CN118908899A - FGFR4 inhibitor and preparation and application thereof - Google Patents

Abstract

The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a FGFR4 inhibitor and its preparation and application. The FGFR4 inhibitor is shown in general formula I, has good FGFR4 inhibitory activity and high FGFR4 selectivity, and can be used to treat malignant tumors closely related to this kinase.

Description

A FGFR4 inhibitor and its preparation and application

Technical Field

The present invention belongs to the field of pharmaceutical chemistry, and specifically relates to a FGFR4 inhibitor and a preparation and application thereof.

Background Art

FGFR (fibroblast growth factor receptor) is a receptor-type protein tyrosine kinase, including different subtypes such as FGFR1, FGFR2, FGFR3, and FGFR4. Each subtype has the structural characteristics of the extracellular region that binds to the ligand, the transmembrane region, and the intracellular region of the receptor phosphorylation. It is part of the tyrosine kinase signaling pathway responsible for cell proliferation and differentiation. They play a key role in maintaining cell growth, proliferation, apoptosis, migration, etc. by forming a ternary complex with 18 different fibroblast growth factors (FGF). FGFR molecular changes lead to abnormal FGF/FGFR signals, which promote cell proliferation, new angiogenesis, invasion, metastasis, anti-apoptosis, etc., and thus participate in a wide range of human malignancies.

Existing studies have found (Clin Cancer Res (2015) 21 (12): 2684-2694) that FGFR mutation subtypes are not the same in different cancers. For example, FGFR1 abnormalities are closely related to non-small cell lung cancer, FGFR2 abnormalities are closely related to gastric cancer, and FGFR3 abnormalities are significantly correlated with bladder cancer. J. Med. Chem. 2019, 62, 2905-2915 reported that the FGF19/FGFR4 signaling pathway promotes the survival, proliferation, invasion and metastasis of hepatocellular carcinoma cells through multiple pathways. J.Clin.Oncol.2015,33(30),3401-3408 and J.Clin.Oncol.2017,35(2),157-165 reported non-selective FGFR inhibitors JNJ-42756493 and BGJ398, respectively. Due to the lack of selectivity for FGFR subtypes, they inhibited FGFR1 and FGFR3, resulting in blocking FGF23-mediated signals and interfering with normal phosphate metabolism, thereby causing hyperphosphatemia side effects (Nat.Rev.DrugDiscovery 2016,15(1),51-69). Therefore, it is necessary to design an inhibitor that only exhibits high inhibitory activity against FGFR4 and does not affect the activity of other FGFR1-3 subtypes, thereby improving the targeting of tumor drugs, reducing drug toxicity and side effects, and improving medication compliance.

Summary of the invention

One object of the present invention is to provide a highly selective FGFR4 inhibitor as shown in general formula I. The 3-substituted ethynylbenzamide compounds shown in general formula I have good FGFR4 inhibitory activity and high FGFR4 selectivity, and can be used to treat malignant tumors closely related to this kinase.

Another object of the present invention is to provide a method for preparing the compound of general formula I of the present invention.

Another object of the present invention is to provide a composition comprising a compound of the general formula I of the present invention and a pharmaceutically acceptable carrier, and a composition comprising a compound of the general formula I of the present invention and one or more other drugs.

Another object of the present invention is to provide a method for treating and/or preventing FGFR4-related diseases using the compounds of general formula I of the present invention, as well as the use of the compounds of general formula I of the present invention in the preparation of drugs for treating and/or preventing FGFR4-related diseases.

To achieve the above purpose, the present invention provides the following technical solutions:

In a first aspect, the present invention provides a compound represented by general formula I,

in,

R ₁ is selected from hydrogen or C _1-6 alkyl;

_R2 is selected from hydrogen or _C1-6 alkyl.

In some preferred embodiments, R ₁ is selected from hydrogen or methyl.

In some preferred embodiments, _R2 is selected from hydrogen or methyl.

In a second aspect, the present invention provides the following compounds:

In a second aspect, the present invention provides a method for preparing a compound of formula I, the method comprising:

(1) the compound of formula (1) reacts with the compound of formula (2) to produce the compound of formula (3);

(2) the compound of formula (4) reacts with the compound of formula (5) to generate the compound of formula (6);

(3) the compound of formula (3) reacts with the compound of formula (6) to form a compound of formula (7);

(4) hydrolyzing the compound of formula (7) to obtain the compound of formula (8);

(5) the compound of formula (8) is subjected to condensation reaction with the compound of formula (9) to obtain the compound of formula (10); (6) the compound of formula (10) is reduced to obtain the compound of formula (11);

(7) The compound of formula (11) is reacted with enoyl chloride to obtain the compound of formula (I). The reaction scheme is as follows:

In a third aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective dose of a compound of formula (I) and a pharmaceutically acceptable carrier.

In a fourth aspect, the present invention relates to the use of a compound of general formula (I) in the preparation of drugs for treating or preventing FGFR4-related diseases, especially in the preparation of drugs for treating and preventing liver cancer.

Explanation of terms

The "alkyl" mentioned in the present invention refers to a straight-chain or branched saturated hydrocarbon group, preferably a C _1-6 alkyl group, more preferably a C _1-3 alkyl group, and a suitable C _1-3 alkyl group is methyl, ethyl, propyl or isopropyl.

The "pharmaceutical composition" of the present invention refers to a mixture comprising any of the compounds described herein and one or more pharmaceutically acceptable carriers and/or excipients. The purpose of the pharmaceutical composition is to facilitate the administration of the compound to an organism. The composition is generally used to treat and/or prevent diseases mediated by FGFR.

