A pyrrolopyrimidine derivative, a preparation method thereof, a pharmaceutical composition and an application

Abstract

The present invention belongs to the technical field of chemical drugs, and particularly relates to a pyrrolo-pyrimidine derivative, a preparation method thereof, a pharmaceutical composition and an application. The structure of the pyrrolo-pyrimidine derivative is shown in Formula I, and Linker is selected from any one of alkyl, alkoxy, heteroatom substituent, substituted azacycle, aryl, substituted aryl, Ph-CH<subgt;2< / subgt>-X- (X can be alkyl, alkoxy, heteroatom substituent, substituted azacycle, spiro ring, fused ring). The preparation process of the present invention is simple and easy to perform. The prepared pyrrolo-pyrimidine derivative or its pharmaceutically acceptable salt can be used in the preparation of drugs for treating and / or preventing cancer, can be used as an active ingredient of a pharmaceutical composition for treating cancer, and can also be used as an irreversible selective fibroblast growth factor receptor 1 (FGFR1) inhibitor, and is suitable for the development of cancer drugs such as breast cancer, ovarian cancer, non-small cell lung cancer, colorectal cancer, etc. Formula I.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drugs, and particularly relates to a pyrrolo[2,3 - d]pyrimidine derivative, a preparation method thereof, a pharmaceutical composition and an application thereof. Background Art

[0002] Multi - target inhibitors and pan - FGFR inhibitors have achieved remarkable performance in clinical research and remain the primary choice for the treatment of FGFR - abnormal diseases. However, aiming at the adverse events of current drugs, improving drug safety, overcoming drug resistance and enhancing the clinical benefit of patients are the driving forces for the continuous progress of drug research.

[0003] FGFR inhibitors are a unique emerging targeted therapy. Currently, at least 89 studies (6 phase III studies) are actively recruiting patients to analyze the role of FGFR inhibitors in various malignancies. Given the expanding role of FGFR inhibitors in cancer treatment, a comprehensive understanding of their unique side effects will help prevent unnecessary dose reductions and interruptions. Importantly, patients should be helped to understand these FGFR - inhibitor - related side effects and possible prevention mechanisms. Effectively manage drug - related toxicities and enhance the understanding of FGFR inhibitor resistance.

[0004] The results of second - generation RNA sequencing of 10,582 solid tumor patients by Gao Yang et al. showed [1] that FGFR abnormalities were present in 754 patients, corresponding to an overall prevalence of 7.0%. Most of the aberrations occurred in FGFR1 (56.8%), followed by FGFR3 (17.7%), FGFR2 (14.4%) and FGFR4 (2.8%). In addition, 8.5% of the patients had aberrations in more than 1 FGFR gene. The most common aberration types were amplification (53.7%), followed by mutation (38.8%) and fusion (5.6%). FGFR fusion and amplification occurred simultaneously in 1.9% of the patients. Among 16 cancers, FGFR abnormalities were detected in 12 cancers, and colorectal cancer (CRC) had the highest prevalence (31%). Other cancer types with FGFR abnormalities included gastric cancer (16.8%), breast cancer (14.3%) and esophageal cancer (12.7%). Compared with other cancer types, breast tumors were also more likely to have FGFR rearrangement and amplification simultaneously (P < 0.001). The occurrence probability of FGFR1 abnormality was greater than that of FGFR2, FGFR3, and FGFR4, and the tumor types caused by it were also more, commonly including breast cancer, ovarian cancer, non - small cell lung cancer, colorectal cancer, etc. Therefore, developing new anti - tumor drugs based on FGFR1 is a promising strategy for treating cancer. It is expected that further breakthroughs of FGFR1 subtype inhibitors in clinical practice will provide a better treatment experience for patients. Summary of the Invention

[0005] The object of the present invention is to solve the deficiencies of the prior art, a pyrrolo[2,3-d]pyrimidine derivative, its preparation method, pharmaceutical composition and application, and the following technical solutions are specifically adopted:

[0006] According to the first aspect of the present invention, there is provided a pyrrolo[2,3-d]pyrimidine derivative, the structure of which is shown in Formula I:

[0007] Formula I, wherein Linker is taken from any one of alkyl, alkoxy, heteroatom substituent, substituted azacycle, aryl, substituted aryl, -Ph-CH2-X-; wherein, in the above -Ph-CH2-X-, X is any one of alkyl, alkoxy, heteroatom substituent, substituted azacycle, spiro ring, fused ring.

[0008] Preferably, in Formula I, Linker is selected from any one of the following structures 1-28:

[0009]

[0010] 。

[0011] Preferably, the above pyrrolo[2,3-d]pyrimidine derivative is selected from any one of the following structures 1-28:

[0012]

[0013]

[0014]

[0015] 。

[0016] Preferably, the above pyrrolo[2,3-d]pyrimidine derivative is selected from any one of the following structures:

[0017] 、 、 、 。More preferably, the structure of the pyrrolo[2,3-d]pyrimidine derivative is shown in Formula II:

[0018] Formula II. The results of kinase selectivity experiments show that Formula II has high selectivity for FGFR1 and low inhibition rates for targets such as EGFR and VEGFR. In vitro anti-proliferation experiments show that Formula II can effectively inhibit the proliferation of NCI-H1581 tumor cells with high expression of FGFR1 at low nanomolar concentrations. In vivo anti-proliferation experiments show that Formula II can significantly inhibit the growth of NCI-H1581 tumor cells in mice in a dose-dependent manner and has good safety, indicating that Formula II is a potential drug molecule for the treatment of cancers with FGFR1 abnormalities.

[0019] According to a second aspect of the present invention, there is also provided a method for preparing the above pyrrolopyrimidine derivative, and the preparation route is as follows:

[0020] ;

[0021] The above preparation route starts from the commercially available and easily obtained starting material 2-chloro-7H-pyrrolo[2,3-d]pyrimidine, and obtains the target compound through 7 steps of reactions, including two substitution reactions, Suzuki coupling reaction, Mitsunobu reaction, methylamine substitution reaction, deprotection reaction, and amide condensation reaction. The route is applicable to the synthesis of all targets 1-28, and the operation is simple and the purification is convenient.

[0022] According to a third aspect of the present invention, the present invention also provides the use of the above pyrrolopyrimidine derivative or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing cancer. The above cancer is a cancer associated with FGFR1 abnormality. Specifically, the above cancer is breast cancer, ovarian cancer, non-small cell lung cancer, and colorectal cancer.

[0023] According to a fourth aspect of the present invention, the present invention also provides a pharmaceutical composition, which comprises the above pyrrolopyrimidine derivative or a pharmaceutically acceptable salt thereof as the main active ingredient. The above pharmaceutical composition contains one or more pharmaceutically acceptable excipients.

[0024] The above excipients include at least one of carbohydrates, polymers, lipids, or minerals. The excipients have stable properties, no incompatibility with the main drug, no side effects, do not affect the efficacy, are not easily deformed, cracked, mildewed, or infested by insects at room temperature, are harmless to the human body, have no physiological effects, do not produce chemical or physical effects with the main drug, and do not affect the content determination of the main drug.

[0025] The above pharmaceutical composition and pharmaceutically acceptable excipients can be formulated into various preparations, preferably solid preparations and liquid preparations, such as tablets, pills, capsules, powders, suspensions, granules, syrups, emulsions, suspensions and other dosage forms, as well as various sustained-release agents, preferably in the form of oral administration.

[0026] The beneficial effects of the present invention are as follows: The preparation process of the present invention is simple and feasible. The prepared pyrrolopyrimidine derivative or a pharmaceutically acceptable salt thereof can be used in the preparation of a medicament for treating and / or preventing cancer, can be used as the active ingredient of a pharmaceutical composition for treating cancer, and can also be used as an irreversible selective fibroblast growth factor receptor 1 (FGFR1) inhibitor. In vitro and in vivo, the compound shows significant anti-proliferative effects on the NCI-H1581 cancer cell line, and is applicable to the development of cancer drugs such as breast cancer, ovarian cancer, non-small cell lung cancer, and colorectal cancer. Description of the Drawings

[0027] Figure 1 Shown is the tumor volume curve graph of compound 24 inhibiting tumor proliferation in the subcutaneous xenograft tumor model of NCI-H1581 tumor cells;

[0028] Figure 2 Shown is the statistical graph of the tumor weight in mice after 17 days of treatment with compound 24 in the subcutaneous xenograft tumor model of NCI-H1581 tumor cells;

[0029] Figure 3 Shown is the body weight change curve graph of mice during the treatment with compound 24 in the subcutaneous xenograft tumor model of NCI-H1581 tumor cells;

[0030] Figure 4 Shown is the photo of the tumor in mice after 17 days of treatment with compound 24 in the subcutaneous xenograft tumor model of NCI-H1581 tumor cells. Detailed implementation manners

[0031] The concept, specific structure and technical effects of the present invention will be clearly and completely described below in combination with the embodiments and the drawings, so as to fully understand the purpose, scheme and effects of the present invention.

