A pyrimidinequinoxaline CDK inhibitor and its preparation method and application

Abstract

The present invention discloses a pyrimidine quinoxaline CDK inhibitor and a preparation method and application thereof, wherein the compound is shown in formula (S). The compound of the present invention can inhibit the continuous proliferation of cancer cells and can be used to prepare drugs for treating cancer or tumor-related diseases.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceutical chemistry, and in particular to a pyrimidinequinoxaline CDK inhibitor and a preparation method and application thereof. Background Art

[0002] The progression of the cell cycle has a huge impact on cell proliferation. Cyclin-dependent kinases (CDKs) play an important regulatory role in the progression of the cell cycle. Under the induction of carcinogenic factors, CDKs will be upregulated, the progression of the cell cycle will be accelerated, and cancer cells will continue to proliferate, leading to the occurrence of cancer. In recent years, the treatment of cancer by inhibiting the activity of CDKs has attracted widespread attention. CDK2 and CDK6 both play an important regulatory role in the progression of the cell cycle. Therefore, inhibiting CDK2 or CDK6 is an effective cancer treatment strategy. Summary of the invention

[0003] Purpose of the invention: The present invention provides a pyrimidine quinoxaline CDK inhibitor, which inhibits CDK2 or CDK6. The present invention also provides a preparation method and application of the compound.

[0004] Technical solution: The compound of the present invention as shown in formula (S) or a pharmaceutically acceptable salt thereof:

[0005]

[0006] in,

[0007] R1 is selected from hydrogen or NR4R5, wherein R4 and R5 are selected from C1-C3 alkyl;

[0008] R2 is selected from halogen;

[0009] R3 is selected from hydrogen, -C(O)C1-C3 alkyl or -S(O)2R6, wherein R6 is selected from C1-C3 alkyl or C3-C5 cycloalkyl.

[0010] Preferably:

[0011] Said R1 is selected from hydrogen or NR4R5, wherein R4 and R5 are selected from C1-C3 alkyl;

[0012] Said R2 is selected from F;

[0013] The R3 is selected from hydrogen, -C(O)CH3 or -S(O)2R6, wherein R6 is selected from C1-C3 alkyl or cyclopropyl.

[0014] Preferably:

[0015] Said R1 is selected from hydrogen or NR4R5, wherein R4 and R5 are selected from methyl or ethyl;

[0016] Said R2 is selected from F;

[0017] The R3 is selected from hydrogen, -C(O)CH3 or -S(O)2R6, wherein R6 is selected from C1-C3 alkyl or cyclopropyl.

[0018] Preferably:

[0019] Said R1 is selected from hydrogen or NR4R5, wherein R4 and R5 are selected from methyl or ethyl;

[0020] Said R2 is selected from F;

[0021] The R3 is selected from hydrogen, -C(O)CH3 or -S(O)2R6, wherein R6 is selected from methyl, isopropyl or cyclopropyl.

[0022] In some specific embodiments of the present invention, the present invention also provides a compound selected from S-1 to S-44 or a pharmaceutically acceptable salt thereof, selected from the following compounds:

[0023]

[0024]

[0025] The above-mentioned pharmaceutically acceptable salts are acid addition salts of the compound of general formula (S), wherein the acid used for salt formation includes inorganic acids and organic acids, the inorganic acids include: hydrochloric acid, sulfuric acid, phosphoric acid and methanesulfonic acid, and the organic acids include acetic acid, trichloroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid and tartaric acid.

[0026] Preferably, the pharmaceutically acceptable salt described in the present invention is hydrochloride.

[0027] The preparation method of the compound of the general formula (S) of the present invention comprises: preparing compound S by coupling reaction of compound A and compound B under the action of palladium catalyst;

[0028]

[0029] or compound C reacts with compound D under the action of a base to prepare compound S;

[0030]

[0031] R1 is selected from hydrogen or NR4R5, wherein R4 and R5 are selected from C1-C3 alkyl;

[0032] R2 is selected from halogen;

[0033] R3 is selected from hydrogen, -C(O)C1-C3 alkyl or -S(O)2R6, wherein R6 is selected from C1-C3 alkyl or C3-C5 cycloalkyl.

[0034] The present invention also provides a pharmaceutical composition of a compound as described in formula (S) or a pharmaceutically acceptable salt, ester, stereoisomer, solvent compound or prodrug thereof, and a pharmaceutically acceptable carrier.

