CN117886801B - Pyridone pyrimidine CDK inhibitors and preparation method and application thereof - Google Patents

Abstract

The invention discloses a pyridone pyrimidine CDK inhibitor, a preparation method and application thereof, wherein the compound is shown as a formula (S). The compound of the invention can inhibit malignant proliferation of cancer, has good treatment effect and low toxicity, and can be used for preparing medicines for treating cancers or tumor-related diseases.

Description

Pyridone pyrimidine CDK inhibitors and preparation method and application thereof

Technical Field

The present invention relates to the field of pharmaceutical chemistry, and in particular to a pyridone pyrimidine CDK inhibitor and a preparation method and application thereof.

Background Art

Cyclin-dependent kinases (CDKs) play a crucial regulatory role in cell proliferation by regulating the progression of the cell cycle. Therefore, when CDK activity is upregulated, the cell cycle accelerates, ultimately leading to malignant cell proliferation and the occurrence and development of cancer. CDK2 and CDK6 regulate the transition of the cell cycle from the G1 phase to the S phase, and CDK2 has a very important regulatory effect on DNA synthesis in the S phase. Therefore, inhibiting CDK2 or CDK6 can significantly slow down the progression of the cell cycle, thereby inhibiting the malignant proliferation of cancer cells and producing a significant anti-cancer effect.

Summary of the invention

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

Technical solution: The compound represented by formula (S) or a pharmaceutically acceptable salt thereof according to the present invention:

;

in,

R ₁ is selected from hydrogen, halogen or C ₁ -C ₃ alkyl;

R ₂ is selected from C ₁ -C ₈ alkyl or -CH ₂ CHC(CH ₃ ) ₂ alkenyl;

_R3 is selected from hydrogen or halogen;

R ₄ is selected from hydrogen, acetyl, -C(O)OC(CH ₃ ) ₃ or -S(O) ₂ R ₅ , R ₅ is selected from C ₁ -C ₅ alkyl, C ₃ -C ₅ cycloalkyl, -CF ₃ or -CH ₂ CH ₂ OCH ₃ .

Preferably:

The R ₁ is selected from hydrogen, fluorine or methyl;

The R ₂ is selected from C ₁ -C ₆ alkyl or -CH ₂ CHC(CH ₃ ) ₂ alkenyl;

Said R ₃ is selected from hydrogen or fluorine;

The R ₄ is selected from hydrogen, acetyl, -C(O)OC(CH ₃ ) ₃ or -S(O) ₂ R ₅ , and R ₅ is selected from C ₁ -C ₅ alkyl, C ₃ -C ₅ cycloalkyl, -CF ₃ or -CH ₂ CH ₂ OCH ₃ .

Preferably:

The R ₁ is selected from hydrogen, fluorine or methyl;

The R ₂ is selected from C ₁ -C ₄ alkyl or -CH ₂ CHC(CH ₃ ) ₂ alkenyl;

Said R ₃ is selected from hydrogen or fluorine;

The R ₄ is selected from hydrogen, acetyl, -C(O)OC(CH ₃ ) ₃ or -S(O) ₂ R ₅ , and R ₅ is selected from C ₁ -C ₄ alkyl, C ₃ -C ₅ cycloalkyl, -CF ₃ or -CH ₂ CH ₂ OCH ₃ .

Preferably:

The R ₁ is selected from hydrogen, fluorine or methyl;

The R ₂ is selected from C ₁ -C ₄ alkyl or -CH ₂ CHC(CH ₃ ) ₂ alkenyl;

Said R ₃ is selected from hydrogen or fluorine;

The R ₄ is selected from hydrogen, acetyl, -C(O)OC(CH ₃ ) ₃ or -S(O) ₂ R ₅ , and R ₅ is selected from C ₁ -C ₄ alkyl, cyclopropyl, -CF ₃ or -CH ₂ CH ₂ OCH ₃ .

Preferably:

The R ₁ is selected from hydrogen, fluorine or methyl;

The R ₂ is selected from methyl, ethyl, isopropyl, n-butyl, sec-butyl, isobutyl or -CH ₂ CHC(CH ₃ ) ₂ alkenyl;

Said R ₃ is selected from hydrogen or fluorine;

The R ₄ is selected from hydrogen, acetyl, -C(O)OC(CH ₃ ) ₃ or -S(O) ₂ R ₅ , and R ₅ is selected from C ₁ -C ₄ alkyl, cyclopropyl, -CF ₃ or -CH ₂ CH ₂ OCH ₃ .

Preferably:

The R ₁ is selected from hydrogen, fluorine or methyl;

The R ₂ is selected from methyl, ethyl, isopropyl, n-butyl, sec-butyl, isobutyl or -CH ₂ CHC(CH ₃ ) ₂ alkenyl;

Said R ₃ is selected from hydrogen or fluorine;

The R ₄ is selected from hydrogen, acetyl, -C(O)OC(CH ₃ ) ₃ or -S(O) ₂ R ₅ , R ₅ is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CF ₃ or -CH ₂ CH ₂ OCH ₃ .

Preferably:

The R ₁ is selected from hydrogen or fluorine;

The R ₂ is selected from methyl, ethyl, isopropyl, n-butyl, sec-butyl, isobutyl or -CH ₂ CHC(CH ₃ ) ₂ alkenyl;

Said R ₃ is selected from hydrogen or fluorine;

The R ₄ is selected from hydrogen, acetyl, -C(O)OC(CH ₃ ) ₃ or -S(O) ₂ R ₅ , R ₅ is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CF ₃ or -CH ₂ CH ₂ OCH ₃ .

In some specific embodiments of the present invention, the present invention also provides a compound selected from S-1 to S-30 or a pharmaceutically acceptable salt thereof, selected from the following compounds:

The pharmaceutically acceptable salts are acid addition salts of the compounds of the general formula (S), wherein the acids used for salt formation include inorganic acids and organic acids, wherein 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.

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

The method for preparing a compound of the general formula (S) of the present invention, compound A and compound B are subjected to a coupling reaction 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;

The R ₁ is selected from hydrogen, halogen or C ₁ -C ₃ alkyl;

The R ₂ is selected from C ₁ -C ₈ alkyl or -CH ₂ CHC(CH ₃ ) ₂ alkenyl;

Said R ₃ is selected from hydrogen or halogen;

The R ₄ is selected from hydrogen, acetyl, -C(O)OC(CH ₃ ) ₃ or -S(O) ₂ R ₅ , R ₅ is selected from C ₁ -C ₅ alkyl, C ₃ -C ₅ cycloalkyl, -CF ₃ or -CH ₂ CH ₂ OCH ₃ ;

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

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.

The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of one or more compounds or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable excipient.

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 an anti-tumor drug, wherein the tumor is a tumor associated with CDK2 or CDK6 kinase.

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.

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. 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, endometrial cancer, etc.

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.

Beneficial effects: The compound represented by the general formula (S) of the present invention can inhibit the malignant proliferation of cancer, 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

The following examples are provided for 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.

1. Synthesis of intermediate reactants

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

(1) Synthesis of 5-bromo-1-isopropylpyridin-2(1H)-one (M1)

2-Hydroxy-5-bromopyridine (3.48 g, 20 mmol) and sodium carbonate (6.36 g, 60 mmol) were dissolved in N,N-dimethylformamide (150 mL), and then 2-iodopropane (10.20 g, 60 mmol) was added, heated to 70°C, reacted for 12 h, and purified by rapid silica gel column to obtain compound M1 (2.38 g, yield 55%). ¹ H NMR (400 MHz, Chloroform- d ) δ8.17 (d, J = 2.5 Hz, 1H), 7.60 (dd, J = 8.8, 2.5 Hz, 1H), 6.59 (d, J = 8.8 Hz, 1H),5.26 – 5.20 (m, 1H), 1.33 (d, J = 6.2 Hz, 6H).

(2) Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropylpyridin-2(1H)-one (M2)

Compound M1 (2.16 g, 10.0 mmol), bis(pyrimidine) (2.79 g, 11 mmol), dissolved in 1,4-dioxane (80 mL), then added Pd(dppf)Cl ₂ (365.5 mg, 0.5 mmol), potassium acetate (2.94 g, 30 mmol), replaced argon three times, heated to 100 ° C, reacted for 12 h. After the reaction was completed, water was added to quench, ethyl acetate was used, and the compound M1-2 was obtained by evaporation under reduced pressure and concentrated without purification. 2,4-dichloro-5-fluoropyrimidine (2.00 g, 12 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (351 mg, 0.5 mmol), sodium carbonate (2.65 g, 25 mmol), water (15 mL) and ethylene glycol dimethyl ether (20 mL) were added to a three-necked flask, and argon was replaced three times. Compound M1-2 dissolved in ethylene glycol dimethyl ether (80 mL) was slowly added to a three-necked flask, heated to 80°C, reacted for 12 h, and purified by rapid silica gel column to obtain compound M2 (1.66 g, yield 62%). ¹ H NMR (300 MHz, Chloroform- d ) δ 8.47 – 8.44 (m, 2H), 8.18– 8.14 (m, 1H), 6.67 (d, J = 9.7 Hz, 1H), 5.36 – 5.27 (m, 1H), 1.45 (d, J = 6.8Hz, 6H).