[0032] Example 1

[0033] Preparation of pyrrolopyrimidine derivatives, and the structures of compounds 1-28 are as follows:

[0034] Compound 1; Compound 2; Compound 3;

[0035] Compound 4; Compound 5; Compound 6;

[0036] Compound 7; Compound 8; Compound 9;

[0037] Compound 10; Compound 11; Compound 12;

[0038] Compound 13; Compound 14; Compound 15;

[0039] Compound 16; Compound 17; Compound 18;

[0040] Compound 19; Compound 20; Compound 21;

[0041] Compound 22; Compound 23;

[0042] Compound 24; Compound 25; Compound 26;

[0043] Compound 27; Compound 28.

[0044] (1) Preparation of Compound 1:

[0045] Step 1: Preparation of Compound A1:

[0046] The structure of Compound A1 is as follows:

[0047] ;

[0048] Dissolve 2-chloro-7H-pyrrolo[2,3-d]pyrimidine (3.00 g, 19.5 mmol) in acetonitrile (60 mL). Under ice bath and argon protection, add N-iodosuccinimide (5.28 g, 23.5 mmol), and slowly warm to room temperature and continue the reaction for 1 h. Concentrate the reaction solution, add a small amount of acetonitrile for suction filtration, collect the filter cake, and dry it under vacuum to obtain white solid Compound A1 (4.75 g, 85.7%).

[0049] The NMR test results of Compound A1 are as follows:

[0050] 1 H NMR (400 MHz, DMSO- d 6) δ 12.74 (s, 1H), 8.63 (s, 1H), 7.83 (s, 1H). 13 C NMR (100 MHz, DMSO- d 6) δ 153.6, 153.3, 151.7, 151.4, 133.3, 120.3, 54.2. HRMS(ESI): calculated for C6H4ClIN3 + [M+H]+ : 279.9133, found 279.9138。

[0051] Step 2: Preparation of Compound A2

[0052] The structure of Compound A2 is as follows:

[0053] ;

[0054] Dissolve Compound A1 (4.75 g, 17.0 mmol), triethylamine (4.31 mL, 17.0 mmol), and 4-dimethylaminopyridine (146 mg, 1.19 mmol) in 50 mL of THF. Under ice bath and argon protection, add di-tert-butyl dicarbonate (4.31 mL, 18.7 mmol) dropwise, and slowly warm to room temperature and continue the reaction for 0.5 h. Quench the reaction mixture with saturated sodium chloride solution (100 mL), extract with ethyl acetate (300 mL), collect the organic phase, dry it over anhydrous sodium sulfate, and concentrate it under reduced pressure to obtain the crude product. The crude product is purified by silica gel column chromatography (PE:EA = 8:1) to obtain white solid Compound A2 (5.20 g, 95.3%).

[0055] The NMR test results of Compound A2 are as follows:

[0056] 1 H NMR (400 MHz, CDCl3) δ 8.59 (s,1H), 7.77 (s, 1H), 1.66 (s, 9H). 13 C NMR (100 MHz, CDCl3) δ 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 C 11 H 12 ClIN3O2 + [M+H] + : 379.9657, found379.9658。

[0057] Step 3: Preparation of Compound A3

[0058] The structure of Compound A3 is as follows:

[0059] ;

[0060] 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). 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 purged with argon three times, and the oil bath was heated to 75 °C. The reaction was carried out for 4 h. After the reaction was completed, the reaction was quenched with saturated sodium chloride, and the mixture was 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%).

[0061] The NMR test results of compound A3 are as follows:

[0062] 1 HNMR (400 MHz, DMSO- d 6 ) δ 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 ) δ 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 ClIN3O2 + [M+H] + : 290.0691, found 290.0690。

[0063] Step 4: Preparation of compound A4

[0064] The structure of compound A4 is as follows:

[0065] ;

[0066] Compound A3 (500 mg, 1.73 mmol), triphenylphosphine (815 mg, 3.11 mmol), and tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate (635 mg, 2.60 mmol) were dissolved in dry dichloromethane (17 mL). Under ice bath and argon protection, di-tert-butyl azodicarboxylate (716 mg, 3.11 mmol) was slowly added dropwise. Subsequently, the reaction system was slowly warmed to room temperature and reacted for an additional 1 h. The raw materials were monitored by TLC, and the reaction was stopped after the raw materials disappeared. Then, the reaction solution was concentrated under reduced pressure, and the crude product was purified by silica gel column chromatography (CH2Cl2:MeOH = 45:1) to obtain white solid compound A4 (450 mg, 51%).

[0067] The NMR test results of compound A4 are as follows:

[0068] 1 H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 7.40 (s, 1H), 6.69 (s, 2H), 6.44(s, 1H), 4.35 (t, J = 6.8Hz, 2H), 3.84 (s, 6H), 3.39 (d, J = 5.2 Hz, 4H), 2.35(t, J = 3.6Hz, 6H), 2.09 - 2.03 (m, 2H), 1.44 (s, 9H). 13 C NMR (100 MHz, CDCl3)δ161.4, 161.4, 154.7, 153.8, 152.4, 150.7, 134.7, 126.7, 116.1, 116.0, 105.2,105.2, 98.9, 79.7, 55.4, 55.4, 54.9, 54.9, 52.9, 52.9, 42.7, 42.7, 28.4,28.4,28.4, 26.9. HRMS (ESI): calculated for C 26 H 35 ClN5O4 + [M+H] + : 517.0390, found 517.0392。

[0069] Step 5: Preparation of compound A5

[0070] The structure of compound A5 is as follows:

[0071] ;

[0072] Dissolve compound A4 (186 mg, 0.36 mmol) in 1,4-dioxane (8 mL), and slowly add aqueous methylamine solution (14 μL, 0.43 mmol) at room temperature. Heat the reaction mixture to 80 °C and continue the reaction for 8 - 10 h. Quench the reaction mixture with H2O (16 mL), extract with ethyl acetate (48 mL), collect the organic phase, dry over anhydrous sodium sulfate, and concentrate under reduced pressure. The crude product is purified by silica gel column chromatography (CH2Cl2:MeOH = 50:1 to 40:1) to obtain white solid compound A5 (94 mg, 48%).

[0073] The NMR test results of compound A5 are as follows:

[0074] 1 H NMR (400 MHz, CDCl3) δ 8.80 (s,1H), 7.04 (s, 1H), 6.71 (s, 2H), 6.40(s, 1H), 4.19 (t, J = 6.9 Hz, 2H),3.84 (s, 6H), 3.43 (t, J = 5.0 Hz, 4H), 3.04(d, J = 4.8 Hz, 3H),2.37 (d, J = 6.1 Hz, 6H), 2.05 (d, J = 6.9 Hz, 2H), 1.45 (s,9H). 13 C NMR (100 MHz, CDCl3) δ 161.2, 161.2, 159.7,154.7, 153.6, 149.9, 136.2,122.3, 115.8, 109.8, 104.7, 104.7, 98.5, 79.7,55.4, 55.4, 55.2, 55.2, 52.9,52.9, 42.0, 29.7, 29.6, 28.4, 28.4, 28.4, 26.9. HRMS (ESI): calculated forC 27 H 39 N6O4 + [M+H] + :511.6390, found 511.6393。

[0075] Step 6: Preparation of compound 1, the specific steps are as follows:

[0076] The NMR test results of Compound 1 are as follows:

[0077] M.p. 121.3 - 121.6 °C; IR (KBr): 3314, 3306, 2971, 2714, 1596, 1381, 1377 cm -1 . 1 1H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.03 (s, 1H), 6.70 (s, 2H), 6.54 (dd, J J = 16.8, 10.4 Hz, 1H), 6.40 (s, 1H), 6.31 – 6.23 (dd, 1H), 5.68 (dd, J J = 12.2 Hz, 1H), 4.19 (t, J J = 6.9 Hz, 2H), 3.84 (s, 6H), 3.71 – 3.65 (m, 2H), 3.58 – 3.51 (m, 2H), 3.04 (d, J J = 5.1 Hz, 3H), 2.45 – 2.35 (m, 6H), 2.06 – 2.02 (m, 2H). 13 13C NMR (100 MHz, CDCl3) δ 165.3, 161.2, 161.2, 159.7, 153.6, 150.1, 136.2, 129.2, 127.8, 127.4, 122.2, 115.9, 109.9, 104.7, 104.7, 98.5, 55.4, 55.4, 55.1, 53.4, 52.6, 45.8, 42.0, 28.7, 26.8. HRMS (ESI): calculated for C 25 H 33 N6O3 + [M + H] + : 465.5700, found 465.5702。

[0078] (2) Preparation of Compound 2

[0079] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl 4-(2-hydroxybutyl)piperazine-1-carboxylate. Yellow solid, yield 60%.