DETAILED DESCRIPTION

A method for preparing the above-mentioned phenylacetylene compounds targeting FGFR4, the steps are as follows: Example 1: Preparation of 3-((2-((2-acrylamido-6-methylphenyl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

Synthesis of Methyl 3-Ethynyl-4-Methylbenzoate

Under ice bath conditions, methyl 3-iodo-4-methylbenzoate (4g, 14.5mmol) was dissolved in N, N-dimethylformamide (15ml), bis(triphenylphosphine)palladium dichloride (0.2g, 0.28mmol) and cuprous iodide (0.275g, 1.44mmol) were added, triethylamine solution (4.39g, 43.46mmol) was added dropwise, the system was replaced with nitrogen 3 times, ethynyltrimethylsilane was slowly added dropwise under ice bath conditions, the ice bath was removed after stirring for 10 minutes, the reaction mixture was reacted at room temperature for 2h, and then tetrabutylammonium fluoride (10% tetrahydrofuran solution, 4.6g, 17.6mmol) was added thereto. The reaction was stirred at room temperature for 30min. TLC monitoring showed that the reaction was complete. The reaction mixture was cooled to room temperature, and 100 ml of ethyl acetate was slowly added to quench the reaction. The reaction solution was filtered through diatomaceous earth to obtain a mother liquor. Water was added to the filtrate for extraction (100 ml × 3). The organic layers were combined, washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and concentrated to obtain a solid. The residue was purified by silica gel column chromatography to obtain 2.3 g of a white solid compound with a yield of 91%.

Synthesis of 5-iodo-N-(2-methyl-6-nitrophenyl)pyrimidin-2-amine

Under ice bath conditions, weigh 2-amino-5-iodopyrimidine (3 g, 13.57 mmol) into a flask, add DMF and stir to make it evenly dispersed, react for 20 minutes, then slowly add 2-fluoro-3-nitrotoluene (2.74 g, 17.67 mmol) dropwise into the reaction flask, stir for 5 minutes, and react at 60°C for 2 hours. After the reaction is completed, cool to room temperature, add the reaction system to water, extract twice with ethyl acetate, combine the organic layers and wash with saturated brine, then dry over anhydrous sodium sulfate, remove the solvent under reduced pressure, concentrate and purify by silica gel column chromatography to obtain 3.8 g of light yellow solid compound with a yield of 78%.

Synthesis of methyl 4-methyl-3-(2-(2-methyl-6-nitrophenyl)amino)pyrimidin-5-yl)ethynyl)benzoate

The compounds methyl 3-ethynyl-4-methylbenzoate (2 g, 11.5 mmol), 5-iodo-N-(2-methyl-6-nitrophenyl)pyrimidin-2-amine (2.72 g, 7.66 mmol), bis(triphenylphosphine)palladium dichloride (0.12 g, 1.17 mmol) and cuprous iodide (0.33 g, 1.7 mmol) were weighed in sequence, put into a 250 mL reaction bottle, 15 mL of dry DMF solution was added to dissolve it, triethylamine solution (2.67 g, 26.4 mmol) was dropped into it, the system was replaced with nitrogen three times, and then reacted at room temperature for 2 h under nitrogen protection. TLC monitoring until the raw material reaction is complete, add 150ml of ethyl acetate to quench the reaction, the reaction solution is filtered through diatomaceous earth to obtain the mother liquor, water is added to the filtrate for extraction (150ml×3), the organic layers are combined, the organic layers are washed with saturated brine, and then dried over anhydrous sodium sulfate, the solvent is removed under reduced pressure, and the solid is concentrated. The residue is purified by silica gel column chromatography to obtain 2.6g of yellow solid compound with a yield of 56%. Synthesis of 4-methyl-3-(2-(2-methyl-6-nitrophenyl)amino)pyrimidin-5-yl)ethynyl)benzoic acid

In a 250 mL reaction bottle, methyl 4-methyl-3-(2-(2-methyl-6-nitrophenyl)amino)pyrimidin-5-yl)ethynyl)benzoate (2.6 g, 6.5 mmol), potassium hydroxide (2.21 g, 39.5 mmol), 15 ml of ethanol and 3 mL of water were added in sequence, and the reaction was carried out at 60°C for 1 h. TLC was monitored until the reaction was complete, and the solvent was removed under reduced pressure. 4 mol/L hydrochloric acid was slowly added to the residue under ice bath conditions to adjust the pH. After stirring for 5 min, a brown solid was precipitated, which was filtered and dried to obtain the target compound. Purification by silica gel column chromatography gave 2 g of a yellow solid compound with a yield of 79.7%. Synthesis of 4-methyl-3-(2-(2-methyl-6-nitrophenyl)amino)pyrimidin-5-yl)ethynyl)-N-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

To a 250 mL reaction bottle, compound 4-methyl-3-(2-(2-methyl-6-nitrophenyl)amino)pyrimidin-5-yl)ethynyl)benzoic acid (1.9 g, 4.89 mmol), HATU (2.23 g, 5.87 mmol) and 15 mL of dry DMF were added in sequence, DIEA (1.26 g, 9.76 mmol) was slowly added dropwise, and stirred at room temperature for 1 h. 4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline was added, and the reaction temperature was raised to 60 ° C for 5 h. TLC was monitored until the reaction of the raw material was complete, 150 mL of water was added to quench the reaction, and ethyl acetate (150 mL×3) was used for extraction. The organic phases were combined, washed with saturated NaCl in sequence, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 2.5 g of a light yellow solid compound with a yield of 79.4%.

Synthesis of 3-((2-((2-amino-6-methylphenyl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

To a 250 mL reaction bottle was added the compound 4-methyl-3-(2-(2-methyl-6-nitrophenyl)amino)pyrimidin-5-yl)ethynyl)-N-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (2.5 g, 3.88 mmol), iron powder (1.09 g, 19.46 mmol), ammonium chloride (1.05 g, 19.44 mmol), 15 mL of ethanol and 3 mL of water. The mixture was heated under reflux at 90 °C for 1 h and monitored by TLC until the reaction was complete. The reaction solution was filtered through diatomaceous earth while hot to obtain a mother liquor. The solvent was removed under reduced pressure, and saturated sodium carbonate, water and ethyl acetate (100 mL×3) were added for extraction. The organic phases were combined, dried over anhydrous sodium sulfate, and the residue was purified by silica gel column chromatography to obtain 600 mg of the compound as a light yellow solid in a yield of 25.2%.