[0035] A pharmaceutically acceptable carrier refers to an excipient or diluent that does not cause significant irritation to an organism and does not interfere with the biological activity and properties of the administered compound.

[0036] The present invention also provides a use of a compound of formula (S) or a pharmaceutically acceptable salt, ester, stereoisomer, solvent compound or prodrug thereof or the composition of the present invention in preparing a drug.

[0037] The present invention also provides a use of a compound of formula (S) or a pharmaceutically acceptable salt, ester, stereoisomer, solvent compound or prodrug thereof or the composition of the present invention in the preparation of a CDK2 or CDK6 inhibitor; the CDK2 or CDK6 kinase inhibitor is used to treat cancer or tumor-related diseases.

[0038] The use of the compound of the present invention or its pharmaceutically acceptable salt, ester, stereoisomer, solvate or prodrug or the composition of the present invention in the preparation of a drug for treating cancer or tumor-related diseases. The cancer or tumor is a cancer or tumor related to CDK2 or CDK6. Cancer or tumor-related diseases include but are not limited to leukemia, breast cancer, prostate cancer, lung cancer, multiple myeloma, liver cancer, gastric cancer, bone cancer, brain cancer, head and neck cancer, intestinal cancer, pancreatic cancer, bladder cancer, testicular cancer, ovarian cancer, esophageal cancer, liposarcoma, endometrial cancer, etc.

[0039] The compound of the general formula (S) or a pharmaceutically acceptable salt thereof of the present invention has CDK2 or CDK6 target inhibitory activity and has a therapeutic effect on malignant cell proliferation tumors.

[0040] Beneficial effects: The compound represented by the general formula (S) of the present invention can inhibit the malignant proliferation of cancer cells, has good therapeutic effect, low toxicity, good drug metabolism characteristics, and is not prone to drug resistance. It can be used to prepare drugs for treating cancer or tumor-related diseases. DETAILED DESCRIPTION

[0041] The following examples are provided to facilitate a better understanding of the present invention, but are not intended to limit the present invention. The experimental methods in the following examples are conventional methods unless otherwise specified. The test materials used in the following examples are purchased from conventional biochemical reagent stores unless otherwise specified. The present application is described in detail below in conjunction with specific embodiments.

[0042] 1. Synthesis of intermediate reactants

[0043] The specific preparation method of the independently developed intermediate reactant (M) is as follows:

[0044] (1) Synthesis of 6-(2-chloro-5-fluoropyrimidin-4-yl)quinoxaline (M1)

[0045]

[0046] 6-Bromoquinoxaline (4.18 g, 20 mmol) and bis(pyrimidine) (5.58 g, 22 mmol) were dissolved in 1,4-dioxane (100 mL), and then Pd(dppf)Cl2 (731 mg, 1 mmol) and potassium acetate (5.88 g, 60 mmol) were added. The argon atmosphere was replaced three times, and the mixture was heated to 100 °C for 12 h. After the reaction was completed, water was added to quench the mixture, and the mixture was concentrated by evaporation under reduced pressure with ethyl acetate to obtain compound M1-1, which was used directly in subsequent reactions without purification. 2,4-Dichloro-5-fluoropyrimidine (4.01 g, 24 mmol), Pd(PPh3)2Cl2 (702 mg, 1 mmol), sodium carbonate (5.30 g, 50 mmol), water (20 ml) and ethylene glycol dimethyl ether (20 mL) were added to a three-necked flask, and the argon atmosphere was replaced three times. Compound M1-1 dissolved in ethylene glycol dimethyl ether (80 mL) was slowly added into a three-necked flask, heated to 80° C., reacted for 12 h, and purified by rapid silica gel column to obtain compound M1 (3.54 g, yield 68%). 1 H NMR (400 MHz, Chloroform-d) δ8.97-8.95 (m, 3H), 8.65 (d, J = 2.9 Hz, 1H), 8.60-8.57 (m, 1H), 8.30-8.27 (m, 1H).

[0047] (2) Synthesis of 7-bromo-N,N-dimethylquinoxalin-2-amine (M2)

[0048]

[0049] Compound 7-bromo-2-chloroquinoxaline (4.87 g, 20 mmol) and dimethylamine (1.13 g, 25 mmol) were dissolved in tetrahydrofuran (100 mL), heated to 50°C, and reacted for 18 h. Rapid silica gel column purification gave compound M2 (4.13 g, yield 82%). MS (M+H) + :found,252.1.