[0080] The NMR test results of Compound 2 are as follows:

[0081] M.p. 133.3 - 134.6 °C; IR (KBr): 3308, 3215, 2911, 2715, 1607, 1381, 1076 cm -1 . 1 H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.02 (s, 1H), 6.70 (s, 2H), 6.52 (dd, J J = 16.8, 10.5 Hz, 1H), 6.39 (s, 1H), 6.32 – 6.19 (m, 1H), 5.71 – 5.61 (m, 1H), 4.13 (t, J J = 6.9 Hz, 2H), 3.83 (s, 6H), 3.67 (d, J J = 5.8 Hz, 2H), 3.57 – 3.48 (m, 2H), 3.03 (d, J J = 4.8 Hz, 3H), 2.38 (t, J J = 7.2 Hz, 6H), 1.88 (p, J J = 7.1 Hz, 2H), 1.51 (p, J J = 7.4 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 165.3, 161.2, 161.2, 159.6, 153.6, 149.9, 136.1, 127.8, 127.4, 121.9, 116.1, 109.8, 104.7, 104.7, 98.6, 57.6, 55.4, 55.4, 53.3, 52.7, 45.7, 43.5, 41.8, 28.7, 27.7, 23.8. HRMS (ESI): calculated for C 26 H 35 N6O3 + [M + H] + : 479.5970, found 479.5974。

[0082] (3)Preparation of Compound 3

[0083] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl 4-(2-hydroxypentyl)piperazine-1-carboxylate. Yellow solid, yield 61%.

[0084] The NMR test results of Compound 3 are as follows:

[0085] M.p 141.3 - 142.2 °C; IR(KBr): 3331, 2806, 2671, 2512, 1593, 1382, 1095 cm -1 . 1 1H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 7.02 (s, 1H), 6.72 (s, 2H), 6.54 (dd, J J = 16.8, 10.6 Hz, 1H), 6.40 (s, 1H), 6.27 (dd, J J = 16.8, 1.9 Hz, 1H), 5.68 (dd, J J = 10.6, 1.9 Hz, 1H), 4.12 (t, J J = 7.0 Hz, 2H), 3.84 (s, 6H), 3.60 (dt, J J = 57.1, 5.2 Hz, 4H), 3.05 (d, J J = 5.0 Hz, 3H), 2.40 (q, J J = 5.3 Hz, 4H), 2.34 – 2.29 (m, 2H), 1.87 (p, J J = 7.2 Hz, 2H), 1.55 (p, J J = 7.6 Hz, 2H), 1.35 (h, J J = 7.3, 6.3 Hz, 2H). 13 13C NMR (100 MHz, CDCl3) δ165.3, 161.2, 161.2, 159.8, 153.6, 150.0, 136.2, 127.8, 127.5, 121.9, 115.9, 109.8, 104.7, 104.7, 98.5, 58.2, 55.4, 55.4, 53.4, 52.7, 45.7, 43.6, 41.9, 29.8, 28.7, 26.2, 24.5. HRMS (ESI): calculated for C 27 H 37 N6O3 + [M+H] + : 493.6240, found 493.6244。

[0086] (4) Preparation of Compound 4

[0087] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl 4-(2-hydroxyhexyl)piperazine-1-carboxylate. White solid, yield 61%.

[0088] The NMR test results of Compound 4 are as follows:

[0089] M.p. 145.3 - 145.8 °C; IR (KBr): 3342, 3202, 2952, 2738, 1696, 1332, 1073 cm -1 . 1 H NMR (400 MHz, CDCl3) δ 8.81 (s, 1H), 7.02 (s, 1H), 6.72 (s, 2H), 6.54 (dd, J = 16.8, 10.5 Hz, 1H), 6.40 (s, 1H), 6.27 (dd, J = 16.8 Hz, 1H), 5.68 (dd, J = 10.5 Hz, 1H), 4.12 (t, J = 7.1 Hz, 2H), 3.84 (s, 6H), 3.68 (s, 2H), 3.54 (s, 2H), 3.05 (d, J = 5.0 Hz, 3H), 2.41 (s, 4H), 2.31 (t, J = 7.6 Hz, 2H), 1.91 – 1.80 (m, 4H), 1.50 (d,J = 13.6 Hz, 2H), 1.36 (d, 2H). 13 C NMR (100 MHz, CDCl3) δ 165.3, 161.2, 161.2, 159.8, 153.6, 150.0, 136.3, 127.8, 127.5, 122.0, 115.9, 109.8, 104.7, 104.7, 98.5, 58.4, 55.4, 55.4, 53.4, 52.8, 45.7, 43.7, 41.9, 29.9, 28.9, 27.0, 26.6, 26.6. HRMS (ESI): calculated for C 28 H 39 N6O3 + [M + H] + : 507.6510, found 507.6512

[0090] (5) Preparation of Compound 5

[0091] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to 1-Boc-4-piperidinemethanol. Yellow solid, yield 51%.

[0092] The NMR test results of Compound 5 are as follows:

[0093] M.p. 111.3 - 112.6 °C; IR (KBr): 3213, 2951, 2733, 1794, 1162, 1106, 965 cm -1 . 1 H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 6.97 (s, 1H), 6.71 (d, J = 2.2 Hz, 2H), 6.55 (dd, J = 16.8, 10.5 Hz, 1H), 6.40 (s, 1H), 6.24 (dd, J = 16.8, 1.9 Hz, 1H), 5.65 (dd, J = 10.6, 1.9 Hz, 1H), 4.02 (d, J = 7.2 Hz, 2H), 3.83 (s, 6H), 3.03 (d, J= 5.0 Hz, 3H), 2.64 (t, J = 12.7 Hz, 1H), 2.38 – 2.25 (m, 1H), 2.17 (t, J =13.1 Hz, 1H), 1.80 – 1.61 (m, 2H). 13 C NMR (100 MHz, CDCl3) δ 165.4, 161.2,161.2, 159.8, 153.8, 150.2, 136.0, 127.8, 127.6, 122.2,116.2, 109.6, 104.7,104.7, 98.6, 55.4, 55.4, 49.0, 45.6, 41.8, 37.2, 30.5,29.5, 28.7. HRMS(ESI):calculated for C 24 H 30 N5O3 + [M+H] + :436.5280, found 436.5283.

[0094] (6) Preparation of Compound 6

[0095] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate. Yellow solid, yield 60%.

[0096] The NMR test results of Compound 6 are as follows:

[0097] M.p.121.3-121.6 °C; IR (KBr): 3305, 3204, 2973, 2562, 1764, 1452, 973cm -1 . 1 HNMR (400 MHz, CDCl3) δ 8.81 (d, J = 1.5 Hz, 1H), 6.98(s, 1H), 6.71 (s, 2H),6.44 – 6.39 (m, 1H), 6.34 (dd, J = 17.0, 2.1 Hz,1H), 6.22 – 6.12 (m, 1H), 5.67(dd, J = 10.3, 2.0 Hz, 1H), 4.42 (dd, J= 14.1, 8.3 Hz, 1H), 4.33 – 4.26 (m, 2H), 4.24 – 4.12 (m, 2H), 3.99 (dd, J = 10.7, 5.4 Hz, 1H), 3.84 (s, 6H), 3.26 – 3.17 (m, 1H), 3.04 (d, J = 4.8 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 165.8, 161.2, 161.2, 159.9, 153.8, 150.3, 135.7, 127.5, 125.6, 121.5, 116.8, 109.7, 104.8, 104.8, 98.8, 55.4, 55.4, 53.6, 51.1, 47.0, 29.4, 28.7. HRMS (ESI): calculated for C 22 H 26 N5O3 + [M+H] + : 408.4740, found 408.4743。

[0098] (7) Preparation of Compound 7

[0099] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl 4-hydroxypiperidine-1-carboxylate. Yellow solid, yield 60%.