(3) Synthesis of 5-bromo-1-isopropyl-3-methylpyridin-2(1H)-one (M3)

2-Hydroxy-3-methyl-5-bromopyridine (3.76 g, 20 mmol) and sodium carbonate (6.36 g, 60 mmol) were dissolved in N,N-dimethylformamide (150 mL), and then 2-iodopropane (10.20 g, 60 mmol) was added, heated to 70°C, reacted for 12 h, and purified by rapid silica gel column to obtain compound M3 (2.76 g, yield 60%). ¹ H NMR (400 MHz, Chloroform- d ) δ 7.99 (d, J = 2.5 Hz, 1H), 7.46 (dd, J = 2.5, 1.1 Hz, 1H), 5.28 –5.22 (m, 1H), 2.13 (s, 3H), 1.33 (d, J = 6.2 Hz, 6H).

(4) Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-isopropyl-3-methylpyridin-2(1H)-one (M4)

Compound M3 (2.30 g, 10.0 mmol), bis(pyrimidine) (2.79 g, 11 mmol), dissolved in 1,4-dioxane (80 mL), then added Pd(dppf)Cl ₂ (365.5 mg, 0.5 mmol), potassium acetate (2.94 g, 30 mmol), replaced argon three times, heated to 100 ° C, reacted for 12 h. After the reaction was completed, water was added to quench, ethyl acetate was used, and the compound M3-2 was obtained by evaporation under reduced pressure without purification and used directly in subsequent reactions. 2,4-dichloro-5-fluoropyrimidine (2.00 g, 12 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (351 mg, 0.5 mmol), sodium carbonate (2.65 g, 25 mmol), water (15 mL) and ethylene glycol dimethyl ether (20 mL) were added to a three-necked flask, and argon was replaced three times. Compound M3-2 dissolved in ethylene glycol dimethyl ether (80 mL) was slowly added to a three-necked flask, heated to 80°C, reacted for 12 h, and purified by rapid silica gel column to obtain compound M4 (1.69 g, yield 60%). ¹ H NMR (400 MHz, Chloroform- d ) δ 8.51 (d, J = 1.7 Hz, 1H), 7.67 (dd, J = 8.5, 1.3 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 5.43 – 5.37 (m, 1H), 2.47 (d, J = 2.2 Hz, 3H), 1.37 (d, J = 6.2 Hz, 6H).

(5) Synthesis of 5-bromo-1-ethylpyridin-2(1H)-one (M5)

2-Hydroxy-5-bromopyridine (3.48 g, 20 mmol) and sodium carbonate (6.36 g, 60 mmol) were dissolved in N,N-dimethylformamide (150 mL), and then iodoethane (9.36 g, 60 mmol) was added, heated to 70°C, reacted for 12 h, and purified by rapid silica gel column to obtain compound M5 (2.14 g, yield 53%). ¹ H NMR (400 MHz, Chloroform- d ) δ8.17 (d, J = 2.5 Hz, 1H), 7.62 (dd, J = 8.8, 2.5 Hz, 1H), 6.63 (d, J = 8.8 Hz, 1H),4.31 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H).

(6) Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-ethyl-3-methylpyridin-2(1H)-one (M6)

Compound M5 (2.02 g, 10.0 mmol), bis(pyrimidine) (2.79 g, 11 mmol), dissolved in 1,4-dioxane (80 mL), then added Pd(dppf)Cl ₂ (365.5 mg, 0.5 mmol), potassium acetate (2.94 g, 30 mmol), replaced argon three times, heated to 100 ° C, reacted for 12 h. After the reaction was completed, water was added to quench, ethyl acetate was used, and the compound M5-2 was obtained by evaporation under reduced pressure and concentrated without purification. 2,4-dichloro-5-fluoropyrimidine (2.00 g, 12 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (351 mg, 0.5 mmol), sodium carbonate (2.65 g, 25 mmol), water (15 mL) and ethylene glycol dimethyl ether (20 mL) were added to a three-necked flask, and argon was replaced three times. Compound M5-2 dissolved in ethylene glycol dimethyl ether (80 mL) was slowly added to a three-necked flask, heated to 80°C, reacted for 12 h, and purified by rapid silica gel column to obtain compound M6 (1.42 g, yield 56%). ¹ H NMR (400 MHz, Chloroform- d ) δ 8.45 – 8.44 (m, 2H), 8.19– 8.16 (m, 1H), 6.67 (d, J = 9.7 Hz, 1H), 4.12 (q, J = 7.2 Hz, 2H), 1.45 (t, J =7.2 Hz, 3H).

(7) Synthesis of 5-bromo-3-fluoro-1-isopropylpyridin-2(1H)-one (M7)

2-Hydroxy-3-fluoro-5-bromopyridine (3.84 g, 20 mmol) and sodium carbonate (6.36 g, 60 mmol) were dissolved in N,N-dimethylformamide (150 mL), and then 2-iodopropane (10.20 g, 60 mmol) was added, heated to 70°C, reacted for 12 h, and purified by rapid silica gel column to obtain compound M7 (2.57 g, yield 55%). ¹ H NMR (400 MHz, Chloroform- d ) δ 7.96 (d, J = 2.1 Hz, 1H), 7.45 (dd, J = 9.3, 2.1 Hz, 1H), 5.38 –5.29 (m, 1H), 1.38 (d, J = 6.4 Hz, 6H).

(8) Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-3-fluoro-1-isopropylpyridin-2(1H)-one (M8)

Compound M7 (2.34 g, 10.0 mmol), bis(pyrimidine) (2.79 g, 11 mmol), dissolved in 1,4-dioxane (80 mL), then added Pd(dppf)Cl ₂ (365.5 mg, 0.5 mmol), potassium acetate (2.94 g, 30 mmol), replaced argon three times, heated to 100 ° C, reacted for 12 h. After the reaction was completed, water was added to quench, ethyl acetate was used, and the compound M7-2 was obtained by evaporation under reduced pressure and concentrated without purification. 2,4-dichloro-5-fluoropyrimidine (2.00 g, 12 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (351 mg, 0.5 mmol), sodium carbonate (2.65 g, 25 mmol), water (15 mL) and ethylene glycol dimethyl ether (20 mL) were added to a three-necked flask, and argon was replaced three times. Compound M7-2 dissolved in ethylene glycol dimethyl ether (80 mL) was slowly added to a three-necked flask, heated to 80°C, reacted for 12 h, and purified by rapid silica gel column to obtain compound M8 (1.49 g, yield 52%). ¹ H NMR (400 MHz, Chloroform- d ) δ 8.48 (d, J = 3.5 Hz, 1H), 8.32 – 8.28 (m, 1H), 7.98 (dd, J = 10.4, 2.4 Hz, 1H), 5.39 – 5.31 (m, 1H), 1.47(d, J = 6.8 Hz, 6H).

(9) Synthesis of 5-bromo-3-fluoro-1-methylpyridin-2(1H)-one (M9)

2-Hydroxy-3-fluoro-5-bromopyridine (3.84 g, 20 mmol) and sodium carbonate (6.36 g, 60 mmol) were dissolved in N,N-dimethylformamide (150 mL), and then iodomethane (8.51 g, 60 mmol) was added. The mixture was heated to 70°C and reacted for 12 h. The compound M9 (2.10 g, yield was 51%) was obtained by rapid silica gel column purification. ¹ H NMR (400 MHz, Chloroform- d ) δ 7.29 – 7.28 (m, 1H), 7.20 (dd, J = 8.5, 2.4 Hz, 1H), 3.60 (s, 3H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ 155.39, 155.13, 153.1 0, 150.56, 133.48, 133.42, 124.01,123.81, 94.84, 94.77, 37.51, 37.49.