Synthesis of 3-((2-((2-acrylamido-6-methylphenyl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide

Compound 3-((2-((2-amino-6-methylphenyl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide (300 mg, 0.48 mmol) was placed in a 25 mL reaction bottle, 10 mL of dry DCM and triethylamine (98 mg, 0.97 mmol) were added, and the mixture was protected by nitrogen. Stirring was carried out under ice-salt bath for 10 min, and a solution of acryloyl chloride (88 mg, 0.97 mmol) in dichloromethane (1 mL) was slowly added dropwise. The raw material was monitored by TLC until the reaction was complete. 2 mL of ice water was added to quench the reaction, and the product was extracted with ethyl acetate (20 mL×3), washed with saturated sodium carbonate and saturated NaCl in turn, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography to obtain 80 mg of white powder with a yield of 14.7%. ¹ H NMR (600 MHz, DMSO-d ₆ )δ10.51(s,1H),9.49(s,1H),8.82(s,1H),8.57(s,2H),8.20(d,J＝2.2Hz,1H),8.12(d,J＝2.0Hz,1H),8.06(m,1H),7.90(m,1H),7.70(d,J＝8.6Hz,2H) ,7.50(d,J＝8.1Hz,1H),7.20(m,1H),7.12-7.07(m,1H),6.53(m,1H),6.23(m,1H),5.71(m,1H),3.56(s,2H),2.52(s,3H),2.47-2.24(m,8H),2.16( s,3H),2.14(s,3H). ¹³ CNMR (151MHz, DMSO-d ₆ )165.15,163.91,160.22,143.87,138.64,137.13,135.39,132.61,132.53,132.28,131.67,130.74,130.37,128.47,127.72, 127.30,126.97,126.76,123.95,122.75,117.73,107.86,90.94,89.65,57.92,55.15,53.13,46.14,20.87,18.84.

Example 2: Preparation of 3-(2-(2-(2-chloroacetamide)-6-methylphenyl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

The operation was the same as in Example 1, and 83 mg of a white solid was obtained by column chromatography. ¹ H NMR (600MHz, DMSO-d ₆ ) δ10.49 (s, 1H), 9.39 (s, 1H), 8.97 (s, 1H), 8.58 (m, 2H), 8.20 (d, J = 2.2Hz, 1H), 8.13 (d, J = 2.0Hz, 1H), 8.06 (m, 1H), 7.90 (m, 1H), 7 .71(m,2H),7.49(d,J＝8.1Hz,1H),7.21(t,J＝7.9Hz,1H),7.15-7.09(m,1H),4.29(s,2H),3.57(s,2H),2.53(s,3H),2.38-2.36(m,8H),2.20(s,3H),2 .16(s,3H). ¹³ C NMR (151MHz, DMSO-d ₆ )165.19,160.74,160.29,143.87,138.67,137.01,135.06,132.64,132.47,131.72,130.79,130.37,128.46,128.02,127.82,127 .12,126.92,123.98,123.58,123.18,122.76,121.07,117.82,116.09,108.04,91.01,89.57,57.88,55.05,52.90,45.89,43.75,20.84,18.68.

Example 3: Preparation of (E)-3-(2-((2-(2-(4-(dimethylamino)but-2-enamido)-6-methylphenyl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

The operation was the same as in Example 1, and 60 mg of white powder was obtained by column chromatography. ¹ H NMR (600 MHz, DMSO-d ₆ )δ10.60(s,1H),9.60(s,1H),8.91(s,1H),8.57(s,2H),8.24(d,J＝2.2Hz,1H),8.14(d,J＝2.0Hz,1H),8.09(m,1H),7.93(m,1H),7.71(t,J＝8.7Hz,2H),7.49(d,J＝8 .1Hz,1H),7.19(t,J＝7.8Hz,1H),7.11-7.06(m,1H),6.73(m,1H),6.42(m,1H),3.59(s,2H),3.15-3.10(m,2H),2.53(s,3H),2.28(s,3H),2.22(s,6 H),2.14(s,3H). ¹³ C NMR(151MHz,DMSO-d ₆ )δ165.18,163.86,160.64,160.18,143.84,140.83,138.74,137.12,135.47,132.57,132.27,131.69,130.80,130.35,129.71,128.48,127.98,1 27.78,127. 04,126.82,126.72,125.70,123.99,123.89,122.76,121.48,117.79,117.75,107.85,90.93,89.64,59.81,57.74,54.72,52.41,45.38,45.21, 20.86,18.85.

Example 4: Preparation of 4-methyl-3-((2-((2-methyl-6-propionamidophenyl)amino)pyrimidin-5-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

The operation was the same as in Example 1, and 78 mg of white powder was obtained by column chromatography. ¹ H NMR (600 MHz, DMSO-d ₆ )δ10.51(s, 1H),9.21(s, 1H),8.75(s, 1H),8.57(s, 2H),8.20(d, J＝2.2Hz, 1H),8.12(d, J＝2.0Hz, 1H),8.05(m, 1H),7.90(m, 1H),7.70(d, J＝8.5Hz, 1H),7.58(d, J＝8.1Hz, 1H),7.72(d, J＝8.0Hz, 1H),7.62(d, J＝8.1Hz, 1H),7. .50(d,J＝8.1Hz,1H),7.16(t,J＝7.8Hz,1H),7.06(d,J＝7.6Hz,1H),3.56(s,2H),2.53(s,3H),2.50-2.32(m,8H),2.29(m,2H),2.16(s,3H),2.14(s,3 H),1.01(t,J＝7.5Hz,3H). ¹³ CNMR(151MHz,DMSO-d ₆ )δ174.21,172.70,165.14,160.65,160.16,143.83,138.65,137.01,135.54,132.61,132.48,131.66,130.74,130.35,128.45,127.96,127.76,1 26.67,126.61,125.71,123.93,122.75,121.57,117.73,107.82,90.93,89.64,57.90,55.13,53.05,46.05,20.86,18.84,17.69,10.25.