[0100] The NMR test results of Compound 7 are as follows:

[0101] M.p.141.2 - 142.2 °C; IR (KBr): 3114, 3101, 2953, 2930, 1714, 1302, 901 cm -1 . 1 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 7.01 (s, 1H), 6.73 (s, 2H), 6.57 (dd, J = 16.8, 10.6, 1.1 Hz, 1H), 6.41 (s, 1H), 6.25 (dd, J = 16.8, 1.7 Hz, 1H), 5.66 (dd, J= 10.6, 1.8 Hz, 1H), 4.19 (t, J = 6.9 Hz, 2H), 3.84 (d, J = 1.1 Hz, 6H),3.04 (dd, J = 5.1, 1.2Hz, 4H), 2.57 (t, J = 12.7 Hz, 1H), 1.80 (q, J = 6.9 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 165.4, 161.2, 161.2, 159.8,153.8, 150.2, 136.0,127.8, 127.6, 122.2, 116.2, 109.6, 104.7, 104.7, 98.6,55.4, 55.4, 49.0, 45.6,37.2, 30.5, 29.5, 28.7. HRMS (ESI): calculated for C 23 H 28 N5O3 + [M+H] + :422.5010,found 422.5012。

[0102] (8) Preparation of Compound 8

[0103] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to 3-aminobenzyl alcohol. Yellow solid, yield 62%.

[0104] The NMR test results of Compound 8 are as follows:

[0105] M.p.161.3 - 162.1 °C; IR (KBr): 3412, 2933, 2711, 1382, 1214, 1257,1161,1032 cm -1 . 1 H NMR (400 MHz, CDCl3) δ 8.76 (s,1H), 7.68 (d, J = 8.2 Hz, 1H),7.40 (s, 1H), 7.29 (t, J = 7.9 Hz,1H), 7.03 (d, J= 7.7 Hz, 1H), 6.99 (s, 1H), 6.67 (d, J = 2.2 Hz, 2H), 6.44 – 6.33 (m, 2H), 6.18 (dd, J = 16.8, 10.2 Hz, 1H), 5.68 (dd, J = 10.2, 1.3 Hz, 1H), 5.28 (s, 2H), 3.80 (s, 6H), 2.97 (s, J = 4.4 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 163.7, 161.2, 161.2, 159.9, 153.8, 150.0, 138.6, 138.3, 135.9, 131.0, 129.5, 127.9, 123.5, 121.9, 119.3, 118.7, 116.6, 109.6, 104.7, 104.7, 98.6, 55.4, 55.4, 46.9, 28.7. HRMS (ESI): calculated for C 25 H 26 N5O3 + [M + H] + : 444.5070, found 444.5073。

[0106] (9) Preparation of Compound 9

[0107] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to 4-aminophenethyl alcohol. Yellow solid, yield 61%.

[0108] The NMR test results of Compound 9 are as follows:

[0109] M.p. 171.5 - 172.1 °C; IR (KBr): 3110, 2887, 2725, 1608, 1154, 1057, 1034, 997 cm -1 . 1 H NMR (400 MHz, CDCl3) δ 8.80 (s, 1H), 7.49 (d, J= 8.0 Hz, 2H), 7.20 (s, 1H), 7.15 – 7.10 (m, 2H), 6.81(s, 1H), 6.66 (d, J = 2.3 Hz, 2H), 6.48– 6.36 (m, 2H), 6.23 (dd, J = 16.8, 10.2 Hz, 1H), 5.83 – 5.73 (m, 1H), 4.34 (t, J = 7.2 Hz, 2H), 3.83 (s, 6H), 3.12 (t, J = 7.2 Hz, 2H), 3.06 (d, J = 5.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 165.6, 161.2, 161.2, 160.1, 153.3, 150.6, 136.9, 136.2, 135.6, 130.8, 129.6, 129.6, 126.5, 123.4, 123.4, 121.4, 117.8, 110.7, 105.0, 105.0, 99.0, 55.4, 55.4, 40.6, 35.2, 29.7, 28.7. HRMS (ESI): calculated for C 26 H 28 N5O3 + [M+H] + : 458.5340, found 458.5343。

[0110] Preparation of Compound 10

[0111] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to N-BOC-2-tetraiodobenzylamine. Yellow solid, yield 60%.

[0112] The NMR test results of Compound 10 are as follows:

[0113] M.p. 246.8 - 247.5 °C; IR (KBr): 3237, 2835, 1678, 1521, 1436, 1305, 1234, 1165, 864, 802 cm -1 . 1 H NMR (400 MHz, CDCl3) δ8.88 (s,1H), 7.85 – 7.66 (m,2H), 7.49 – 7.39 (m, 2H), 7.31 (s, 1H), 6.76 (s,2H), 6.45 (t, J J = 2.3 Hz, 1H),6.36 (dd, J J = 17.0, 1.5 Hz, 1H),6.15 (dd, J J = 17.0, 10.2 Hz, 1H), 5.70 (dd, J J =10.3, 1.5 Hz,1H), 4.58 (d, J J = 5.8 Hz, 2H), 3.85 (s, 6H), 3.03 (d, J J = 5.0 Hz,3H). 13 C NMR (100 MHz, CDCl3) δ 165.4, 161.3,161.3, 160.3, 153.4, 150.8, 137.1,136.0, 135.5, 130.6, 128.8, 128.8, 127.0,123.4, 123.4, 121.1, 117.9, 110.7,105.0, 105.0, 99.0, 55.4, 55.4, 43.2, 28.7. HRMS (ESI): calculated forC 25 H 26 N5O3 + [M+H] + :444.5070, found 444.5074。

[0114] (11) Preparation of Compound 11

[0115] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to N-BOC-2-tetraiodophenethylamine. Yellow solid, yield 64%.

[0116] The NMR test results of Compound 11 are as follows:

[0117] M.p.187.8-188.6 °C; IR (KBr): 3286, 3039, 2925,2852, 1606, 1518,1267, 1126, 835, 805 cm -1 . 1 H NMR (400 MHz, CDCl3)δ 8.88 (s,1H), 7.75 (d, J J = 8.0Hz, 2H), 7.32 (t, J J = 4.3 Hz, 3H), 6.77 (s,2H), 6.45 (s, 1H), 6.29 (d, J J = 16.9Hz, 1H), 6.07 (dd, J J = 16.9,10.2 Hz, 1H), 5.64 (d, J J = 10.3 Hz, 1H), 3.85 (s,6H), 3.64 (q, J J = 6.7 Hz, 2H), 3.03 (d, J J = 4.9 Hz, 3H), 2.92 (t, J J = 7.0 Hz,2H). 13 CNMR (100 MHz, CDCl3) δ 165.6, 161.3,161.3, 160.1, 153.3, 150.6, 136.9, 136.2,135.6, 130.8, 129.6, 129.6, 126.5,123.4, 123.4, 121.4, 117.8, 110.7, 105.0,105.0, 99.0, 55.4, 55.4, 40.6, 35.2,29.7, 28.7. HRMS(ESI): calculated forC 26 H 28 N5O3 + [M+H] + :458.5340, found 458.5343。

[0118] (12) Preparation of Compound 12

[0119] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to N-BOC-2-tetraiodobenzylamine. Yellow solid, yield 64%.

[0120] The NMR test results of Compound 12 are as follows:

[0121] M.p.160.3-160.6 °C; IR (KBr): 3274, 2843, 1669,1541, 1455, 1302,1243, 1155, 889, 803 cm -1. 1 1H NMR (400 MHz, CDCl3) δ 8.88 (s,1H), 7.71 (d, J J = 6.3Hz, 2H), 7.37 – 7.28 (m, 3H), 6.77 (s, 2H), 6.44(s, 1H), 6.32 – 6.22 (m, 1H),6.07 (ddd, J J = 16.9, 10.3, 2.1 Hz, 1H),5.63 (d, J J = 10.2 Hz, 1H), 3.85 (s, 6H),3.41 (q, J J = 6.8, 5.8Hz, 2H), 3.03 (d, 3H), 2.80 – 2.65 (m, 2H), 2.00 – 1.84(m, 2H). 13 13C NMR (100 MHz, CDCl3) δ 165.6, 161.3, 161.3, 160.2, 153.3,150.6,139.5, 135.8, 135.7, 130.8, 129.1, 129.1, 126.4, 123.3, 123.3, 121.5,117.6,110.7, 105.0, 105.0, 99.0, 55.4, 55.4, 39.2, 32.8, 31.19, 28.7. HRMS (ESI):calculated for C 27 H 30 N5O3 + [M+H] + :472.5610, found 472.5612。

[0122] (13) Preparation of Compound 13

[0123] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl 4-(4-bromobenzyl)piperazine-1-carboxylate. Yellow solid, yield 61%.