(10) Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-3-fluoro-1-methylpyridin-2(1H)-one (M10)

Compound M9 (2.06 g, 10.0 mmol), bis(pyrimidine) (2.79 g, 11 mmol), dissolved in 1,4-dioxane (80 mL), then added Pd(dppf)Cl ₂ (365.5 mg, 0.5 mmol), potassium acetate (2.94 g, 30 mmol), replaced argon three times, heated to 100 ° C, reacted for 12 h. After the reaction was completed, water was added to quench, ethyl acetate was used, and the compound M9-2 was obtained by evaporation under reduced pressure without purification and used directly in subsequent reactions. 2,4-dichloro-5-fluoropyrimidine (2.00 g, 12 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (351 mg, 0.5 mmol), sodium carbonate (2.65 g, 25 mmol), water (15 mL) and ethylene glycol dimethyl ether (20 mL) were added to a three-necked flask, and argon was replaced three times. Compound M9-2 dissolved in ethylene glycol dimethyl ether (80 mL) was slowly added to a three-necked flask, heated to 80°C, reacted for 12 h, and purified by rapid silica gel column to obtain compound M10 (1.44 g, yield 56%). ¹ H NMR (400 MHz, Chloroform- d ) δ 8.48 (d, J = 3.4 Hz,1H), 8.29 – 8.28 (m, 1H), 8.00 (dd, J = 10.4, 2.4 Hz, 1H), 3.75 (s, 3H).

(11) Synthesis of 5-bromo-1-ethyl-3-fluoropyridin-2(1H)-one (M11)

2-Hydroxy-3-fluoro-5-bromopyridine (3.84 g, 20 mmol) and sodium carbonate (6.36 g, 60 mmol) were dissolved in N,N-dimethylformamide (150 mL), and then iodoethane (9.36 g, 60 mmol) was added, heated to 70°C, reacted for 12 h, and purified by rapid silica gel column to obtain compound M11 (2.33 g, yield 53%). ¹ H NMR (400 MHz, Chloroform- d ) δ 7.26 (dd, J = 2.4, 1.7 Hz, 1H), 7.18 (dd, J = 8.5, 2.4 Hz, 1H), 4.03 (q, J =7.2 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H).

(12) Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-1-ethyl-3-fluoropyridin-2(1H)-one (M12)

Compound M11 (2.20 g, 10.0 mmol), bis(pyrimidine) (2.79 g, 11 mmol), dissolved in 1,4-dioxane (80 mL), then added Pd(dppf)Cl ₂ (365.5 mg, 0.5 mmol), potassium acetate (2.94 g, 30 mmol), replaced argon three times, heated to 100 ° C, reacted for 12 h. After the reaction was completed, water was added to quench, ethyl acetate was used, and the compound M11-2 was obtained by evaporation under reduced pressure and concentrated without purification. 2,4-dichloro-5-fluoropyrimidine (2.00 g, 12 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (351 mg, 0.5 mmol), sodium carbonate (2.65 g, 25 mmol), water (15 mL) and ethylene glycol dimethyl ether (20 mL) were added to a three-necked flask, and argon was replaced three times. Compound M11-2 dissolved in ethylene glycol dimethyl ether (80 mL) was slowly added to a three-necked flask, heated to 80°C, reacted for 12 h, and purified by rapid silica gel column to obtain compound M12 (1.36 g, yield 50%). ¹ H NMR (400 MHz, Chloroform- d ) δ 8.48 (d, J = 3.4 Hz,1H), 8.29 – 8.27 (m, 1H), 7.99 (dd, J = 10.4, 2.4 Hz, 1H), 4.18 (q, J = 7.2 Hz,2H), 1.46 (t, J = 7.2 Hz, 3H).

(13) Synthesis of 5-bromo-1-(sec-butyl)-3-fluoropyridin-2(1H)-one (M13)

2-Hydroxy-3-fluoro-5-bromopyridine (3.84 g, 20 mmol) and sodium carbonate (6.36 g, 60 mmol) were dissolved in N,N-dimethylformamide (150 mL), and then iodine-sec-butylene (11.04 g, 60 mmol) was added. The mixture was heated to 70°C and reacted for 12 h. The compound M13 (2.58 g, yield was 52%) was obtained by rapid silica gel column purification. ¹ H NMR (400 MHz, Chloroform- d ) δ 7.20 (dd, J = 2.5, 1.6 Hz, 1H), 7.16 (dd, J = 8.3, 2.5 Hz, 1H), 5.13 – 5.04 (m, 1H), 1.76 – 1.66 (m, 2H), 1.36 (d, J = 6.8 Hz, 3H), 0.89 (t, J =7.4 Hz, 3H).

(14) Synthesis of 1-(sec-butyl)-5-(2-chloro-5-fluoropyrimidin-4-yl)-3-fluoropyridin-2(1H)-one (M14)

Compound M13 (2.48 g, 10.0 mmol), bis(pyrimidine) (2.79 g, 11 mmol), dissolved in 1,4-dioxane (80 mL), then added Pd(dppf)Cl ₂ (365.5 mg, 0.5 mmol), potassium acetate (2.94 g, 30 mmol), replaced argon three times, heated to 100 ° C, reacted for 12 h. After the reaction was completed, water was added to quench, ethyl acetate was used, and the compound M13-2 was obtained by evaporation under reduced pressure without purification and used directly in subsequent reactions. 2,4-dichloro-5-fluoropyrimidine (2.00 g, 12 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (351 mg, 0.5 mmol), sodium carbonate (2.65 g, 25 mmol), water (15 mL) and ethylene glycol dimethyl ether (20 mL) were added to a three-necked flask, and argon was replaced three times. Compound M13-2 dissolved in ethylene glycol dimethyl ether (80 mL) was slowly added to a three-necked flask, heated to 80°C, reacted for 12 h, and purified by rapid silica gel column to obtain compound M14 (1.62 g, yield 54%). ¹ H NMR (400 MHz, Chloroform- d ) δ 8.49 (d, J = 3.5 Hz,1H), 8.24 – 8.23 (m, 1H), 7.98 (dd, J = 10.4, 2.4 Hz, 1H), 5.19 – 5.10 (m, 1H),1.84 – 1.79 (m, 2H), 1.46 (d, J = 6.8 Hz, 3H), 0.93 (t, J = 7.4 Hz, 3H).

(15) Synthesis of 5-bromo-3-fluoro-1-isobutylpyridin-2(1H)-one (M15)

2-Hydroxy-3-fluoro-5-bromopyridine (3.84 g, 20 mmol) and sodium carbonate (6.36 g, 60 mmol) were dissolved in N,N-dimethylformamide (150 mL), and then isobutyl iodide (11.04 g, 60 mmol) was added. The mixture was heated to 70°C and reacted for 12 h. The compound M15 (2.58 g, 52% yield) was obtained by rapid silica gel column purification. ¹ H NMR (400 MHz, Chloroform- d ) δ 7.22 – 7.21 (m, 1H), 7.20 – 7.18 (m, 1H), 3.79 (d, J = 7.5 Hz, 2H), 2.22 – 2.12 (m, 1H), 0.95 (d, J = 6.7 Hz, 6H). ¹³ C NMR (101 MHz, CDCl ₃ ) δ155.21, 154.96, 153.26, 150.72, 133.22, 133.16, 123.74, 123.54, 94.63, 94.56,57.06, 57.04, 28.09, 19.73.

(16) Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-3-fluoro-1-isobutylpyridin-2(1H)-one (M16)

Compound M15 (2.48 g, 10.0 mmol), bis(pyrimidine) (2.79 g, 11 mmol), dissolved in 1,4-dioxane (80 mL), then added Pd(dppf)Cl ₂ (365.5 mg, 0.5 mmol), potassium acetate (2.94 g, 30 mmol), replaced argon three times, heated to 100 ° C, reacted for 12 h. After the reaction was completed, water was added to quench, ethyl acetate was used, and the compound M15-2 was obtained by evaporation under reduced pressure and concentrated without purification. 2,4-dichloro-5-fluoropyrimidine (2.00 g, 12 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (351 mg, 0.5 mmol), sodium carbonate (2.65 g, 25 mmol), water (15 mL) and ethylene glycol dimethyl ether (20 mL) were added to a three-necked flask, and argon was replaced three times. Compound M15-2 dissolved in ethylene glycol dimethyl ether (80 mL) was slowly added to a three-necked flask, heated to 80°C, reacted for 12 h, and purified by rapid silica gel column to obtain compound M16 (1.59 g, yield 53%). ¹ H NMR (400 MHz, Chloroform- d ) δ 8.50 (d, J = 3.4 Hz,1H), 8.24 – 8.22 (m, 1H), 7.99 (dd, J = 10.5, 2.4 Hz, 1H), 3.95 (d, J = 7.5 Hz,2H), 2.28 – 2.19 (m, 1H), 1.01 (d, J = 6.8 Hz, 6H).