[0050] (3) Synthesis of 7-(2-chloro-5-fluoropyrimidin-4-yl)-N,N-dimethylquinoxalin-2-amine (M3)

[0051]

[0052] Referring to the synthesis method of compound M1, the yield was 60%. 1 H NMR (400MHz, Chloroform-d) δ7.34-7.32(m,2H),7.24(s,1H),6.87-6.84(m,1H),6.75(d,J=8.7Hz,1H),2.07(s,3H).

[0053] (4) Synthesis of 7-bromo-N,N-diethylquinoxaline-2-amine (M4)

[0054]

[0055] Referring to the synthesis method of compound M2, the yield was 83%. MS (M+H) + :found,280.1.

[0056] (5) Synthesis of 7-(2-chloro-5-fluoropyrimidin-4-yl)-N,N-diethylquinoxalin-2-amine (M5)

[0057]

[0058] Referring to the synthesis method of compound M1, the yield was 62%. 1 H NMR(400MHz,Chloroform-d)δ8.48(d,J=3.0Hz,1H),8.41(s,1H),8.36(s,1H),7.9 9-7.96(m,1H),7.88(d,J=8.6Hz,1H),3.63(q,J=7.1Hz,4H),1.23(t,J=7.1Hz,6H).

[0059] 2. Synthesis of Compounds S-1-S-11

[0060] Example 1: Synthesis of 5-fluoro-N-(1-(methylsulfonyl)piperidin-4-yl)-4-(quinoxalin-6-yl)pyrimidin-2-amine (S-1)

[0061]

[0062] Compound M1 (521 mg, 2 mmol) and 1-Boc-4-aminopiperidine (445 mg, 2.5 mmol) were dissolved in dioxane (6 mL), and then Pd2(dba)3 (92 mg, 0.1 mmol), Xantphos (116 mg, 0.2 mmol), cesium carbonate (1.3 g, 4 mmol) were added, argon was replaced three times, heated to 105 ° C, and reacted for 12 h. Cooling, filtration, concentration, and column chromatography gave compound S-1 (386 mg, 48% yield) as a white solid. 1 H NMR (400MHz, DMSO-d6) δ9.05(s,1H),8.68(s,1H),8.57(d,J=3.6Hz,1H),8.45(d,J=9.1Hz,1H),8.27(d,J=8.8Hz,1H),7.50( d,J=7.8Hz,1H),3.95-3.90(m,1H),3.58-3.53(m,2H),2.96-2.92(m,2H),2.89(s,3H),2.06-2.01(m,2H),1.65-1.56(m,2H).

[0063] Example 2: Synthesis of 7-(5-fluoro-2-(piperidin-4-ylamino)pyrimidin-4-yl)-N,N-dimethylquinoxalin-2-amine (S-2)

[0064]

[0065] The synthesis of compound S-2-1 was carried out according to the synthesis method of Example 1, with a yield of 45%, white solid, MS (M+H) + :found,468.6;

[0066] Compound S-2-1 (420 mg, 0.9 mmol) was dissolved in dichloromethane (10 mL), and 2N hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was reacted at room temperature for 4 h. The pH value of the reaction solution was adjusted to neutral, and compound S-2 (314 mg, 95% yield) was obtained by column chromatography as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.77(s,1H),8.52(d,J=3.7Hz,1H),8.20(s,1H),7.96-7.93(m,2H),7.59(d,J=7.2Hz,1 H),4.05-3.95(m,1H),3.31-3.27(m,2H),3.26(s,6H),3.03-2.97(m,2H),2.12-2.06(m,2H),1.76-1.68(m,2H).

[0067] Example 3: Synthesis of 1-(4-((4-(3-(dimethylamino)quinoxalin-6-yl)-5-fluoropyrimidin-2-yl)amino)piperidin-1-yl)ethan-1-one (S-3)

[0068]

[0069] The synthetic method of reference example 1 has a yield of 45%, and the product is a white solid. 1 H NMR(400MHz,Chloroform-d)δ8.57(s,1H),8.39(s,1H),8.28(d,J=3.6Hz,1H),8. 02(d,J=8.7Hz,1H),7.96(d,J=8.7Hz,1H),5.07(d,J=7.7Hz,1H),4.54-4.50(m,1 H),4.12-4.10(m,1H),3.86-3.82(m,1H),3.32(s,6H),3.29-3.25(m,1H),2.96-2 .89(m,1H),2.23-2.20(m,1H),2.14(s,3H),2.12-2.10(m,1H),1.52-1.41(m,2H).