[0124] The NMR test results of Compound 13 are as follows:

[0125] M.p.215.2 - 216.8 °C; IR (KBr): 3265, 2926, 1645,1596, 1437, 1302,1243, 1180, 940, 789 cm-1 . 1 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 7.79 (d, J J = 8.4 Hz, 2H), 7.46 (d, J J = 8.1 Hz, 2H), 7.35 (s, 1H), 6.78 (s, 2H), 6.57 (dd, J J = 16.8, 10.5 Hz, 1H), 6.45 (s, 1H), 6.29 (dd, J J = 16.8, 2.0 Hz, 1H), 5.69 (dd, J J = 10.6, 1.9 Hz, 1H), 3.86 (s, 6H), 3.77 – 3.68 (m, 2H), 3.63 – 3.50 (m, 4H), 3.05 (d, J J = 5.0 Hz, 3H), 2.50 (dt, J J = 9.0, 4.9 Hz, 4H). 13 13C NMR (100 MHz, CDCl3) δ 165.3, 161.3, 161.3, 160.3, 153.3, 150.8, 136.9, 135.7, 135.6, 129.8, 129.8, 127.8, 127.5, 123.0, 123.0, 121.3, 117.8, 110.7, 105.0, 105.0, 99.0, 62.3, 55.5, 55.4, 53.2, 52.7, 45.8, 42.0, 28.7. HRMS (ESI): calculated for C 29 H 33 N6O3 + [M + H] + : 513.6140, found 513.6143。

[0126] Preparation of Compound 14

[0127] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl 4-(4-bromophenethyl)piperazine-1-carboxylate. Yellow solid, yield 50%.

[0128] The NMR test results of Compound 14 are as follows:

[0129] Melting point: 166.3 - 167.4 °C; IR (KBr): 3282, 2925, 1646, 1602, 1453, 1296, 1234, 1152, 969, 831 cm -1 . 1 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 7.71 (s, 1H), 7.64 (dd, J J = 8.1, 1.9 Hz, 1H), 7.43 (t, J J = 7.8 Hz, 1H), 7.35 (s, 1H), 7.17 (d, J J = 7.6 Hz, 1H), 6.78 (s, 2H), 6.57 (dd, J J = 16.8, 10.5 Hz, 1H), 6.45 (s, 1H), 6.29 (dd, J J = 16.8, 2.0 Hz, 1H), 5.70 (dd, J J = 10.5, 2.0 Hz, 1H), 3.86 (s, 6H), 3.74 (s, 2H), 3.61 (s, 2H), 3.05 (d, J J = 5.0 Hz, 3H), 2.91 (dd, J J = 9.9, 6.1 Hz, 2H), 2.71 (dd, J J = 9.9, 6.1 Hz, 2H), 2.55 (s, 4H). 13 13C NMR (100 MHz, CDCl3) δ 165.3, 161.5, 161.3, 160.3, 153.3, 150.8, 141.3, 137.8, 135.6, 129.2, 127.9, 127.4, 126.6, 123.5, 121.3, 120.9, 117.8, 110.7, 105.3, 105.0, 98.9, 60.0, 55.5, 55.4, 53.5, 52.7, 45.8, 41.9, 33.5, 28.7. HRMS (ESI): calculated for C 30 H 35 N6O3 + [M + H] + : 527.6410, found 527.6414。

[0130] Preparation of Compound 15

[0131] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl 4-(3-(4-bromophenyl)propyl)piperazine-1-carboxylate. Yellow solid, yield 62%.

[0132] The NMR test results of Compound 15 are as follows:

[0133] M.p. 201.3 - 202.1 °C; IR (KBr): 3284, 2883, 1669, 1561, 1465, 1306, 1263, 1156, 869, 806 cm -1 . 1 H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 7.72 (d, J = 6.3 Hz, 2H), 7.38 – 7.29 (m, 3H), 6.78 (s, 2H), 6.56 (dd, J = 16.8, 10.5, 2.0 Hz, 1H), 6.45 (s, 1H), 6.29 (dt, J = 16.9, 2.1 Hz, 1H), 5.69 (dt, J = 10.4, 2.1 Hz, 1H), 3.86 (s, 6H), 3.76 – 3.51 (m, 5H), 3.04 (dd, J = 5.1, 2.0 Hz, 3H), 2.71 (t, J = 7.8 Hz, 2H), 2.50 – 2.41 (m, 6H), 1.88 (t, J = 7.6 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ165.3, 161.3, 161.3, 160.2, 153.3, 150.6, 140.0, 135.7, 135.7, 129.1, 129.1, 127.8, 127.5, 123.2, 123.2, 121.5, 117.6, 110.7, 105.0, 105.0, 99.0, 57.6, 55.4, 55.4, 53.4, 52.7, 45.7, 41.9, 33.1, 28.7, 28.3. HRMS (ESI): calculated for C 31 H 37 N6O3 + [M+H] + : 541.6680, found 541.6684。

[0134] (16) Preparation of Compound 16

[0135] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl 2-((4-bromobenzyl)(methylamino)ethyl)(methyl)-1-carboxylate. Yellow solid, yield 62%.

[0136] The NMR test results of Compound 16 are as follows:

[0137] M.p. 161.4 - 162.5 °C; IR (KBr): 3262, 2924, 1656, 1612, 1463, 1286, 1244, 1153, 959, 801 cm -1 . 1 H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 7.77 (dd, J = 11.8, 8.1 Hz, 2H), 7.43 (dd, J = 8.1, 5.6 Hz, 2H), 7.35 (s, 1H), 6.79 (s, 2H), 6.56 (ddd, J = 23.0, 16.8, 10.4 Hz, 1H), 6.45 (s, 1H), 6.38 – 6.24 (m, 1H), 5.66 (ddd, J = 20.9, 10.4, 2.0 Hz, 1H), 3.86 (s, 6H), 3.67 – 3.56 (m, 3H), 3.48 (t, J= 6.9 Hz, 1H), 3.12 – 2.95 (m, 6H), 2.61 (dt, J = 20.4, 6.8 Hz, 2H), 2.31 (s, 3H). 13 13C NMR (100 MHz, CDCl3) δ 161.3, 161.3, 160.3, 153.3, 150.8, 136.7, 135.7, 129.6, 129.5, 127.8, 127.7, 127.5, 123.0, 123.0, 122.9, 121.4, 117.8, 110.7, 105.0, 105.0, 99.0, 62.3, 55.4, 55.4, 48.4, 45.9, 42.5, 34.4, 28.7. HRMS(ESI): calculated for C 28 H 33 N6O3 + [M + H] + : 501.6030, found 501.6033。

[0138] (17) Preparation of Compound 17

[0139] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl 4-(((4-bromobenzyl)(methyl)amino)piperidine-1-carboxylate). Yellow solid, yield 61%.

[0140] The NMR test results of Compound 17 are as follows:

[0141] M.p. 93.3 - 94.6 °C; IR (KBr): 3413, 2931, 1645, 1602, 1514, 1302, 1226, 1153, 831, 791 cm -1 . 1 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.35 (s, 1H), 6.78 (s, 2H), 6.60 (dd, J = 14.5, 12.9 Hz, 1H), 6.45 (s, 1H), 6.28 (d, J= 16.8 Hz, 1H), 5.68 (d, J = 10.5 Hz, 1H),4.74 (d, J = 13.0 Hz, 1H), 4.07 (d, J = 13.6 Hz, 1H), 3.85 (s, 6H), 3.63 (d, J =3.8 Hz, 2H), 3.06 (q, J = 4.5 Hz, 4H), 2.80 – 2.55 (m, 2H), 2.24 (s,3H), 1.92(d, J = 12.8 Hz, 2H), 1.57 (d, J = 12.0 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ 165.3,161.3, 161.3, 160.3, 153.3,150.8, 137.8, 136.6, 135.7, 129.3, 129.3, 127.8,127.6, 123.0, 123.0, 121.3,117.7, 110.7, 105.0, 105.0, 99.0, 60.6, 57.5,55.4, 55.4, 45.5, 41.7, 37.7,28.9, 28., 27.5.HRMS (ESI): calculated forC 31 H 37 N6O3 + [M+H] + :541.6680, found 541.6683。

[0142] Preparation of Compound 18

[0143] The specific preparation method is as follows: Similar to the preparation method of Compound 1, a yellow solid. Only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl (1-(4-bromobenzyl)piperidin-4-yl)(methyl)carbamate. The yield is 61%.