(17) Synthesis of 5-bromo-3-fluoro-1-(3-methylbut-2-en-1-yl)pyridin-2(1H)-one (M17)

2-Hydroxy-3-fluoro-5-bromopyridine (3.84 g, 20 mmol) and sodium carbonate (6.36 g, 60 mmol) were dissolved in N,N-dimethylformamide (150 mL), and then 1-bromo-3-methyl-2-butene (8.94 g, 60 mmol) was added. The mixture was heated to 70°C and reacted for 12 h. The compound M17 (2.71 g, 52% yield) was obtained by rapid silica gel column purification. ¹ H NMR (400 MHz, Chloroform- d ) δ 7.23 – 7.22 (m, 1H), 7.17 (dd, J = 8.4, 2.5 Hz, 1H), 5.27 (t, J =7.4 Hz, 1H), 4.57 (d, J = 7.4 Hz, 2H), 1.81 (s, 3H) , 1.79 (s, 3H).

(18) Synthesis of 5-(2-chloro-5-fluoropyrimidin-4-yl)-3-fluoro-1-(3-methylbut-2-en-1-yl)pyridin-2(1H)-one (M18)

Compound M17 (2.60 g, 10.0 mmol), bis(pyrimidine) (2.79 g, 11 mmol), dissolved in 1,4-dioxane (80 mL), then added Pd(dppf)Cl ₂ (365.5 mg, 0.5 mmol), potassium acetate (2.94 g, 30 mmol), replaced argon three times, heated to 100 ° C, reacted for 12 h. After the reaction was completed, water was added to quench, ethyl acetate was used, and the compound M17-2 was obtained by evaporation under reduced pressure and concentrated without purification. 2,4-dichloro-5-fluoropyrimidine (2.00 g, 12 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (351 mg, 0.5 mmol), sodium carbonate (2.65 g, 25 mmol), water (15 mL) and ethylene glycol dimethyl ether (20 mL) were added to a three-necked flask, and argon was replaced three times. Compound M17-2 dissolved in ethylene glycol dimethyl ether (80 mL) was slowly added to a three-necked flask, heated to 80°C, reacted for 12 h, and purified by rapid silica gel column to obtain compound M18 (1.68 g, yield 54%). ¹ H NMR (400 MHz, Chloroform- d ) δ 8.51 (d, J = 3.5 Hz,1H), 8.33 – 8.31 (m, 1H), 7.98 (dd, J = 10.6, 2.4 Hz, 1H), 5.37 (t, J = 7.5 Hz,1H), 4.72 (d, J = 7.5 Hz, 2H), 1.87 (s, 3H), 1.85 (s, 3H).

(19) Synthesis of 5-bromo-1-butyl-3-fluoropyridin-2(1H)-one (M19)

2-Hydroxy-3-fluoro-5-bromopyridine (3.84 g, 20 mmol) and sodium carbonate (6.36 g, 60 mmol) were dissolved in N,N-dimethylformamide (150 mL), and then n-butyl iodide (11.04 g, 60 mmol) was added. The mixture was heated to 70°C and reacted for 12 h. The compound M19 (2.53 g, 51% yield) was obtained by rapid silica gel column purification. ¹ H NMR (400 MHz, Chloroform- d ) δ 7.24 – 7.22 (m, 1H), 7.18 (dd, J = 8.5, 2.4 Hz, 1H), 3.96 (t, J =7.5 Hz, 2H), 1.77 – 1.70 (m, 2H), 1.41 – 1.33 (m, 2H), 0.96 (t, J = 7.3 Hz, 3H).

(20) Synthesis of 1-butyl-5-(2-chloro-5-fluoropyrimidin-4-yl)-3-fluoropyridin-2(1H)-one (M20)

Compound M19 (2.48 g, 10.0 mmol), bis(pyrimidine) (2.79 g, 11 mmol), dissolved in 1,4-dioxane (80 mL), then added Pd(dppf)Cl ₂ (365.5 mg, 0.5 mmol), potassium acetate (2.94 g, 30 mmol), replaced argon three times, heated to 100 ° C, reacted for 12 h. After the reaction was completed, water was added to quench, ethyl acetate was used, and the compound M19-2 was obtained by evaporation under reduced pressure and concentrated without purification. 2,4-dichloro-5-fluoropyrimidine (2.00 g, 12 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (351 mg, 0.5 mmol), sodium carbonate (2.65 g, 25 mmol), water (15 mL) and ethylene glycol dimethyl ether (20 mL) were added to a three-necked flask, and argon was replaced three times. Compound M19-2 dissolved in ethylene glycol dimethyl ether (80 mL) was slowly added to a three-necked flask, heated to 80°C, reacted for 12 h, and purified by rapid silica gel column to obtain compound M20 (1.56 g, yield 52%). ¹ H NMR (400 MHz, Chloroform- d ) δ 8.49 (d, J = 3.4 Hz,1H), 8.27 – 8.26 (m, 1H), 7.99 (dd, J = 10.5, 2.4 Hz, 1H), 4.12 (t, J = 7.5 Hz,2H), 1.85 – 1.78 (m, 2H), 1.48 – 1.38 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).

(21) Synthesis of 5-(2-chloropyrimidin-4-yl)-1-isopropylpyridin-2(1H)-one (M21)

Compound M1 (2.16 g, 10.0 mmol), bis(pyrimidine) (2.79 g, 11 mmol), dissolved in 1,4-dioxane (80 mL), then added Pd(dppf)Cl ₂ (365.5 mg, 0.5 mmol), potassium acetate (2.94 g, 30 mmol), replaced argon three times, heated to 100 ° C, reacted for 12 h. After the reaction was completed, water was added to quench, ethyl acetate was used, and the compound M1-2 was obtained by evaporation under reduced pressure and concentrated, without purification, and used directly in subsequent reactions. 2,4-Dichloropyrimidine (1.79 g, 12 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (351 mg, 0.5 mmol), sodium carbonate (2.65 g, 25 mmol), water (15 mL) and ethylene glycol dimethyl ether (20 mL) were added to a three-necked flask, and argon was replaced three times. Compound M1-2 dissolved in ethylene glycol dimethyl ether (80 mL) was slowly added to a three-necked flask, heated to 80°C, reacted for 12 h, and purified by rapid silica gel column to obtain compound M21 (1.37 g, yield 55%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.73 (d, J = 5.4 Hz, 1H), 8.63(d, J = 2.6 Hz, 1H), 8.15 (dd, J = 9.6, 2.6 Hz, 1H), 8.10 (d, J = 5.4 Hz, 1H), 6.56(d, J = 9.6 Hz, 1H), 5.11 – 5.04 (m, 1H), 1.40 (d, J = 6.8 Hz, 6H).

(22) Synthesis of 5-(2-chloropyrimidin-4-yl)-3-fluoro-1-isopropylpyridin-2(1H)-one (M22)

Compound M7 (2.34 g, 10.0 mmol), bis(pyrimidine) (2.79 g, 11 mmol), dissolved in 1,4-dioxane (80 mL), then added Pd(dppf)Cl ₂ (365.5 mg, 0.5 mmol), potassium acetate (2.94 g, 30 mmol), replaced argon three times, heated to 100 ° C, reacted for 12 h. After the reaction was completed, water was added to quench, ethyl acetate was used, and the compound M7-2 was obtained by evaporation under reduced pressure and concentrated without purification. 2,4-Dichloropyrimidine (1.79 g, 12 mmol), Pd(PPh ₃ ) ₂ Cl ₂ (351 mg, 0.5 mmol), sodium carbonate (2.65 g, 25 mmol), water (15 mL) and ethylene glycol dimethyl ether (20 mL) were added to a three-necked flask, and argon was replaced three times. Compound M7-2 dissolved in ethylene glycol dimethyl ether (80 mL) was slowly added to a three-necked flask, heated to 80°C, reacted for 12 h, and purified by rapid silica gel column to obtain compound M22 (1.39 g, yield 52%). ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.76 (d, J = 5.4 Hz, 1H), 8.52(dd, J = 2.4, 1.1 Hz, 1H), 8.13 (d, J = 5.4 Hz, 1H), 8.07 (dd, J = 11.1, 2.4 Hz,1H), 5.16 – 5.09 (m, 1H), 1.43 (d, J = 6.8 Hz, 6H).

