrolopyrimidine derivative, characterized in that: Its structure is shown in Formula I: Formula I, In Formula I, Linker, R, and X are independently selected from one of the following structures 1-16: In structure 1, Linker is , R corresponds to , X corresponds to O; In structure 2, Linker is , R corresponds to , X corresponds to O; In structure 3, Linker is , R corresponds to , X corresponds to N; In structure 4, Linker is , R corresponds to , X corresponds to N; In structure 5, Linker is , R corresponds to , X corresponds to N; In structure 6, Linker is , R corresponds to , X corresponds to N; In structure 7, Linker is , R corresponds to , X corresponds to N; In structure 8, Linker is , R corresponds to , X corresponds to N; In structure 9, Linker is , R corresponds to , X corresponds to N; In structure 10, Linker is , R corresponds to , X corresponds to N; In structure 11, Linker is , R corresponds to , X corresponds to N; In structure 12, Linker is , R corresponds to , X corresponds to N; In structure 13, Linker is , R corresponds to , X corresponds to N; In structure 14, Linker is , R corresponds to , X corresponds to N; In structure 15, Linker is , R corresponds to , X corresponds to N; In structure 16, Linker is , R corresponds to , X corresponds to N.

2. The pyrrolopyrimidine derivative according to claim 1, characterized in that Its structure is shown in Formula II or Formula III: Formula II, Formula III.

3. A method for preparing a pyrrolopyrimidine derivative according to claim 1, characterized in that: Its preparation route is: 。 4. Use of the pyrrolopyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2 in the preparation of a FGFR2 inhibitor.

5. The use according to claim 4, characterized in that: The FGFR2 inhibitor can be used to prepare drugs for treating cancers related to FGFR2 abnormality.

6. The use according to claim 5, characterized in that: The relevant cancers include gastric cancer, lung cancer, ovarian cancer and endometrial cancer.

7. A pharmaceutical composition, characterized in that The invention comprises the pyrrolopyrimidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2.

8. The pharmaceutical composition according to claim 7, characterized in that The pharmaceutical composition includes an excipient.

9. The pharmaceutical composition according to claim 8, characterized in that The excipient is at least one of gum arabic, syrup, lanolin and starch.

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