[0144] The NMR test results of Compound 18 are as follows:

[0145] M.p.112.3 - 112.7 °C; IR (KBr): 3285, 2926, 1645,1514, 1222, 1203,1087, 1060, 928, 837 cm -1 .1 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 7.79 (d, J J = 8.0 Hz, 2H), 7.53 – 7.42 (m, 2H), 7.35 (s, 1H), 6.78 (s, 2H), 6.56 (dd, J J = 16.4, 10.6 Hz, 1H), 6.45 (s, 1H), 6.36 – 6.19 (m, 1H), 5.80 – 5.59 (m, 1H), 3.85 (d, J J = 1.6 Hz, 6H), 3.59 (d, J J = 16.5 Hz, 2H), 3.05 (dd, J J = 5.1, 1.7 Hz, 4H), 2.93 (d, J J = 14.9 Hz, 3H), 2.32 – 2.04 (m, 2H), 2.01 – 1.84 (m, 2H), 1.65 (d, J J = 11.5 Hz, 2H). 13 13C NMR (100 MHz, CDCl3) δ 161.29, 161.29, 160.33, 153.35, 150.84, 136.75, 135.70, 129.87, 129.79, 128.62, 128.42, 127.67, 127.14, 122.95, 122.95, 121.30, 117.73, 110.74, 105.02, 105.02, 99.02, 62.49, 62.37, 55.44, 55.44, 52.96, 51.01, 30.13, 29.82, 29.71, 28.75. HRMS (ESI): calculated for C 31 H 37 N6O3 + [M + H] + : 541.6680, found 541.6684。

[0146] (19) Preparation of Compound 19

[0147] The specific preparation method is as follows: similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl 3-((4-bromobenzyl)(methyl)amino)azetidine-1-carboxylate. Yellow solid, yield 56%

[0148] The NMR test results of Compound 19 are as follows.

[0149] M.p. 106.1 - 107.3 °C; IR (KBr): 3268, 2853, 1664, 1531, 1434, 1318, 1263, 1179, 879, 805 cm -1 . 1 H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 7.80 (d, J J = 8.1 Hz, 2H), 7.43 (d, J J = 8.1 Hz, 2H), 7.35 (s, 1H), 6.78 (d, J J = 2.2 Hz, 2H), 6.45 (t, J J = 2.3 Hz, 1H), 6.35 (dd, J J = 17.0, 1.9 Hz, 1H), 6.21 (dd, J J = 17.0, 10.2 Hz, 1H), 5.67 (dd, J J = 10.2, 2.0 Hz, 1H), 4.25 (t, J J = 7.9 Hz, 1H), 4.13 (ddd, J J = 14.1, 9.5, 6.3 Hz, 2H), 4.01 (dd, J J = 10.5, 5.6 Hz, 1H), 3.86 (s, 6H), 3.54 – 3.45 (m, 2H), 3.43 (td, J J = 6.2, 5.3, 1.6 Hz, 1H), 3.05 (d, J J = 4.9 Hz, 3H), 2.15 (s, 3H). 13 C NMR (100 MHz, CDCl3) δ165.7, 161.3, 161.3, 160.3, 153.4, 150.8, 137.0, 135.6, 135.6, 129.7, 129.7, 127.4, 125.9, 123.0, 123.0, 121.2, 117.9, 110.7, 105.0, 105.0, 99.0, 58.4, 55.4, 55.4, 54.4, 54.0, 52.2, 38.1, 28.7. HRMS(ESI): calculated for C 29 H 33 N6O3 + [M+H] + : 513.6140, found 513.6143。

[0150] (20) Preparation of Compound 20

[0151] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl (S)-(1-(4-bromobenzyl)pyrrolidin-3-yl)(methyl)carbamate. Yellow solid, yield 55%.

[0152] The NMR test results of Compound 20 are as follows:

[0153] M.p. 141.2 - 142.1 °C; IR (KBr): 3257, 2841, 1671, 1542, 1437, 1305, 1286, 1188, 882, 803 cm -1 . 1 H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 7.82 – 7.73 (m, 2H), 7.45 (d, J = 5.7 Hz, 2H), 7.35 (s, 1H), 6.78 (s, 2H), 6.56 (d, J = 14.1 Hz, 1H), 6.45 (s, 1H), 6.25 (dd, J = 41.9, 17.0 Hz, 1H), 5.73 – 5.58 (m, 1H), 3.86 (s, 6H), 3.76 – 3.66 (m, 1H), 3.59 (s, 1H), 3.05 (t, J = 18.5 Hz, 6H), 2.71 (t, J= 5.1 Hz, 1H), 2.52 – 2.18 (m, 2H), 1.74 (d, J = 14.4 Hz, 2H). 13 C NMR (101 MHz, CDCl3) δ 161.3, 161.3, 160.2, 153.4, 150.7, 150.7, 141.3, 139.3, 135.6, 129.6, 129.3, 128.2, 123.1, 123.1, 121.3, 117.9, 115.7, 110.7, 105.0, 105.0, 99.1, 59.5, 59.4, 55.4, 55.4, 53.8, 29.7, 29.7, 28.7, 28.7. HRMS (ESI): calculated for C 30 H 35 N6O3 + [M + H] + : 527.6410, found 527.6414。

[0154] (21) Preparation of Compound 21

[0155] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl (R)-(1-(4-bromobenzyl)pyrrolidin-3-yl)(methyl)carbamate. Yellow solid, yield 60%.

[0156] The NMR test results of Compound 21 are as follows:

[0157] M.p. 96.6 - 97.9 °C; IR (KBr): 3278, 2846, 1675, 1542, 1439, 1318, 1284, 1179, 879, 803 cm -1 . 1 H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 7.78 (d, J = 4.3 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.35 (s, 1H), 6.78 (s, 2H), 6.53 – 6.35 (m, 3H), 5.74 – 5.63 (m, 1H), 3.98 (dd, J= 12.9, 8.6 Hz, 1H), 3.85 (s, 6H), 3.76 (d, J = 8.7 Hz, 1H), 3.59 (td, J = 14.8, 14.3, 3.7 Hz, 3H), 3.52 – 3.29 (m, 2H), 3.05 (d, J = 4.6 Hz, 3H), 2.22 (s, 3H), 1.96 (dq, J = 32.7, 9.9 Hz, 2H). 13 C NMR(100 MHz, CDCl3) δ 164.5, 161.3, 161.3, 160.3, 153.4, 150.8, 136.6, 135.7, 129.7, 129.7, 129.5, 128.4, 128.0, 123.0, 123.0, 123.0, 121.3, 117.8, 110.7, 105.0, 105.0, 99.0, 64.2, 62.4, 59.9, 55.4, 55.4, 45.6, 39.9, 30.4, 28.7. HRMS (ESI): calculated for C 30 H 35 N6O3 + [M + H] + : 527.6410, found 527.6413。

[0158] (22) Preparation of Compound 22

[0159] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl 2-(4-bromobenzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate. Yellow solid, yield 60%.