Example 5: Preparation of 3-((2-((2-acrylamidophenyl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

The operation was the same as in Example 1, and 50 mg of white powder was obtained by column chromatography. ¹ H NMR (600 MHz, DMSO-d ₆ )δ10.51(s,1H),9.84(s,1H),9.10(s,1H),8.65(s,2H),8.21(d,J＝2.2Hz,1H),8.14(d,J＝2.0Hz,1H),8.06(m,1H),7.91(m,1H),7.74-7.68(m,2H),7. 64-7.57(m,1H),7.51(d,J＝8.1Hz,1H),7.20(m,2H),6.52(m,1H),6.29(m,1H),5.81-5.74(m,1H),3.57(s,2H),2.54(s,3H),2.45-2.22(m,8H),2. 16(s,3H). ¹³ C NMR (151 MHz, DMSO-d ₆ )δ165.13,164.24,160.59,159.31,143.87,138.66,132.65,132.53,131.99,131.68,131.15,130.83,130.36,128.52,128.00,127.80,127.59,1 25.73,125.59,125.55,124.97,123.95,123.91,122.67,117.79,117.74,108.83,91.28,89.42,57.94,55.18,53.12,46.11,20.86.

Example 6: Preparation of 3-((2-((2-acrylamide-6-methylphenyl)amino)pyrimidin-5-yl)ethynyl)-4-methoxy-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

The operation was the same as in Example 1, and 120 mg of white powder was obtained by column chromatography. ¹ H NMR (600MHz, DMSO-d ₆ ) δ10.42 (s, 1H), 9.51 (s, 1H), 8.80 (s, 1H), 8.52 (s, 2H), 8.17 (m, 2H), 8.04 (m, 2H), 7.70 (t, J = 7.5Hz, 2H), 7.25 (d, J = 8.8Hz, 1H), 7 .19(t,J＝7.8Hz,1H),7.10(d,J＝7.6Hz,1H),6.54(m,1H),6.23(m,1H),5.7 7-5.69(m,1H),3.94(s,3H),3.56(s,2H),2.36(s,8H),2.16(s,3H),2.14(s ,3H). ¹³ C NMR (151 MHz, DMSO-d ₆ )δ164.76,163.93,162.43,160.55,160.10,138.76,137.12,135.36,132.73,132.33,131.65,130.93,129.84,127.93,127.74,127.54,127.31,1 26.98,126.88,126.74,125.73,123.88,121.52,117.67,111.74,111.58,108.09,89.08,88.80,57.92,56.69,55.17,53.12,46.13,18.84.

Example 7: Preparation of 3-((2-((2-acrylamide-6-methylphenyl)amino)pyrimidin-5-yl)ethynyl)-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

The operation was the same as in Example 1, and 130 mg of white powder was obtained by column chromatography. ¹ H NMR (600 MHz, DMSO-d ₆ )δ10.57(s,1H),9.48(s,1H),8.75-8.82(m,1H),8.55(s,2H),8.21(d,J＝2.3Hz,1H),8.13(d,J＝1.8Hz,1H),8.05(m,1H),7.98(m,1H),7.76-7.67(m, 3H),7.60(t,J＝7.8Hz,1H),7.19(t,J＝7.8Hz,1H),7.10(d,J＝7.5Hz,1H),6.53(m,1H),6.22(m,1H),5.71(m,1H),3.57(s,2H),2.37(m,8H),2.17(s,3 H),2.14(s,3H). ¹³ CNMR (151MHz, DMSO-d ₆ )δ165.29,163.93,160.76,160.15,138.64,137.12,135.36,135.33,134.63,132.41,132.30,131.74,130.51,129.80,129.58,128.51,128.00,1 27.81,127.30,126.98,126.75,123.98,123.86,122.96,121.55,117.78,107.62,92.10,85.93,57.73,54.75,52.43,45.40,18.85.

Example 8: Preparation of 5-((2-((2-acrylamide-6-methylphenyl)amino)pyrimidin-5-yl)ethynyl)-2-methyl-N-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

The operation was the same as in Example 1, and 100 mg of white powder was obtained by column chromatography. ¹ H NMR (600 MHz, DMSO-d ₆ )δ10.61(s,1H),9.47(s,1H),8.70-8.79(m,1H),8.51(s,2H),8.18(d,J＝2.3Hz,1H),7.95(m,1H),7.74-7.61(m,3H),7.54(m,1H),7.37(d,J＝8.1Hz, 1H),7.19(t,J＝7.8Hz,1H),7.12-7.04(m,1H),6.52(m,1H),6.22(m,1H),5.76-5.64(m,1H),3.57(s,2H),2.41(s,3H),2.40-2.31(m,8H),2.21(s,3 H),2.13(s,3H). ¹³ CNMR (151MHz, DMSO-d ₆ )δ167.47,163.92,160.65,160.09,138.67,137.29,137.12,136.95,135.34,132.72,132.43,132.29,131.82,131.73,130.40,128.07,127.31,1 26.96,126.74,125.66,123.84,123.45,121.52,120.15,117.15,113.37,107.84,92.15,85.32,57.80,54.95,52.74,45.75,19.84,18.84.