2. Synthesis of Compounds S-1-S-30

Example 1: Synthesis of tert-butyl 4-((5-fluoro-4-(1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl)pyrimidin-2-yl)amino)piperidine-1-carboxylate (S-1)

Compound M2 (268 mg, 1 mmol) and 1-Boc-4-aminopiperidine (250 mg, 1.25 mmol) were dissolved in dioxane (6 mL), and then Pd ₂ (dba) ₃ (46 mg, 0.05 mmol), Xantphos (58 mg, 0.1 mmol), and cesium carbonate (650 mg, 2 mmol) were added, and argon was replaced three times, heated to 105°C, and reacted for 12 h. Cooling, filtration, concentration, and column chromatography gave compound S-1 (178 mg, 41% yield) as a white solid. ¹ H NMR (400 MHz, Chloroform- d ) δ 8.34 (d, J = 2.5 Hz, 1H), 8.16 (d, J = 4.0 Hz, 1H), 8.09 (dd, J = 9.6, 2.5 Hz, 1H), 6.64 (d, J = 9.6 Hz, 1H), 5.36 – 5 .29 (m, 1H), 5.01 (d, J = 7.7 Hz, 1H), 4.11 – 3.89(m, 3H), 3.00 – 2.94 (m, 2H), 2.09 – 2.03 (m, 2H), 1.68 – 1.59 (m, 2H), 1.47(s, 9H), 1 .42 (d, J = 6.8 Hz, 6H).

Example 2: Synthesis of 5-(5-fluoro-2-(piperidin-4-ylamino)pyrimidin-4-yl)-1-isopropylpyridin-2(1H)-one (S-2)

Compound S-1 (174 mg, 0.4 mmol) was dissolved in dichloromethane (5 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 (126 mg, 95% yield) was obtained by column chromatography as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.39 – 8.38 (m, 2H), 8.06 – 8.02 (m, 1H), 7.47 (d, J = 7.0 Hz, 1H), 6.55 (d, J = 9.6 Hz, 1H), 5.10 – 5.04 (m, 1H), 3.98 – 3.87 (m, 1H), 3.25 – 3.21 (m, 2H), 2.97 – 2.89 (m, 2H), 2.08 – 2.01(m, 2H), 1.78 – 1.69 (m, 2H), 1.35 (d, J = 6.8 Hz, 6H).

Example 3: Synthesis of 5-(2-((1-acetylpiperidin-4-yl)amino)-5-fluoropyrimidin-4-yl)-1-isopropylpyridin-2(1H)-one (S-3)

The synthetic method of reference example 1 has a yield of 40%, and the product is a white solid. ¹ H NMR (400 MHz, Chloroform- d ) δ 8.33 (d, J = 2.5 Hz, 1H), 8.17 (d, J = 4.0 Hz, 1H), 8.09 (dd, J =9.6, 2.5 Hz, 1H), 6.64 (d, J = 9.6 Hz, 1H), 5.37 – 5. 27 (m, 1H), 5.01 (d, J = 7.6Hz, 1H), 4.55 – 4.49 (m, 1H), 4.08 – 3.97 (m, 1H), 3.86 – 3.81 (m, 1H), 3.29– 3.22 (m, 1H), 2.93 – 2.86 (m, 1H ), 2.18 – 2.08 (m, 5H), 1.51 – 1.45 (m,2H), 1.42 (d, J = 6.8 Hz, 6H).

Example 4: Synthesis of 5-(5-fluoro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1-isopropylpyridin-2(1H)-one (S-4)

The synthetic method of reference example 1 has a yield of 43%, and is a white solid. ¹ H NMR (400 MHz, Chloroform- d ) δ 8.32 (d, J = 2.5 Hz, 1H), 8.16 (d, J = 4.1 Hz, 1H), 8.10 – 8.07(m, 1H), 6.64 (d, J = 9.6 Hz, 1H), 5.35 – 5.29 (m, 1 ( m, 2H), 1.42 (d, J = 6.8 Hz, 6H).

Example 5: Synthesis of 5-(2-((1-(ethylsulfonyl)piperidin-4-yl)amino)-5-fluoropyrimidin-4-yl)-1-isopropylpyridin-2(1H)-one (S-5)

Compound S-2 (265 mg, 0.8 mmol) and triethylamine (243 mg, 2.4 mmol) were dissolved in dichloromethane (5 mL), placed in an ice bath, ethylsulfonyl chloride (154 mg, 1.2 mmol) was added dropwise, the mixture was returned to room temperature, stirred for 2 h, and concentrated by column chromatography to obtain compound S-5 (288 mg, 85% yield) as a white solid. ¹ H NMR (400 MHz, Chloroform- d ) δ 8.33(d, J = 2.5 Hz, 1H), 8.16 (d, J = 4.1 Hz, 1H), 8.08 (dd, J = 9.6, 2.5 Hz, 1H), 6.64(d, J = 9.6 Hz, 1H), 5.36 – 5 .29 (m, 1H), 5.04 (d, J = 7.7 Hz, 1H), 3.99 – 3.89 (m, 1H), 3.82 – 3.79 (m, 2H), 3.07 – 2.96 (m, 4H), 2.19 – 2.15 (m, 2H), 1.65– 1.58 (m, 2H), 1.42 (d, J = 6.9 Hz, 6H), 1.39 (t, J = 7.7 Hz, 3H).

Example 6: Synthesis of 5-(5-fluoro-2-((1-(propylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1-isopropylpyridin-2(1H)-one (S-6)

The synthetic method of reference example 5 has a yield of 88%, and the product is a white solid. ¹ H NMR (400 MHz, Chloroform- d ) δ 8.33 (d, J = 2.5 Hz, 1H), 8.16 (d, J = 4.0 Hz, 1H), 8.09 (dd, J = 9.6, 2.5 Hz, 1H), 6.65 (d, J = 9.6 Hz, 1H), 5.36 – 5. 29 (m, 1H), 5.02 (d, J = 7.6 Hz, 1H), 3.98 – 3.89 (m, 1H), 3.82 – 3.78 (m, 2H), 3.05 – 2.98 (m, 2H), 2.94 – 2.90 (m, 2H), 2.19 – 2.15 (m, 2H ), 1.90 – 1.84 (m, 2H), 1.65 – 1.59 (m, 2H), 1.42 (d, J = 6.8 Hz, 6H), 1.08 (t, J = 7.4 Hz, 3H).

Example 7: Synthesis of 5-(5-fluoro-2-((1-(isopropylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1-isopropylpyridin-2(1H)-one (S-7)

The synthetic method of reference example 5 has a yield of 86%, and the product is a white solid. ¹ H NMR (400 MHz, Chloroform- d ) δ 8.37 ( J = 2.5 Hz, 1H), 8.15 (d, J = 4.1 Hz, 1H), 8.09 (dd, J =9.6, 2.5 Hz, 1H), 6.65 (d, J = 9.6 Hz, 1H), 5.36 – 5.30 (m, 1H), 4.03 – 3.96 (m, 1H), 3.85 – 3.80 (m, 2H), 3.26 – 3.11 (m, 3H), 2.16 – 2.11 (m, 2H), 1.65 – 1.61 (m, 2H), 1.43 (d, J = 6.8 Hz, 6H) , 1.36 (d, J = 6.9 Hz, 6H).

Example 8: Synthesis of 5-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-5-fluoropyrimidin-4-yl)-1-isopropylpyridin-2(1H)-one (S-8)

The synthetic method of reference example 5 had a yield of 89% and was a white solid. ¹ H NMR (400 MHz, Chloroform- d ) δ 8.33 (d, J = 2.5 Hz, 1H), 8.16 (d, J = 4.0 Hz, 1H), 8.09 (dd, J = 9.6, 2.5 Hz, 1H), 6.65 (d, J = 9.6 Hz, 1H), 5.36 – 5. 29 (m, 1H), 5.01 (d, J = 7.6 Hz, 1H), 3.97 – 3.90 (m, 1H), 3.82 – 3.78 (m, 2H), 3.10 – 3.03 (m, 2H), 2.33 – 2.26(m, 1H), 2.20 – 2.16 (m, 2H ), 1.70 – 1.60 (m, 2H), 1.42 (d, J = 6.8 Hz, 6H), 1.21 – 1.19 (m, 2H), 1.02 – 1.00 (m, 2H).

Example 9: Synthesis of 5-(5-fluoro-2-((1-((2-methoxyethyl)sulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1-isopropylpyridin-2(1H)-one (S-9)

The synthetic method of reference example 5 had a yield of 87%, a white solid. ¹ H NMR (400 MHz, Chloroform- d ) δ 8.33 (d, J = 2.5 Hz, 1H), 8.16 (d, J = 4.0 Hz, 1H), 8.09 (dd, J =9.6, 2.5 Hz, 1H), 6.65 (d, J = 9.6 Hz, 1H), 5.37 – 5. 27 (m, 1H), 5.10 (d, J = 7.7Hz, 1H), 3.98 – 3.88 (m, 1H), 3.79 – 3.74 (m, 4H), 3.40 (s, 3H), 3.23 (t, J =5.9 Hz, 2H), 3.07 – 3.00 (m, 2H), 2 .18 – 2.13 (m, 2H), 1.68 – 1.59 (m, 2H), 1.42 (d, J = 6.8 Hz, 6H).