[0070] Example 4: Synthesis of 7-(5-fluoro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-N,N-dimethylquinoxalin-2-amine (S-4)

[0071]

[0072] The synthetic method of reference example 1, the yield is 44%, white solid. 1H NMR (400MHz, Chloroform-d) δ8.32 (d, J = 2.5Hz, 1H), 8.16 (d, J = 4.1Hz, 1H), 8.10-8.07 (m, 1H), 6.64 (d, J = 9.6Hz, 1H), 5.35-5.29 (m, 1H), 5.02 (d, J = 7.6Hz, 1H), 3.98-3.90 (m, 1H), 3.81-3.75 (m, 2H), 2.98-2.91 (m, 2H), 2.82 (s, 3H), 2.22-2.18 (m, 2H), 1.72-1.65 (m, 2H), 1.42 (d, J = 6.8Hz, 6H).

[0073] Example 5: Synthesis of 7-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-5-fluoropyrimidin-4-yl)-N,N-dimethylquinoxalin-2-amine (S-5)

[0074]

[0075] Compound S-2 (147 mg, 0.4 mmol) and triethylamine (122 mg, 1.2 mmol) were dissolved in dichloromethane (5 mL), placed in an ice bath, and isopropylsulfonyl chloride (172 mg, 1.2 mmol) was added dropwise. The mixture was returned to room temperature and stirred for 2 h. The mixture was concentrated and subjected to column chromatography to obtain compound S-5 (160 mg, 85% yield) as a white solid. 1 H NMR(400MHz,Chloroform-d)δ8.60(s,1H),8.27(d,J=3.6Hz,1H),8.05(d,J=8.7Hz,1H),7.98(d,J=8 .7Hz,1H),5.46(s,1H),4.16-4.06(m,1H),3.81-3.75(m,2H),3.37(s,6H),3.20-3.14(m,2H),2.34-

[0076] 2.30(m,1H),2.24-2.19(m,2H),1.73-1.64(m,2H),1.22-1.18(m,2H),1.04-1.00(m,2H).

[0077] Example 6: Synthesis of 7-(5-fluoro-2-((1-(isopropylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-N,N-dimethylquinoxalin-2-amine (S-6)

[0078]

[0079] The synthetic method of reference example 5 has a yield of 88% and is a white solid. 1 H NMR(400MHz,Chloroform-d)δ8.56(s,1H),8.39(s,1H),8.27(d,J=3.6Hz,1H),8.02(d,J=8.9Hz,1H),7.96(d,J=8.9Hz,1H),5.08(d,J=7.8Hz ,1H),4.04(d,J=9.9Hz,1H),3.86-3.82(m,2H),3.32(s,6H),3.25-3.1 1(m,3H),2.20-2.16(m,2H),1.66-1.60(m,2H),1.37(d,J=6.8Hz,6H).

[0080] Example 7: Synthesis of N,N-diethyl-7-(5-fluoro-2-(piperidin-4-ylamino)pyrimidin-4-yl)quinoxaline-2-amine (S-7)

[0081]

[0082] The synthesis of compound S-7-1 was carried out according to the synthesis method of Example 1, with a yield of 43%, white solid, MS (M+H) + :found,496.7.

[0083] Compound S-7-1 (446 mg, 0.9 mmol) was dissolved in dichloromethane (10 mL), 2N hydrogen chloride-ethyl acetate solution (5 mL) was added, and the mixture was reacted at room temperature for 4 h. The pH value of the reaction solution was adjusted to neutral, and compound S-7 (335 mg, 94% yield) was obtained by column chromatography as a white solid. 1 H NMR (400MHz, DMSO-d6) δ8.70(s,1H),8.51(d,J=3.7Hz,1H),8.18(s,1H),7.97-7.91(m,2H),7.60(d,J=7.1Hz,1H),4.04-3.92(m ,1H),3.71(q,J=7.0Hz,4H),3.29-3.24(m,2H),3.00-2.94(m,2H),2.10-2.05(m,2H),1.80-1.71(m,2H),1.22(t,J=7.0Hz,6H).