Example 9: Preparation of 4-((2-((2-acrylamide-6-methylphenyl)amino)pyrimidin-5-yl)ethynyl)-3-methyl-N-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

The operation was the same as in Example 1, and 77 mg of white powder was obtained by column chromatography. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.78 (d, J = 4.2 Hz, 1H), 9.91 (s, 1H), 9.02 (s, 1H), 8.56 (s, 2H), 8.29 (d, J = 2.2 Hz, 1H), 8.14 (m, 1H), 8.03 (d, J = 1.8 Hz, 1H), 7.90 (m, 1H), 7.69 (t, J = 9.7 Hz, 2H), 7.61 ( d,J＝8.0Hz,1H),7.19(t,J＝7.8Hz,1H),7.10(d,J＝7.6Hz,1H),6.59(m,1H),6.24(m,1H),5.71(m,1H),3.61(s,2H),2.70(s,3H),2.53(s,8H),2.43(s ,3H),2.13(s,3H).

Example 10: Preparation of (E)-3-((6-((2-(4-(dimethylamino)but-2-enamido)-6-methylphenyl)amino)pyridin-3-yl)ethynyl)-N-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

The same operation as in Example 1 was followed by column chromatography to obtain 101 mg of white powder. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.60 (s, 1H), 9.50 (s, 1H), 8.52-8.40 (m, 1H), 8.22 (d, J = 2.3 Hz, 2H), 8.12 (s, 1H), 8.06 (m, 1H), 7.97 (m, 1H), 7.74 (d, J = 8.2 Hz, 1H), 7.71 (m, 2H), 7.63 (m, 1H), 7.57 (t, J = 7.8H z,1H),7.17(t,J＝7.8Hz,1H),7.08(d,J＝7.5Hz,1H),6.68(m,1H),6.47(s,1H),6.37-6.31(m,1H),3.57(s,2H),3.00(m,2H),2.37(m,8H),2.16(s,3H) ),2.14(s,6H),2.13(s,3H). ¹³ C NMR(151MHz,DMSO-d ₆ )δ165.24,163.91,157.30,151.37,143.68,141.41,140.12,138.69,136.92,135.70,132.56,132.41,131.69,130.59,130.44,130.30,128.11,1 27.97,127.7 8,126.95,126.66,126.50,125.71,123.96,123.90,123.20,121.59,117.77,117.72,108.27,92.96,88.24,60.02,57.85,55.01,52.87,49.06, 45.43,18.83.

Example 11: Preparation of (E)-3-((2-(2-(but-2-enamido)-6-methylphenyl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

The same operation as in Example 1 was performed and 88 mg of white powder was obtained by column chromatography. ¹ H NMR (600 MHz, DMSO-d ₆ )δ10.54(s,1H),9.37(s,1H),8.81(s,1H),8.57(s,2H),8.22(d,J＝2.2Hz,1H),8.13(d,J＝2.0Hz,1H),8.08(m,1H),7.91(m,1H),7.69(m,2H),7.50(d ,J＝8.1Hz,1H),7.18(t,J＝7.8Hz,1H),7.10-7.05(m,1H),6.78(m,1H),6.24(m,1H),3.58(s,2H),2.51-2.53(s,3H),2.45(s,8H),2.29(s,3H),2.13( s,3H),1.84(m,3H). ¹³ C NMR (151 MHz, DMSO-d ₆ )δ172.45,165.16,164.24,160.67,160.17,143.86,140.47,138.72,137.12,135.55,132.59,132.28,131.72,130.75,130.37,129.69,128.46,1 27.99,127.79,126.75,126.35,125.70,123.96,122.75,121.37,117.77,107.86,90.94,89.66,57.74,54.76,52.45,45.41,20.87,18.85,17.9 2.

Example 12: Preparation of 3-((2-((2-acrylamide-4-methylphenyl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

The same operation as in Example 1 was performed and 65 mg of white powder was obtained by column chromatography. ¹ H NMR (600 MHz, DMSO-d ₆ )δ10.49(s,1H),9.76(s,1H),8.98(s,1H),8.61(s,2H),8.20(s,1H),8.14(d,J＝2.0Hz,1H),8.06(m,1H),7.91(m,1H),7.70(d,J＝8.5Hz,1H),7.56(d ,J＝8.2Hz,1H),7.50(d,J＝8.1Hz,1H),7.43(s,1H),7.03(m,1H),6.51(m,1H),6.27(m,1H),5.76(m,1H),3.57(s,2H),2.54(s,3H),2.40(s,8H),2.3 1(s,3H),2.18(s,3H). ¹³ C NMR (151 MHz, DMSO-d ₆ )δ165.14,164.16,160.57,159.45,143.85,138.67,134.37,132.63,132.48,132.03,131.69,131.14,130.81,130.35,129.32,128.49,128.00,1 27.80,127.49,126.24,125.65,125.17,123.95,122.71,117.79,117.75,108.54,91.19,89.50,57.91,55.10,53.00,45.98,21.05,20.85.

Example 13: Preparation of 3-((6-((2-acrylamide-6-methylphenyl)amino)pyridin-3-yl)ethynyl)-4-methyl-N-(4-(4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

The same operation as in Example 1 was followed by column chromatography to obtain 110 mg of white powder. ¹ H NMR (600 MHz, DMSO-d ₆ )δ10.49 (s, 1H), 9.53 (s, 1H), 8.35 (s, 1H), 8.27-8.19 (m, 2H), 8.10 (d, J＝2.0 Hz, 1H), 8.06 (m, 1H), 7.90-7.86 (m, 1H), 7.73 (d, J＝8.1 Hz, 1H), 7.69 (d, J＝8.5 Hz, 1H), 7.65 (m, 1H), 7.47 (d,J＝8.0Hz,1H),7.19(t,J＝7.8Hz,1H),7.10(d,J＝7.6Hz,1H),6.55-6.41(m,2H),6.20(m,1H),5.69(m,1H),3.56(s,2H),2.51(s,3H),2.43-2.23(m, 8H),2.16(s,3H),2.14(s,3H). ¹³ C NMR(151MHz,DMSO-d ₆ )δ165.22,163.88,157.26,151.34,143.64,140.08,138.69,136.97,135.47,132.58,132.49,132.43,131.65,130.61,130.26,128.12,127.97,12 7.77,127.04,126.43,125.73,123.98,123.92,123.20,121.68,117.81,117.77,108.34,92.95,88.28,57.95,55.20,53.17,46.16,20.85,18.8 6.