Example 10: Synthesis of 5-(5-fluoro-2-((1-((trifluoromethyl)sulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1-isopropylpyridin-2(1H)-one (S-10)

The synthetic method of reference example 5 has a yield of 82%, and the product is a white solid. ¹ H NMR (400 MHz, Chloroform- d ) δ 8.32 (d, J = 2.5 Hz, 1H), 8.17 (d, J = 4.0 Hz, 1H), 8.08 (dd, J =9.6, 2.5 Hz, 1H), 6.65 (d, J = 9.6 Hz, 1H), 5.35 – 5. 29 (m, 1H), 5.05 (d, J = 7.5Hz, 1H), 4.06 – 3.95 (m, 3H), 3.32 – 3.26 (m, 2H), 2.24 – 2.18 (m, 2H), 1.72– 1.63 (m, 2H), 1.42 (d, J = 6.8 Hz, 6H).

Example 11: Synthesis of 5-(5-fluoro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1-isopropyl-3-methylpyridin-2(1H)-one (S-11)

The synthetic method of reference example 1 has a yield of 38%, and is a white solid. ¹ H NMR (400 MHz, Chloroform- d ) δ 8.20 (d, J = 2.5 Hz, 1H), 8.15 (d, J = 4.1 Hz, 1H), 7.96 – 7.95 (m, 1H), 5.39 – 5.32 (m, 1H), 5.01 (d, J = 7.6 Hz, 1H 1 .41 (d, J = 6.8 Hz, 6H).

Example 12: Synthesis of 1-ethyl-5-(5-fluoro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (S-12)

The synthetic method of reference example 1 has a yield of 44%, and is a white solid. ¹ H NMR (400 MHz, Chloroform- d ) δ 8.26 (d, J = 2.5 Hz, 1H), 8.16 (d, J = 4.0 Hz, 1H), 8.12 (dd, J = 9.6, 2.5 Hz, 1H), 6.64 (d, J = 9.6 Hz, 1H), 5.02 (d, J 1 .71 – 1.67 (m, 2H), 1.42 (t, J = 7.2 Hz, 3H).

Example 13: Synthesis of 3-fluoro-5-(5-fluoro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1-isopropylpyridin-2(1H)-one (S-13)

The synthetic method of reference example 1, the yield is 42%, white solid. ¹ H NMR (400 MHz, Chloroform- d ) δ 8.19 – 8.16 (m, 2H), 7.91 (dd, J = 10.6, 2.2 Hz, 1H), 5.39 – 5.33 (m, 1H), 5.07 (d, J = 7.7 Hz, 1H), 3.95 – 3.92 (m, 1H), 3.82 – 3.77 (m, 2H), 2.98 – 2.91(m, 2H), 2.83 (s, 3H), 2.22 – 2.16 (m, 2H), 1.69 – 1.65 (m, 2H), 1.44 (d, J =6.8 Hz, 6H).

Example 14: Synthesis of 5-(2-((1-(ethylsulfonyl)piperidin-4-yl)amino)-5-fluoropyrimidin-4-yl)-3-fluoro-1-isopropylpyridin-2(1H)-one (S-14)

1. Synthesis of (3-fluoro-5-(5-fluoro-2-(piperidin-4-ylamino)pyrimidin-4-yl)-1-isopropylpyridin-2(1H)-one) (S-14-2)

The synthesis of compound S-14-1 was carried out according to the synthesis method of Example 1, with a yield of 43%, white solid, MS (M + H) ⁺ : found, 450.2;

Using compound S-14-1 as raw material and referring to the synthesis method of Example 2, compound S-14-2 was obtained with a yield of 93% as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.37 (d, J = 3.9 Hz, 1H), 8.23 (s, 1H), 7.88 (dd, J = 11.2, 2.2 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 5.15 – 5.08 (m, 1H ),3.75 – 3.71 (m, 1H), 3.01 – 2.96 (m, 2H), 2.59 – 2.53 (m, 2H), 1.87 – 1.83(m, 2H), 1.42 – 1.33 (m, 8H).

2. Synthesis of (5-(2-((1-(ethylsulfonyl)piperidin-4-yl)amino)-5-fluoropyrimidin-4-yl)-3-fluoro-1-isopropylpyridin-2(1H)-one) (S-14)

Using compound S-14-2 as raw material and referring to the synthesis method of Example 5, compound S-14 was obtained with a yield of 89% as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.40 (d, J = 3.9 Hz, 1H), 8.23 – 8.22 (m,1H), 7.90 (dd, J = 11.2, 2.1 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 5.14 – 5.07 (m,1H), 3.89 – 3.83 (m, 1H), 3.62 – 3.57 (m, 2H), 3.06 (q, J = 7.4 Hz, 2H), 3.01 –2.94 (m, 2H), 1.98 – 1.94 (m, 2H), 1.57 – 1.47 (m, 2H), 1.38 (d, J = 6.8 Hz, 6H), 1.22 (t, J = 7.4 Hz, 3H).

Example 15: Synthesis of 3-fluoro-5-(5-fluoro-2-((1-(propylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1-isopropylpyridin-2(1H)-one (S-15)

The synthetic method of reference example 5 had a yield of 89% and was a white solid. ⁽ m , _1H ), 3.90 – 3.84 (m, 1H), 3.60 – 3.57 (m, 2H) , 3.03 – 2.93 (m, 4H) , 1.98 – 1.94 (m, 2H), 1.73 – 1.68 (m, 2H), 1.57– 1.48 (m, 2H), 1. 38 (d, J = 6.8 Hz, 6H), 1.00 (t, J = 7.4 Hz, 3H).

Example 16: Synthesis of 3-fluoro-5-(5-fluoro-2-((1-(isopropylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1-isopropylpyridin-2(1H)-one (S-16)

The synthetic method of reference example 5 had a yield of 89% and was a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ8.40 (d, J = 3.9 Hz, 1H), 8.23 – 8.22 (m, 1H), 7.90 (dd, J = 11.0, 2.1 Hz, 1H), 7.33 (d, J = 7.7 Hz, 1H), 5.16 – 5.07 ( m, 1H), 3.92 – 3.85 (m, 1H), 3.67 – 3.62 (m, 2H), 3.31 – 3.27 (m, 1H), 3.08 – 3.02 (m, 2H), 1.96 – 1.91 (m, 2H), 1.53 –1.44 (m, 2H), 1.3 8 (d, J = 6.8 Hz, 6H), 1.23 (d, J = 6.7 Hz, 6H).

Example 17: Synthesis of 5-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-5-fluoropyrimidin-4-yl)-3-fluoro-1-isopropylpyridin-2(1H)-one (S-17)

The synthetic method of reference example 5 has a yield of 86%, and the product is a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ8.41 (d, J = 3.8 Hz, 1H), 8.23 – 8.22 (m, 1H), 7.92 – 7.89 (m, 1H), 7.33 (d, J =7.6 Hz, 1H), 5.14 – 5.08 (m, 1H), 3 .90 – 3.82 (m, 1H), 3.63 – 3.58 (m, 2H), 3.03 – 2.97 (m, 2H), 2.62 – 2.56 (m, 1H), 2.00 – 1.96 (m, 2H), 1.61 – 1.51(m, 2H), 1.38 (d, J = 6. 8 Hz, 6H), 1.01 – 0.97 (m, 2H), 0.95 – 0.92 (m, 2H).

Example 18: Synthesis of 3-fluoro-5-(5-fluoro-2-((1-((2-methoxyethyl)sulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1-isopropylpyridin-2(1H)-one (S-18)

The synthetic method of reference example 5 had a yield of 87%, a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ8.41 (d, J = 3.8 Hz, 1H), 8.23 – 8.22 (m, 1H), 7.90 (dd, J = 11.1, 2.2 Hz, 1H),7.33 (d, J = 7.7 Hz, 1H), 5.14 – 5.08 m, 1H), 3.87 – 3.81 (m, 1H), 3.67 (t, J =6.1 Hz, 2H), 3.60 – 3.56 (m, 2H), 3.32 – 3.29 (m, 2H), 3.29 (s, 3H), 2.98 –2.91 (m, 2H), 1.99 – 1 .95 (m, 2H), 1.56 – 1.47 (m, 2H), 1.38 (d, J = 6.8 Hz,6H).

Example 19: Synthesis of 3-fluoro-5-(5-fluoro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1-methylpyridin-2(1H)-one (S-19)

The synthetic method of reference example 1, the yield is 44%, white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ8.41 (d, J = 3.9 Hz, 1H), 8.33 – 8.32 (m, 1H), 7.96 (dd, J = 11.4, 2.3 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 3.89 – 3.83 (m, 1H), 3.63 (s, 3H), 3.55 – 3.51 (m,2H), 2.95 – 2.90 (m, 2H), 2.88 (s, 3H), 2.00 – 1.94 (m, 2H), 1.60 – 1.50 (m,2H).