[0160] The NMR test results of Compound 22 are as follows:

[0161] M.p.142.3 - 142.9 °C; IR (KBr): 3254, 2841, 1664, 1531, 1428, 1318, 1281, 1179, 879, 804 cm -1 . 1 H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 7.81 (d, J= 8.1Hz, 2H), 7.48 (d, J = 8.1 Hz, 2H), 7.34 (s, 1H), 6.77 (s,2H), 6.56 (dd, J = 16.8,10.6 Hz, 1H), 6.44 (s, 1H), 6.25 (dd, J = 16.8, 1.9 Hz, 1H), 5.67 (dd, J = 10.5,1.9 Hz, 1H), 3.85 (s, 6H), 3.82(s, 2H), 3.57 (s, 2H), 3.46 (s, 2H), 3.27 (d, J = 27.5 Hz, 4H), 3.04 (d, J = 4.9 Hz, 3H), 1.83 (d, J = 24.2 Hz, 4H). 13 C NMR(100MHz, CDCl3) δ 165.4, 161.3, 161.3, 160.3, 153.4, 150.8,150.8, 137.3, 135.6,129.6, 129.6, 127.7, 127.7, 123.1, 123.1, 121.1, 117.9,110.7, 105.0, 105.0,99.0, 63.4, 62.2, 55.4, 55.4, 43.1, 39.3, 36.1, 35.7,34.8, 34.7, 28.7.HRMS(ESI): calculated for C 32 H 37 N6O3 + [M+H] + :553.6790, found 553.6794。

[0162] Preparation of Compound (23)

[0163] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl 4-(4-bromobenzyl)-1,4-diazepane-1-carboxylate. Yellow solid, yield 60%.

[0164] The NMR test results of Compound 23 are as follows:

[0165] M.p. 161.3 - 162.6 °C; IR (KBr): 3262, 2845, 1664, 1542, 1433, 1306, 1284, 1179, 891, 796 cm -1 . 1 1H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 7.78 (d, J J = 7.8 Hz, 2H), 7.55 – 7.44 (m, 2H), 7.35 (s, 1H), 6.78 (s, 2H), 6.66 – 6.52 (m, 1H), 6.45 (s, 1H), 6.35 (dd, J J = 16.5, 5.8 Hz, 1H), 5.76 – 5.62 (m, 1H), 3.86 (s, 6H), 3.71 (td, J J = 9.6, 4.4 Hz, 4H), 3.67 – 3.60 (m, 2H), 3.06 (d, J J = 4.4 Hz, 3H), 2.74 (dd, J J = 23.1, 12.9, 5.3 Hz, 4H), 1.98 – 1.88 (m, 2H). 13 13C NMR (100 MHz, CDCl3) δ 167.0, 161.3, 161.3, 160.3, 153.4, 150.7, 136.8, 135.6, 129.6, 129.5, 127.9, 127.7, 123.0, 123.0, 121.3, 117.8, 110.7, 105.0, 105.0, 105.0, 99.1, 61.8, 55.4, 55.4, 54.2, 47.9, 46.9, 45.7, 44.9, 28.7. HRMS(ESI): calculated for C 30 24 35 H + N6O3 + [M + H]+: 527.6410, found 527.6414。

[0166] (24) Preparation of Compound 24

[0167] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl 5-(4-bromobenzyl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate. Yellow solid, yield 58%.

[0168] The NMR test results of Compound 24 are as follows:

[0169] M.p. 87.3 - 88.2 °C; IR (KBr): 3314, 2924, 2789, 2231, 1647, 1438, 1204, 1011, 835, 792 cm -1 . 1 H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 7.73 (d, J = 8.2 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 6.73 (s, 2H), 6.47 – 6.25 (m, 3H), 5.61 (dd, J = 9.9, 2.5 Hz, 1H), 3.79 (s, 6H), 3.76 – 3.67 (m, 2H), 3.60 (s, 2H), 3.50 (dd, J = 12.8, 4.4 Hz, 1H), 3.40 (dd, J = 10.8, 4.5 Hz, 1H), 2.98 (d, J = 4.7 Hz, 3H), 2.85 (ddq, J = 30.1, 8.5, 4.3 Hz, 3H), 2.64 (t, J = 8.2 Hz, 2H), 2.50 (ddd, J = 16.7, 9.5, 3.7 Hz, 2H). 13 C NMR (100 MHz, CDCl3) δ164.2, 161.3, 161.3, 160.3, 153.3, 150.8, 137.1, 136.6, 135.7, 129.2, 129.2, 128.6, 127.5, 123.0, 123.0, 121.3, 117.7, 110.7, 105.0, 105.0, 99.1, 60.2, 60.0, 59.0, 55.4, 52.5, 51.6, 42.50, 40.50, 28.76. HRMS (ESI): calculated for C 31 H 35 N6O3 + [M+H] + : 539.6520, found 539.6522。

[0170] (25) Preparation of Compound 25

[0171] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl 6-(4-bromobenzyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate. Yellow solid, yield 55%.

[0172] The NMR test results of Compound 25 are as follows:

[0173] M.p. 151.3 - 152.2 °C; IR (KBr): 3266, 2842, 1675, 1542, 1418, 1306, 1263, 1178, 879, 804 cm -1 . 1 H NMR (400 MHz, CDCl3) δ 8.89 (s, 1H), 7.79 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.34 (s, 1H), 6.77 (s, 2H), 6.45 (s, 1H), 6.32 (dd, J = 17.0, 1.9 Hz, 1H), 6.16 (dd, J = 17.0, 10.3 Hz, 1H), 5.67 (dd, J= 10.3, 1.9 Hz, 1H), 4.33 (s, 2H), 4.14 (s, 2H), 3.85 (s, 6H), 3.67 (s, 2H), 3.52 – 3.38 (m, 4H), 3.04 (d, J = 5.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3) δ 165.4, 161.3, 161.3, 160.2, 153.4, 150.7, 137.0, 135.6, 129.3, 129.3, 127.5, 125.8, 125.8, 123.2, 123.2, 121.2, 117.9, 110.7, 105.0, 105.0, 99.0, 64.1, 64.1, 62.6, 60.5, 57.5, 55.4, 55.4, 33.6, 28.7. HRMS (ESI): calculated for C 30 H 33 N6O3 + [M + H] + : 525.6250, found 525.6253。

[0174] (26) Preparation of Compound 26

[0175] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl 6-(4-bromobenzyl)-2,6-diazaspiro[3.4]octane-2-carboxylate. Yellow solid, yield 59%.

[0176] The NMR test results of Compound 26 are as follows:

[0177] M.p. 144.3 - 144.9 °C; IR (KBr): 3254, 2847, 1634, 1543, 1443, 1322, 1275, 1176, 856, 797 cm -1 . 1 H NMR (400 MHz, CDCl3) δ 8.88 (s, 1H), 7.78 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.1 Hz, 2H), 7.35 (s, 1H), 6.77 (s, 2H), 6.45 (s, 1H), 6.31 (d,J = 16.9 Hz, 1H), 6.15 (dd, J = 16.9, 10.2 Hz, 1H), 5.64 (d, J = 10.3 Hz,1H), 4.13 (d, J = 4.1Hz, 2H), 4.01 (d, J = 2.9 Hz, 2H), 3.85 (s, 6H), 3.67 (s,2H), 3.04 (d, J = 4.3 Hz, 3H), 2.82 – 2.64 (m, 4H), 2.12 (t, J = 7.1 Hz, 2H). 13 13C NMR (100 MHz, CDCl3) δ 165.5, 161.3, 160.2, 153.4, 150.5,136.8, 135.6,129.5, 129.5, 127.3, 125.9, 123.4, 123.0, 123.0, 121.4, 117.8,110.7, 105.3,105.0, 105.0, 99.0, 65.2, 62.7, 59.5, 55.4, 55.4, 53.6, 39.6,37.2, 31.9,28.7, 22.7. HRMS (ESI): calculated for C 31 H 35 N6O3 + [M+H] + : 539.6520, found 539.6523。

[0178] (27) Preparation of Compound 27

[0179] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl 7-(4-bromobenzyl)-2,7-diazaspiro[3.5]nonane-2-carboxylate. Yellow solid, yield 63%.

[0180] The NMR test results of Compound 27 are as follows:

[0181] M.p. 161.3 - 162.6 °C; IR (KBr): 3244, 2827, 1654,1511, 1428, 1304,1286, 1176, 879, 801 cm -1 .1 1H NMR (400 MHz, CDCl3) δ 8.90 (s, 1H), 7.78 (d, J J = 8.2Hz, 2H), 7.45 (d, J J = 8.2 Hz, 2H), 7.35 (s, 1H), 6.78 (s,2H), 6.45 (s, 1H),6.34 (dd, J J = 16.9, 1.9 Hz, 1H), 6.19 (dd, J J =17.0, 10.3 Hz, 1H), 5.66 (dd, J J =10.2, 2.0 Hz, 1H), 3.88 (s, 2H), 3.86(s, 6H), 3.77 (s, 2H), 3.53 (s, 2H),3.05 (d, J J = 5.0 Hz, 3H), 2.42 (s,4H), 1.82 (s, 4H). 13 13C NMR (100 MHz, CDCl3) δ 165.8, 161.3, 161.3, 160.3, 153.3, 150.8, 150.8, 136.8, 135.7, 129.8, 129.8,127.2, 125.9, 122.9, 122.9, 121.3, 117.8, 110.7, 105.0, 105.0, 99.0, 62.5,60.0, 57.6, 55.4, 55.4, 50.4, 50.4, 35.5, 33.7, 28.8, 28.8. HRMS (ESI):calculated for C 32 H 37 N6O3 + [M+H] + :553.6790, found 553.6794。

[0182] Preparation of Compound (28)

[0183] The specific preparation method is as follows: Similar to the preparation method of Compound 1, only change tert-butyl 4-(3-hydroxypropyl)piperazine-1-carboxylate used in the preparation of A4 to tert-butyl 7-(4-bromobenzyl)-2,7-diazaspiro[4.4]nonane-2-carboxylate. Yellow solid, yield 62%.