Example 14: Preparation of (E)-3-((2-(2-(4-(dimethylamino)but-2-enamido)-6-methylphenyl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)phenyl)benzamide;

The same operation as in Example 1 was followed by column chromatography to obtain 100 mg of white powder. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.30-10.24 (m, 1H), 9.56 (s, 1H), 8.88 (s, 1H), 8.55 (s, 2H), 8.10 (d, J = 2.0 Hz, 1H), 7.94-7.87 (m, 1H), 7.77-7.64 (m, 3H), 7.46 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.2 Hz, 2H), 7 .18(t,J＝7.8Hz,1H),7.07(d,J＝7.5Hz,1H),6.71(m,1H),6.38(m,1H),3.41(s,2H),3.02(d,J＝6.1Hz,2H),2.51(s,3H),2.33(m,8H),2.15(s,6H),2. 14(s,3H),2.13(s,3H). ¹³ C NMR (151MHz, DMSO-d ₆ ) δ164.81,164.01,160.61,160.18,143.40,141.85,138.36,137.11,135.50,134.05,133.16,130.82,130.22,129.79,129.4 6,128.40,126.79,126.67,126.41,122.69,121.51,120.72,107.94,91.05,89.53,62.16,60.19,55.23,52.98,46.20,45.60,20.82,18.84.

Example 15: Preparation of (E)-3-((2-(2-(4-(dimethylamino)but-2-enamido)-6-methylphenyl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(4-(morpholinomethyl)phenyl)benzamide;

The same operation as in Example 1 was followed by column chromatography to obtain 90 mg of white powder. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.31 (t, J = 3.6 Hz, 1H), 9.70-9.57 (m, 1H), 8.96-8.86 (m, 1H), 8.55 (s, 2H), 8.11 (d, J = 1.9 Hz, 1H), 7.92 (m, 1H), 7.72 (m, 3H), 7.46 (d, J = 8.1 Hz, 1H), 7.27 (d, J = 8.4 Hz, 2H), 7.17 (t,J＝7.8Hz,1H),7.07(d,J＝7.1Hz,1H),6.71(m,1H),6.39(m,1H),3.57(t,J＝4.6Hz,4H),3.43(s,2H),3.02(m,2H),2.51(s,3H),2.35(t,J＝4.7Hz,4H) ,2.15(s,6H),2.13(s,3H). ¹³ C NMR (151MHz, DMSO-d ₆ ) δ164.83,164.00,160.61,160.15,143.41,141.84,138.47,137.10,135.47,133.50,133.13,130.84,130.22,129.81,129.5 8,128.42,126.79,126.65,126.41,122.69,121.55,120.74,107.93,91.05,89.53,66.69,62.54,60.19,53.61,45.60,20.81,18.85.

Example 16: Preparation of (E)-3-(2-((2-(2-(4-(dimethylamino)but-2-enamido)-6-methylphenyl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(4-(4-methylpiperazin-1-yl)phenyl)benzamide;

The same operation as in Example 1 was followed by column chromatography to obtain 70 mg of white powder. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ10.14 (s, 1H), 9.71 (s, 1H), 8.95 (s, 1H), 8.55 (s, 2H), 8.13-8.07 (m, 1H), 7.94-7.88 (m, 1H), 7.68 (d, J＝8.1 Hz, 1H), 7.64 (d, J＝8.7 Hz, 2H), 7.45 (d, J＝8.0 Hz, 1H), 7.17 (t, J＝7.8 Hz, 1H), 7.70 (d, J＝7.9 Hz, 2H), 7. .07(d,J＝7.6Hz,1H),6.91(d,J＝8.7Hz,2H),6.71(m,1H),6.39(m,1H),3.32(s,3H),3.10(t,J＝4.9Hz,4H),3.02(d,J＝6.0Hz,2H),2.46(s,4H),2.22(s ,3H),2.14-2.17(s,6H),2.13(s,3H). ¹³ C NMR (151MHz, DMSO-d ₆ ) δ164.30,164.00,160.60,160.12,148.01,143.11,141.80,137.10,135.43,133.30,131.43,130.75,130.16,129.92,129.8 5,128.31,126.80,126.61,126.44,122.63,122.04,115.88,107.95,91.11,89.43,60.19,55.12,48.98,46.24,45.60,20.79,18.86.

Example 17: Preparation of (E)-N-(4-((1H-1,2,4-triazol-1-yl)methyl)phenyl)-3-((2-(2-(4-(dimethylamino)but-2-enamido)-6-methylphenyl)amino)pyrimidin-5-yl)ethynyl)-4-methylbenzamide;

The same operation as in Example 1 was followed by column chromatography to obtain 86 mg of white powder. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.36 (d, J = 7.1 Hz, 1H), 9.58 (t, J = 9.2 Hz, 1H), 8.89 (d, J = 9.3 Hz, 1H), 8.65 (s, 1H), 8.55 (s, 2H), 8.11 (d, J = 2.0 Hz, 1H), 7.97 (s, 1H), 7.91 (m, 1H), 7.79 (m, 2H), 7.70 (d, J = 8.1 Hz, 1H), 7.47 (d ,J＝8.0Hz,1H),7.29(d,J＝8.4Hz,2H),7.18(t,J＝7.8Hz,1H),7.08(d,J＝7.5Hz,1H),6.71(m,1H),6.38(m,1H),5.39(s,2H),3.02(d,J＝4.3Hz,2H),2.51 (s,3H),2.14-2.16(s,6H),2.14(s,3H). ¹³ C NMR (151MHz, DMSO-d ₆ ) δ164.94,164.02,160.62,160.18,152.11,144.53,143.53,141.86,139.33,137.11,135.50,132.97,131.86,130.83,130.2 5,129.79,128.76,128.44,126.79,126.67,126.40,122.71,121.52,121.02,107.92,91.01,89.56,60.18,52.28,45.60,20.82,18.84.