Example 20: Synthesis of 1-ethyl-3-fluoro-5-(5-fluoro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (S-20)

The synthetic method of reference example 1 has a yield of 48%, and is a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ8.41 (d, J = 3.8 Hz, 1H), 8.32 – 8.31 (m, 1H), 7.94 (dd, J = 11.2, 2.2 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 4.11 (q, J = 7 .1 Hz, 2H), 3.91 – 3.82 (m, 1H), 3.56 –3.51 (m, 2H), 2.95 – 2.89 (m, 2H), 2.88 (s, 3H), 2.00 – 1.95 (m, 2H), 1.60 –1.50 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H).

Example 21: Synthesis of 1-(sec-butyl)-3-fluoro-5-(5-fluoro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (S-21)

The synthetic method of reference example 1 has a yield of 50%, and is a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ8.41 (d, J = 3.8 Hz, 1H), 8.15 – 8.14 (m, 1H), 7.92 – 7.89 (m, 1H), 7.35 (d, J =7.8 Hz, 1H), 4.97 – 4.92 (m, 1H), 3 .87 – 3.80 (m, 1H), 3.55 – 3.51 (m, 2H), 2.93 – 2.85 (m, 5H), 2.00 – 1.96 (m, 2H), 1.80 – 1.70 (m, 2H), 1.60 – 1.52(m, 2H), 1.36 (d, J = 6. 8 Hz, 3H), 0.80 (t, J = 7.4 Hz, 3H).

Example 22: Synthesis of 1-(sec-butyl)-3-fluoro-5-(5-fluoro-2-(piperidin-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one (S-22)

The synthesis of compound S-22-1 was carried out according to the synthesis method of Example 1, with a yield of 40%, white solid, MS (M + H) ⁺ : found, 464.2;

Using compound S-22-1 as raw material and referring to the synthesis method of Example 2, compound S-22 was obtained with a yield of 90% as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.41 (d, J = 3.8 Hz, 1H), 8.16 – 8.15 (m,1H), 7.93 (d, J = 11.2 Hz, 1H), 7.45 (d, J = 7.4 Hz, 1H), 4.98 – 4.92 (m, 1 H),3.96 – 3.85 (m, 1H), 3.23 – 3.18 (m, 2H), 2.93 – 2.85 (m, 2H), 2.02 – 1.98(m, 2H), 1.82 – 1.73 (m, 2H), 1.71 – 1.58 (m, 2H), 1.36 (d, J = 6.8 Hz, 3H),0.80 (t, J = 7.3 Hz, 3H).

Example 23: Synthesis of 1-(sec-butyl)-5-(2-((1-(ethylsulfonyl)piperidin-4-yl)amino)-5-fluoropyrimidin-4-yl)-3-fluoropyridin-2(1H)-one (S-23)

Referring to the synthesis method of Example 5, the yield was 85%. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.40 (d, J =3.8 Hz, 1H), 8.15 – 8.14 (m, 1H), 7.90 (dd, J = 11.1, 2.2 Hz, 1H), 7.34 (d, J =7.7 Hz, 1H), 4.97 – 4.92 ( m, 1H), 3.89 – 3.84 (m, 1H), 3.62 – 3.58 (m, 2H), 3.06 (q, J = 7.3 Hz, 2H), 3.01 – 2.95 (m, 2H), 1.99 – 1.93 (m, 2H), 1.80 – 1.71(m, 2H), 1.56 – 1.48 (m, 2H), 1.36 (d, J = 6.8 Hz, 3H), 1.23 (t, J = 7.3 Hz, 3H), 0.80 (t, J = 7.3 Hz, 3H).

Example 24: Synthesis of 1-(sec-butyl)-5-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)-5-fluoropyrimidin-4-yl)-3-fluoropyridin-2(1H)-one (S-24)

The synthetic method of reference example 5 has a yield of 86%, and the product is a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ8.41 (d, J = 3.8 Hz, 1H), 8.15 (s, 1H), 7.90 (d, J = 11.1 Hz, 1H), 7.35 (d, J = 7.6Hz, 1H), 4.97 – 4.92 (m, 1H), 3.9 0 – 3.82 (m, 1H), 3.63 – 3.58 (m, 2H), 3.03 – 2.97 (m, 2H), 2.61 – 2.58 (m, 1H), 2.01 – 1.94 (m, 2H), 1.80 – 1.72 (m, 2H), 1.61 – 1.51 (m, 2H), 1.36 (d, J = 6.8 Hz, 3H), 1.02 – 0.99 (m, 2H), 0.95 –0.91 (m, 2H), 0.80 (t, J = 7.3 Hz, 3H).

Example 25: Synthesis of 1-(sec-butyl)-3-fluoro-5-(5-fluoro-2-((1-((2-methoxyethyl)sulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (S-25)

The synthetic method of reference example 5 had a yield of 87%, a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ8.40 (d, J = 3.8 Hz, 1H), 8.15 – 8.14 (m, 1H), 7.89 (dd, J = 11.0, 2.2 Hz, 1H), 7.36 – 7.31 (m, 1H), 4.97 – 4.92 (m, 1H), 3.86 – 3.80 (m, 1H), 3.67 (t, J = 6.1Hz, 2H), 3.61 – 3.55 (m, 2H), 3.32 (t, J = 6.1 Hz, 2H), 3.29 (s, 3H), 2.94 (t, J = 11.6 Hz, 2H), 1. 99 – 1.94 (m, 2H), 1.80 – 1.71 (m, 2H), 1.57 – 1.48 (m,2H), 1.36 (d, J = 6.8 Hz, 3H), 0.80 (t, J = 7.3 Hz, 3H).

Example 26: Synthesis of 3-fluoro-5-(5-fluoro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1-isobutylpyridin-2(1H)-one (S-26):

The synthetic method of reference example 1 has a yield of 43%, and is a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ8.41 (d, J = 3.9 Hz, 1H), 8.24 – 8.23 (m, 1H), 7.95 (dd, J = 11.2, 2.2 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 3.93 ( d , J = 7 0 .89 (d, J = 6.7 Hz, 6H).

Example 27: Synthesis of 1-butyl-3-fluoro-5-(5-fluoro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (S-27)

The synthetic method of reference example 1 has a yield of 43%, and is a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ8.41 (d, J = 3.9 Hz, 1H), 8.29 – 8.28 (m, 1H), 7.94 (dd, J = 11.4, 2.2 Hz, 1H), 7.34 (d, J = 7.8 Hz, 1H), 4.08 (t, J = 7 .3 Hz, 2H), 3.89 – 3.81 (m, 1H), 3.55 –3.51 (m, 2H), 2.93 – 2.87 (m, 5H), 1.99 – 1.95 (m, 2H), 1.70 – 1.63 (m, 2H), 1.60 – 1.50 (m, 2H), 1 .36 – 1.26 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H).

Example 28: Synthesis of 3-fluoro-5-(5-fluoro-2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-1-(3-methylbut-2-en-1-yl)pyridin-2(1H)-one (S-28)

The synthetic method of reference example 1 has a yield of 46%, and is a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ8.40 (d, J = 3.9 Hz, 1H), 8.26 – 8.25 (m, 1H), 7.94 (dd, J = 11.3, 2.2 Hz, 1H), 7.34 (d, J = 7.4 Hz, 1H), 5.32 (t, J = 7 .4 Hz, 1H), 4.68 (d, J = 7.2 Hz, 2H), 3.89– 3.81 (m, 1H), 3.56 – 3.51 (m, 2H), 2.92 – 2.85 (m, 5H), 1.99 – 1.95 (m,2H), 1.79 (s, 3H), 1.7 3 (s, 3H), 1.60 – 1.51 (m, 2H).

Example 29: Synthesis of 1-isopropyl-5-(2-((1-(methylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (S-29)

The synthetic method of reference example 1 has a yield of 32%, and is a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ8.47 (d, J = 2.6 Hz, 1H), 8.29 (d, J = 5.3 Hz, 1H), 8.11 (d, J = 9.5 Hz, 1H), 7.20(s, 1H), 7.12 (d, J = 5.3 Hz, 1H), 6.50 (d, J = 9.5 Hz, 1H), 5.12 – 5.05 (m, 1H), 3.96 – 3.86 (m, 1H), 3.58 – 3.53 (m, 2H), 2.94 – 2.85 (m, 5H), 2.04 – 1.95(m, 2H), 1.63 – 1. 53 (m, 2H), 1.37 (d, J = 6.8 Hz, 6H).