[0084] Example 8: Synthesis of 1-(4-((4-(3-(diethylamino)quinoxalin-6-yl)-5-fluoropyrimidin-2-yl)amino)piperidin-1-yl)ethan-1-one (S-8)

[0085]

[0086] The synthetic method of reference example 1 has a yield of 43% and is a white solid. 1 H NMR(400MHz,Chloroform-d)δ8.48(s,1H),8.34(s,1H),8.27(d,J=3.6Hz,1H),7.98(d,J= 8.7Hz,1H),7.93(d,J=8.7Hz,1H),5.07(d,J=7.7Hz,1H),4.54-4.49(m,1H),4.13-4.10(m ,1H),3.85-3.81(m,1H),3.71(q,J=7.1Hz,4H),3.32-3.25(m,1H),2.96-2.89(m,1H),2.2 3-2.19(m,1H),2.13(s,3H),2.12-2.10(m,1H),1.52-1.41(m,2H),1.30(t,J=7.1Hz,6H).

[0087] Example 9: Synthesis of N,N-diethyl-7-(5-fluoro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)quinoxaline-2-amine (S-9)

[0088]

[0089] The synthetic method of reference example 1, the yield is 46%, white solid. 1H NMR (400MHz, Chloroform-d) δ8.48 (s, 1H), 8.34 (s, 1H), 8.27 (d, J = 3.6 Hz, 1H), 7.98 (d, J = 9.0 Hz, 1H), 7.93 (d, J = 8.6 Hz, 1H), 5.10 (d, J = 7.6 Hz, 1H), 4.06-3.99 (m, 1H), 3.80-3.76 (m, 2H), 3.71 (q, J = 7.1 Hz, 4H), 3.01-2.95 (m, 2H), 2.83 (s, 3H), 2.26-2.21 (m, 2H), 1.74-1.67 (m, 2H), 1.30 (t, J = 7.1 Hz, 6H).

[0090] Example 10: Synthesis of 7-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-5-fluoropyrimidin-4-yl)-N,N-diethylquinoxalin-2-amine (S-10)

[0091]

[0092] The synthetic method of reference example 5 has a yield of 82% and is a white solid. 1 H NMR(400MHz,Chloroform-d)δ8.35(d,J=1.7Hz,1H),8.18(d,J=4.1Hz,1H),8.06(d,J=8.5Hz,1H),7.58(d,J=8.5Hz,1H),4.98(d,J=7.8Hz, 1H),4.11-3.96(m,3H),3.62(q,J=7.1Hz,4H),3.03-2.96(m,2H),2.10-2.05(m,2H),1.48(s,9H),1.44-1.34(m,2H),1.32(t,J=7.1Hz,6H).

[0093] Example 11: Synthesis of N,N-diethyl-7-(5-fluoro-2-((1-(isopropylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)quinoxaline-2-amine (S-11)

[0094]

[0095] The synthetic method of reference example 5 has a yield of 43%, and the product is a white solid. 1 H NMR(400MHz,Chloroform-d)δ8.48(s,1H),8.34(s,1H),8.27(d,J=3.6Hz,1H) ,7.98(d,J=8.5Hz,1H),7.93(d,J=8.5Hz,1H),5.09(d,J=7.7Hz,1H),4.08-4. 01(m,1H),3.86-3.83(m,2H),3.72(q,J=7.1Hz,4H),3.25-3.14(m,3H),2.20- 2.16(m,2H),1.66-1.62(m,2H),1.37(d,J=6.8Hz,6H),1.31(t,J=7.1Hz,6H).

[0096] 3. Biological Evaluation Experiment

[0097] (1) CDK2 kinase activity analysis method

[0098] a) Prepare ATP / substrate solution and CDK2 kinase solution using kinase reaction buffer.

[0099] b) Transfer compound dilutions to a 384-well plate; centrifuge and add CDK2 kinase solution to the 384-well plate, continue centrifugation for 1 minute, and then incubate at 25°C for 10 minutes.

[0100] c) Add ATP / substrate solution to the 384-well plate, centrifuge for 1 minute, and then incubate at 25°C for 60 minutes.

[0101] d) Add ADP-Glo ​​to the 384-well plate, centrifuge for 1 minute, and then incubate at 25°C for 40 minutes.

[0102] e) The reaction solution was transferred to another 384-well plate, centrifuged at 1000 rpm for 1 minute, and then incubated at 25°C for 40 minutes.