Example 18: Preparation of 3-(2-((2-(2-(cyclopropanecarboxamido)-6-methylphenyl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

The same operation as in Example 1 was performed and 102 mg of white powder was obtained by column chromatography. ¹ H NMR (600 MHz, DMSO-d ₆ )δ10.58-10.50 (m, 1H), 9.73-9.54 (m, 1H), 8.80 (d, J=6.2 Hz, 1H), 8.57 (s, 2H), 8.22 (s, 1H), 8.14 (s, 1H), 8.07 (d, J=8.7 Hz, 1H), 7.92 (m, 1H), 7.69 (d, J=8.5 Hz, 1H), 7.59 (d, J=8.2 Hz, 1H),7.49(d,J＝8.0Hz,1H),7.15(t,J＝7.8Hz,1H),7.06(d,J＝7.6Hz,1H),3.56(s,2H),2.53(s,3H),2.36(m,8H),2.15-2.19(m,6H),1.89(s,1H),0.83 -0.77(m,2H),0.70-0.77(m,2H). ¹³ C NMR (151MHz, DMSO-d ₆ )δ172.49,165.17,160.66,160.22,143.82,138.69,137.10,135.61,132.64,132.53,131.66,130.81,130.33,129.67,128.47,127.98,127.79,1 26. 67,126.57,125.74,123.99,123.92,122.79,121.45,117.82,117.78,107.90,90.96,89.66,57.96,55.21,53.17,46.16,20.85,18.84,14.75,7 .70.

Example 19: Preparation of (E)-3-(2-((2-(2-(4-(dimethylamino)but-2-enamido)-6-methylphenyl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(3-methyl-4-(4-methylpiperazine-1-carbonyl)phenyl)benzamide;

The same operation as in Example 1 was followed by column chromatography to obtain 60 mg of white powder. ¹ H NMR (600 MHz, DMSO-d ₆ )δ10.30(d, J＝6.5 Hz, 1H),9.43(s, 1H),8.82(s, 1H),8.56(s, 2H),8.10(s, 1H),7.89(d, J＝8.0 Hz, 1H),7.69(m, 3H),7.48(d, J＝8.2 Hz, 1H),7.18(t, J＝7.9 Hz, 1H),7.13(d, J＝8.2 Hz, 1 H),7.08(d,J＝7.6Hz,1H),6.71(m,1H),6.37(m,1H),3.65(s,2H),3.16(s,2H),3.02(d,J＝6.0Hz,2H),2.52(s,3H),2.36(s,2H),2.22(s,5H),2.19(s ,3H),2.15(s,6H),2.14(s,3H). ¹³ C NMR(151MHz,DMSO-d ₆ )δ168.87,165.01,163.92,160.62,160.18,143.59,141.38,139.73,137.10,135.49,134.76,132.94,132.10,130.79,130.27,129.66,128.42,1 26.78,126.71,126.68,122.70,122.10,121.43,118.07,107.86,90.97,89.57,59.98,55.28,54.78,46.02,45.40,20.83,19.40,18.83.

Example 20: Preparation of (E)-3-(2-((2-(2-(4-(dimethylamino)but-2-enamido)-6-methylphenyl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(4-(4-methylpiperazine-1-carbonyl)-3-(trifluoromethyl)phenyl)benzamide;

The same operation as in Example 1 was followed by column chromatography to obtain 88 mg of white powder. ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 10.82 (t, J = 3.0 Hz, 1H), 9.71-9.61 (m, 1H), 8.93 (s, 1H), 8.56 (s, 2H), 8.35 (d, J = 2.1 Hz, 1H), 8.20 (m, 1H), 8.17 (d, J = 2.0 Hz, 1H), 7.98 (m, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.4 Hz, 1H), 7.18 (t,J＝7.8Hz,1H),7.08(d,J＝7.5Hz,1H),6.71(m,1H),6.39(m,1H),3.63(m,2H),3.19-3.12(m,1H),3.10-3.04(m,1H),3.02(m,2H),2.53(s,3H),2.4 0(m,1H),2.34-2.22(m,2H),2.19(s,3H),2.15(s,7H),2.13(s,3H). ¹³ C NMR(151MHz,DMSO-d ₆ )δ166.50,165.44,164.00,160.63,160.16,143.99,141.79,140.50,137.10,135.45,132.41,130.97,130.35,130.04,129.82,128.63,128.59,1 26.80,126.6 4,126.44,126.29,126.08,125.00,124.08,123.54,123.19,122.82,118.09,118.05,107.87,90.92,89.69,60.18,54.62,47.07,46.04,45.59, 20.86,18.85.

Example 21: Preparation of 3-((2-((2-acrylamido-6-chlorophenyl)amino)pyrimidin-5-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

The same operation as in Example 1 was performed and 75 mg of white powder was obtained by column chromatography. ¹ H NMR (600MHz, DMSO-d ₆ ) δ10.48(s,1H),9.59(s,1H),9.03(s,1H),8.59(s,2H),8.19(d,J＝2.3Hz,1H),8.12(d,J＝2.0Hz,1H),8.05(m,1H),7.96(m,1H) ,7.90(m,1H),7.70(d,J＝8.5Hz,1H),7.50(d,J＝8.1Hz,1H),7.35-7.28(m,2H),6.59(m,1H),6.25(m,1H),5.74(m,1H),3.57(s,2H),2.53(s,3H),2. 37(m,8H),2.17(s,3H). ¹³ C NMR (151MHz, DMSO-d ₆ ) δ165.16,164.13,160.54,160.23,143.91,138.67,137.68,133.53,132.67,132.55,132.14,131.71,130.81,130.36,128.5 1,128.41,128.01,12 7.99,127.82,127.77,125.75,125.73,123.97,123.92,122.71,122.32,117.81,117.76,108.56,91.10,89.46,57.94,55.18,53.12,46.11,20. 85.