Example 30: Synthesis of 5-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-3-fluoro-1-isopropylpyridin-2(1H)-one (S-30)

1. Synthesis of 3-fluoro-1-isopropyl-5-(2-(piperidin-4-ylamino)pyrimidin-4-yl)pyridin-2(1H)-one (S-30-2)

The synthesis of compound S-30-1 was carried out according to the synthesis method of Example 1, with a yield of 41%, white solid, MS (M + H) ⁺ : found, 432.2;

Using compound S-30-1 as raw material and referring to the synthesis method of Example 2, compound S-30-2 was obtained with a yield of 90% as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.42 – 8.41 (m, 1H), 8.33 (d, J = 5.3Hz, 1H), 8.10 (d, J = 10.3 Hz, 1H), 7.46 – 7.42 (m, 1H), 7.23 (d, J = 5.3 Hz, 1H ), 5.16 – 5.10 (m, 1H), 4.14 – 3.99 (m, 1H), 3.31 – 3.25 (m, 2H), 3.06 –2.95 (m, 2H), 2.10 – 2.06 (m, 2H), 1.84 – 1.74 (m, 2H), 1.42 (d, J = 6.8 Hz,6H).

2. Synthesis of 5-(2-((1-(cyclopropylsulfonyl)piperidin-4-yl)amino)pyrimidin-4-yl)-3-fluoro-1-isopropylpyridin-2(1H)-one (S-30)

Using compound S-30-2 as raw material and referring to the synthesis method of Example 5, compound S-30 was obtained with a yield of 82% as a white solid. ¹ H NMR (400 MHz, DMSO- d ₆ ) δ 8.37 (s, 1H), 8.32 (d, J = 5.2 Hz, 1H), 8.06 (d, J = 11.2 Hz, 1H), 7.26 (s, 1H), 7.18 (d, J = 5.3 Hz, 1H), 5.17 – 5. 07(m, 1H), 3.98 – 3.88 (m, 1H), 3.64 – 3.59 (m, 2H), 3.04 – 2.96 (m, 2H), 2.62 – 2.58 (m, 1H), 2.01 – 1.97 (m, 2H), 1.62 – 1.53 (m, 2H), 1.40 (d, J = 6.8 Hz, 6H), 1.03 – 0.97 (m, 2H), 0.95 – 0.91 (m, 2H).

3. Biological Evaluation Experiment

(1) CDK2 kinase activity analysis method

a) Prepare ATP/substrate solution and CDK2 kinase solution in kinase reaction buffer.

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 incubate at 25 °C for 10 minutes.

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

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

e) Transfer the reaction solution to another 384-well plate, centrifuge at 1000 rpm for 1 minute, and then incubate at 25°C for 40 minutes.

f) Read the luminescent signal using a multifunctional microplate reader and calculate the inhibition rate and _IC50 value of the compound on CDK2 kinase.

(2) CDK6 kinase activity analysis method

a) Prepare ATP/substrate solution and CDK6 kinase solution in kinase reaction buffer.

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 incubate at 25 °C for 10 minutes.

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

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

e) Transfer the reaction solution to another 384-well plate, centrifuge at 1000 rpm for 1 minute, and then incubate at 25°C for 40 minutes.

f) Read the luminescent signal using a multifunctional microplate reader and calculate the inhibition rate and _IC50 value of the compound on CDK6 kinase.

Table 1 Inhibitory activity of compounds S-1 to S-10 of the present invention on CDK kinase

A: IC ₅₀ ≤ 100 nM; B: 100 nM< IC ₅₀ ≤ 200 nM; C: 200 nM< IC ₅₀ ≤ 1000 nM; “-”: Not tested.

Table 2 Inhibitory activity of compounds S-11 to S-30 of the present invention on CDK kinase

A: IC ₅₀ ≤ 100 nM; B: 100 nM< IC ₅₀ ≤ 200 nM; C: 200 nM< IC ₅₀ ≤ 1000 nM; “-”: Not tested.

Claims (10)

1. A compound represented by formula (S) or a pharmaceutically acceptable salt thereof, characterized in that:

Wherein R ₁ is selected from hydrogen, halogen, or C ₁-C₃ alkyl;

r ₂ is selected from C ₁-C₈ alkyl or-CH ₂CHC(CH₃)₂ alkenyl;

R ₃ is selected from hydrogen or halogen;

R ₄ is selected from hydrogen, acetyl, -C (O) OC (CH ₃)₃ or-S (O) ₂R₅, R₅ is selected from C ₁-C₅ alkyl, C ₃-C₅ cycloalkyl, -CF ₃ or-CH ₂CH₂OCH₃.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

Said R ₁ is selected from hydrogen, fluoro, or methyl;

The R ₂ is selected from C ₁-C₆ alkyl or-CH ₂CHC(CH₃)₂ alkenyl;

the R ₃ is selected from hydrogen or fluorine;

The R ₄ is selected from hydrogen, acetyl, -C (O) OC (CH ₃)₃ or-S (O) ₂R₅, R₅ is selected from C ₁-C₅ alkyl, C ₃-C₅ cycloalkyl, -CF ₃ or-CH ₂CH₂OCH₃.

3. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

Said R ₁ is selected from hydrogen, fluoro, or methyl;

The R ₂ is selected from C ₁-C₄ alkyl or-CH ₂CHC(CH₃)₂ alkenyl;

the R ₃ is selected from hydrogen or fluorine;

the R ₄ is selected from hydrogen, acetyl, -C (O) OC (CH ₃)₃ or-S (O) ₂R₅, R₅ is selected from C ₁-C₄ alkyl, C ₃-C₅ cycloalkyl, -CF ₃ or-CH ₂CH₂OCH₃.

4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

Said R ₁ is selected from hydrogen, fluoro, or methyl;

The R ₂ is selected from C ₁-C₄ alkyl or-CH ₂CHC(CH₃)₂ alkenyl;

the R ₃ is selected from hydrogen or fluorine;

The R ₄ is selected from hydrogen, acetyl, -C (O) OC (CH ₃)₃ or-S (O) ₂R₅, R₅ is selected from C ₁-C₄ alkyl, cyclopropyl, -CF ₃ or-CH ₂CH₂OCH₃.

5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

Said R ₁ is selected from hydrogen, fluoro, or methyl;

The R ₂ is selected from methyl, ethyl, isopropyl, n-butyl, sec-butyl, isobutyl or-CH ₂CHC(CH₃)₂ alkenyl;

the R ₃ is selected from hydrogen or fluorine;

The R ₄ is selected from hydrogen, acetyl, -C (O) OC (CH ₃)₃ or-S (O) ₂R₅, R₅ is selected from C ₁-C₄ alkyl, cyclopropyl, -CF ₃ or-CH ₂CH₂OCH₃.

6. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

Said R ₁ is selected from hydrogen, fluoro, or methyl;

The R ₂ is selected from methyl, ethyl, isopropyl, n-butyl, sec-butyl, isobutyl or-CH ₂CHC(CH₃)₂ alkenyl;

the R ₃ is selected from hydrogen or fluorine;

The R ₄ is selected from hydrogen, acetyl, -C (O) OC (CH ₃)₃ or-S (O) ₂R₅, R₅ is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CF ₃ or-CH ₂CH₂OCH₃.

7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

The R ₁ is selected from hydrogen or fluorine;

The R ₂ is selected from methyl, ethyl, isopropyl, n-butyl, sec-butyl, isobutyl or-CH ₂CHC(CH₃)₂ alkenyl;

the R ₃ is selected from hydrogen or fluorine;

The R ₄ is selected from hydrogen, acetyl, -C (O) OC (CH ₃)₃ or-S (O) ₂R₅, R₅ is selected from methyl, ethyl, n-propyl, isopropyl, cyclopropyl, -CF ₃ or-CH ₂CH₂OCH₃.

8. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein: a compound selected from any one of the following:

。

9. A process for the preparation of a compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein:

the compound A and the compound B are subjected to a coupling reaction under the action of a palladium catalyst to prepare a compound S;

or the compound C reacts with the compound D under the action of alkali to prepare a compound S;

R ₁ is selected from hydrogen, halogen, or C ₁-C₃ alkyl;

r ₂ is selected from C ₁-C₈ alkyl or-CH ₂CHC(CH₃)₂ alkenyl;

R ₃ is selected from hydrogen or halogen;

R ₄ is selected from hydrogen, acetyl, -C (O) OC (CH ₃)₃ or-S (O) ₂R₅, R₅ is selected from C ₁-C₅ alkyl, C ₃-C₅ cycloalkyl, -CF ₃ or-CH ₂CH₂OCH₃.

10. Use of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, in the preparation of a CDK2 or CDK6 kinase inhibitor.