[0103] f) Read the luminescent signal with a multifunctional microplate reader and calculate the inhibition rate and IC of the compound on CDK2 kinase 50 value.

[0104] (2) CDK6 kinase activity analysis method

[0105] a) Prepare ATP / substrate solution and CDK6 kinase solution using kinase reaction buffer.

[0106] b) Transfer compound dilutions to a 384-well plate; centrifuge and add CDK6 kinase solution to the 384-well plate, continue centrifugation for 1 minute, and then incubate at 25°C for 10 minutes.

[0107] c) Add ATP / substrate solution to the 384-well plate, centrifuge for 1 minute, and then incubate at 25°C for 60 minutes.

[0108] d) Add ADP-Glo ​​to the 384-well plate, centrifuge for 1 minute, and then incubate at 25°C for 40 minutes.

[0109] e) The reaction solution was transferred to another 384-well plate, centrifuged at 1000 rpm for 1 minute, and then incubated at 25°C for 40 minutes.

[0110] f) Read the luminescent signal with a multifunctional microplate reader and calculate the inhibition rate and IC of the compound on CDK6 kinase 50 value.

[0111] Table 1 CDK kinase inhibitory activity of the compounds of the present invention

[0112] Example CDK2 kinase inhibitory activity CDK6 kinase inhibitory activity 1 A B 2 C - 3 A C 4 A A 5 A A 6 A A 7 B C 8 B C 9 A A 10 A A 11 A B

[0113] A:IC 50 ≤100nM; B:100nM <IC 50 ≤200nM; C:200nM <IC 50 ≤1000nM; “-”: not tested.

Claims

1. A compound represented by formula (S) or a pharmaceutically acceptable salt thereof, characterized in that: in, R1 is selected from hydrogen or NR4R5, wherein R4 and R5 are selected from C1-C3 alkyl; R2 is selected from halogen; R3 is selected from hydrogen, -C(O)C1-C3 alkyl or -S(O)2R6, wherein R6 is selected from C1-C3 alkyl or C3-C5 cycloalkyl.

2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: Said R1 is selected from hydrogen or NR4R5, wherein R4 and R5 are selected from C1-C3 alkyl; Said R2 is selected from F; The R3 is selected from hydrogen, -C(O)CH3 or -S(O)2R6, wherein R6 is selected from C1-C3 alkyl or cyclopropyl.

3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: Said R1 is selected from hydrogen or NR4R5, wherein R4 and R5 are selected from methyl or ethyl; Said R2 is selected from F; The R3 is selected from hydrogen, -C(O)CH3 or -S(O)2R6, wherein R6 is selected from C1-C3 alkyl or cyclopropyl.

4. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: Said R1 is selected from hydrogen or NR4R5, wherein R4 and R5 are selected from methyl or ethyl; Said R2 is selected from F; The R3 is selected from hydrogen, -C(O)CH3 or -S(O)2R6, wherein R6 is selected from methyl, isopropyl or cyclopropyl.

5. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: Select any of the following compounds:

6. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The pharmaceutically acceptable salt is an acid addition salt of the compound of formula (S), wherein the acid used for salt formation includes inorganic acids and organic acids, the inorganic acids include hydrochloric acid, sulfuric acid, phosphoric acid and methanesulfonic acid, and the organic acids include acetic acid, trichloroacetic acid, propionic acid, butyric acid, maleic acid, p-toluenesulfonic acid, malic acid, malonic acid, cinnamic acid, citric acid, fumaric acid, camphoric acid, digluconic acid, aspartic acid and tartaric acid.

7. A method for preparing the compound according to claim 1, characterized in that: Compound A and compound B are reacted with each other under the action of a palladium catalyst to prepare compound S; or compound C reacts with compound D under the action of a base to prepare compound S; R1 is selected from hydrogen or NR4R5, wherein R4 and R5 are selected from C1-C3 alkyl; R2 is selected from halogen; R3 is selected from hydrogen, -C(O)C1-C3 alkyl or -S(O)2R6, wherein R6 is selected from C1-C3 alkyl or C3-C5 cycloalkyl.

8. A pharmaceutical composition, characterized in that: The invention comprises a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

9. Use of the compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof in the preparation of a CDK inhibitor.

10. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a drug for preventing and / or treating tumors, wherein the tumor is a CDK-related tumor.

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