Example 22: Preparation of (E)-3-((6-((2-(4-(dimethylamino)but-2-enamido)-6-methylphenyl)amino)pyridin-3-yl)ethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide;

The same operation as in Example 1 was followed by column chromatography to obtain 78 mg of white powder. ¹ H NMR (600 MHz, DMSO-d ₆ )δ10.53 (s, 1H), 9.46 (s, 1H), 8.35 (s, 1H), 8.24 (d, J＝2.4 Hz, 1H), 8.23 (s, 1H), 8.11 (d, J＝2.0 Hz, 1H), 8.07 (m, 1H), 7.88 (m, 1H), 7.75 (d, J＝8.0 Hz, 1H), 7.70 (d, J＝8.6 Hz, 1H), 7.65 (m, 1H), 7.48 (d,J＝8.1Hz,1H),7.18(t,J＝7.8Hz,1H),7.12-7.07(m,1H),6.69(m,1H),6.43(s,1H),6.35(m,1H),3.57(s,2H),3.04(m,2H),2.51(s,3H),2.41(s,8H ),2.21(s,3H),2.16(s,6H),2.14(s,3H). ¹³ C NMR(151MHz,DMSO-d ₆ )δ165.24,163.91,157.30,151.37,143.68,141.41,140.12,138.69,136.92,135.70,132.56,132.41,131.69,130.59,130.44,130.30,128.11,1 27.97,127.78,126.95,12 6.66,126.50,125.71,123.96,123.90,123.20,121.59,117.77,117.72,108.27,92.96,88.24,60.02,57.85,55.01,52.87,49.06,45.43,20.85,18.83. Experimental Example 1 FGFR4 kinase inhibition activity test

In a 384-well reaction plate, positive control wells and negative control wells were set up, and different concentrations of compounds and FGFR4 kinase were added to the remaining wells. After centrifugation, the wells were incubated at room temperature for 15 minutes, and fluorescent substrates and ATP were added. After the reaction was completed, the stop solution was added to stop the reaction, and the conversion rate was read using the Caliper EZ reader. The percentage inhibition rate was then calculated using the following formula: Enzyme inhibition rate = Mean (maximum) - sample signal / Mean (maximum) - blank multiplied by 100%. The experimental results are shown in Table 1

Table 1. Inhibition ^rate of compounds on FGFR4 and FGFR1 at 100 and 10 nM concentrationsa

The results showed that except for compounds I-9, I-19, and 1-20, the compounds of the present invention all showed FGFR4 selectivity, especially compound I-7, which had an inhibitory activity of more than 90% on FGFR4 kinase at a concentration of 100 nM, and an inhibitory activity of more than 50% on FGFR4 kinase at a concentration of 10 nM, that is, its FGFR4 inhibition IC ₅₀ value was 10 nM. At the same time, even at a concentration of 100 nM, it did not show inhibitory activity on FGFR1, indicating that the compound had strong inhibitory activity on FGFR4 and high selectivity, and had excellent application prospects.

Experimental Example 2 Cell proliferation inhibition activity test

The experiment set up a solvent control group and a drug experimental group. Each drug experimental group had 8 concentrations, and 3 parallel wells were set under each concentration. Each experiment was repeated three times. In a 96-well plate, 100 μL of cell suspension with a cell concentration of 1×10 ⁵ /mL was added to each well, that is, each well contained 3×10 ³ cells. When inoculating, pay attention to make the cells evenly distributed in each well. To prevent liquid evaporation, cells were not inoculated in a circle of wells around the 96-well plate, and PBS was added to keep moist. After the cells adhered to the wall, 100 μL of target compounds of different concentrations were added to each well in the drug experimental group. The 96-well plate was placed in an incubator at 37°C and 5% CO2 for continued culture, and the culture was terminated after 72 hours. After the cells were treated with drugs for 72 hours, the 96-well plate was taken out, and the MTT method solution was added to each well. After continuing to incubate in the cell culture incubator for 4 hours, the absorbance value (A) of each well was measured at 570nm on an automatic microplate reader. The inhibition rate was calculated by the formula. The inhibition rate was used for linear regression analysis of drug concentration, and the IC ₅₀ value was calculated using a linear equation. The test results were expressed as mean ± standard deviation, and the experimental results were statistically analyzed using SPSS15.0 software, with P < 0.05 indicating a significant difference. The results are shown in Table 2, indicating that the IC ₅₀ of compounds I-7 and I-21 against Huh-7 cells and Hep3B cells was comparable to that of Ponatinib (purchased from MacLean).

Table 2. Proliferation inhibition activity of compounds on different tumor cell linesa

The results showed that compound I-7 exhibited a strong inhibitory effect on Hep3B and HuH-7 liver cancer cell lines.

Claims (6)

1. A selective FGFR4 inhibitor of formula I,

Wherein,

R ₁ is selected from hydrogen or C _1-6 alkyl;

r ₂ is selected from hydrogen, C _1-6 alkoxy or C _1-6 alkyl.

2. The inhibitor according to claim 1, characterized in that: r ₁ is selected from hydrogen or methyl.

3. The inhibitor according to claim 1, characterized in that: r ₂ is selected from hydrogen, methoxy or methyl.

4. The inhibitor according to any one of claims 1 to 3, wherein the inhibitor is a compound selected from the group consisting of:

5. A pharmaceutical composition comprising the inhibitor of any one of claims 1-3, or the compound of claim 4 and a pharmaceutically acceptable carrier.

6. Use of an inhibitor according to any one of claims 1 to 3, or a compound according to claim 4, or a composition according to claim 5, for the preparation of a medicament for the treatment and/or prophylaxis of tumors.