[0184] The NMR test results of Compound 28 are as follows:

[0185] M.p. 153.3 - 153.6 °C; IR (KBr): 3255, 2853, 1663, 1546, 1458, 1311, 1284, 1184, 885, 794 cm -1 . 1 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 7.75 (d, J J = 6.6 Hz, 2H), 7.42 (d, J J = 7.7 Hz, 2H), 6.76 (s, 2H), 6.46 – 6.29 (m, 3H), 5.70 – 5.54 (m, 1H), 3.83 (s, 6H), 3.65 (s, 2H), 3.59 – 3.41 (m, 4H), 3.01 (s, 3H), 2.84 – 2.49 (m, 4H), 2.02 – 1.80 (m, 4H). 13 13C NMR (100 MHz, CDCl3) δ 164.5, 161.3, 161.3, 160.2, 153.3, 150.6, 136.7, 135.6, 129.4, 129.4, 128.6, 128.2, 127.5, 123.0, 122.9, 121.3, 117.7, 110.6, 104.9, 104.9, 99.0, 59.6, 58.4, 57.1, 55.4, 55.4, 53.5, 48.7, 45.3, 37.9, 36.1, 28.7. HRMS (ESI): calculated for C 32 1H 37 6N6O3 + [M + H] + : 553.6791, found 553.6795。

[0186] Example 2

[0187] In this example, the compound 1 - 28 prepared in Example 1 was subjected to enzyme activity testing

[0188] In the present invention, AZD4547 was used as a positive control, and homogeneous time - resolved fluorescence (HTRF) was adopted to evaluate the kinase inhibitory activities of compounds 1 - 28 against three subtypes of FGFR1, 2, and 3.

[0189] Table 1. Structure - activity relationship study based on enzyme activity results

[0190]

[0191] The results showed that compounds 1-28 could all inhibit the protein activities of FGFR1 / 2 / 3 to varying degrees.

[0192] Example 3

[0193] Perform a kinase profile selectivity experiment

[0194] In the present invention, compound 24 was selected to evaluate its kinase selectivity for FGFR1, and the selectivity for 207 common kinases was selected. The test concentration of the selected kinases was 0.5 μM.

[0195] The results of the kinase selectivity experiment showed (Table 2) that compared with other isoforms of the same family, compound 24 had high selectivity for FGFR1 and low inhibition rates for targets such as EGFR and VEGFR. The study found that it had a high inhibition rate for less than 10% of the kinases and an inhibition rate of less than 50% for most kinases. It was shown that 24 was a small molecule inhibitor targeting FGFR1 with high selectivity.

[0196] Table 2. Kinase selectivity of compound 24

[0197]

[0198]

[0199] Example 4

[0200] In this example, the anti-proliferative activities of compounds 13-14, 16-28 against specific cancer cell lines were detected.

[0201]

[0202] Example 5

[0203] In this example, the anti-tumor efficacy of compound 24 in vivo was evaluated.

[0204] To evaluate the anti-tumor efficacy of compound 24 in vivo, a mouse subcutaneous xenograft tumor model was established using human squamous cell lung cancer cells NCI-H1581 with high expression of FGFR1. 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 8 / mL with a resuspension solution (1640 medium: Matrigel = 1:1), and at 5*10 6The number of cells was inoculated under the axilla of the forelimbs of 5-week-old female Balb / c Nude mice. When the tumor volume grew to 50 - 100 mm 3 , the mice were randomly divided into four groups (control group, 25 mg / kg Erdafitinib group, 100 mg / kg and 150 mg / kg of group 24), with 6 mice in each group. Compound 24 and Erdafitinib were administered orally every day. The tumor volume and mouse body weight were measured. After 17 days of administration, the mice were sacrificed, and the tumor tissues were dissected and fixed in formalin solution for standby.

[0205] Figure 3 The results showed that the change in mouse body weight after administration was small, indicating that the compound had low toxicity. Figure 1 、 2 As can be seen from, the tumors of the mice were significantly inhibited after administration, and the tumor inhibition rate of the high-dose group of compound 24 reached 69%. It shows that compound 24 has good tolerance to all doses in vivo.

[0206] Figure 1 is the tumor volume curve graph of compound 24 inhibiting tumor proliferation in the subcutaneous xenograft tumor model of NCI-H1581 tumor cells; from Figure 2 it can be seen that compound 24 can significantly inhibit the growth of NCI-H1581 tumor cells in mice.

[0207] Figure 2 is the statistical graph of the tumor weight in mice after 17 days of treatment with compound 24 in the subcutaneous xenograft tumor model of NCI-H1581 tumor cells; from Figure 2 it can be seen that compound 24 has an obvious inhibitory effect on NCI-H1581 tumors in mice, and it is dose-dependent.

[0208] Figure 3 is the curve graph of the body weight change of mice during the treatment with compound 24 in the subcutaneous xenograft tumor model of NCI-H1581 tumor cells; from Figure 3 it can be seen that the administration of compound 24 has little effect on the body weight of mice and has good safety.

[0209] Figure 4 is the photo graph of the tumor in mice after 17 days of treatment with compound 24 in the subcutaneous xenograft tumor model of NCI-H1581 tumor cells; from Figure 4 it can be seen that compound 24 has an obvious inhibitory effect on NCI-H1581 tumors in mice, and it is dose-dependent. The high-dose group is comparable to the positive drug.

[0210] In summary, the inventors have first discovered a novel derivative compound 24 of 7H-pyrrolo[2,3-d]pyrimidine, which is an effective and selective inhibitor of FGFR1. The results of kinase selectivity experiments further verified the high FGFR1 selectivity of compound 24. In vitro anti-proliferation experiments showed that compound 24 could effectively inhibit the proliferation of NCI-H1581 tumor cells with high FGFR1 expression at low nanomolar concentrations. In in vivo anti-proliferation experiments, compound 24 could significantly inhibit the growth of NCI-H1581 tumor cells in mice in a dose-dependent manner and had good safety, indicating that compound 24 is a potential drug molecule for the treatment of cancers with FGFR1 abnormalities.

[0211] As mentioned above, it is only a preferred embodiment of the present invention. The present invention is not limited to the above-mentioned embodiments. As long as the same means are used to achieve the technical effects of the present invention, they should fall within the protection scope of the present invention. Within the protection scope of the present invention, various different modifications and changes can be made to its technical solutions and / or embodiments.

Claims

1. A pyrrolopyrimidine derivative, characterized in that, The pyrrolopyrimidine derivative is selected from any one of the following structures: 、 、 、 、 、 、 、 、 、 、 。 2. The pyrrolopyrimidine derivative according to claim 1, wherein The pyrrolopyrimidine derivative is selected from any one of the following structures: 。 3. The pyrrolopyrimidine derivative according to claim 2, wherein The structure of the pyrrolopyrimidine derivative is as follows: 。 4. A method for preparing the pyrrolopyrimidine derivative according to claim 1, characterized in that, Its preparation route is as follows: Among them, Linker is selected from any one of the following structures: 、 、 、 、 、 、 、 、 、 、 。 5. Use of a pyrrolopyrimidine derivative according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating and / or preventing cancer associated with FGFR1 abnormality, characterized in that, The cancer is squamous cell lung cancer.

6. A pharmaceutical composition, characterized in that, Using the pyrrolopyrimidine derivative according to any one of claims 1-3 or a pharmaceutically acceptable salt thereof as the main active ingredient.

7. The pharmaceutical composition according to claim 6, characterized in that, The pharmaceutical composition contains one or more pharmaceutically acceptable excipients.

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