Cyclic small molecule compound with hexa-penta-aromatic heterocyclic ring and application of cyclic small molecule compound

Abstract

The invention provides a cyclic small molecule compound with hexa-penta-aromatic heterocycle and application thereof, and particularly provides a compound as shown in the formula I. The definition of each group is as shown in the specification. The invention further provides a preparation method of the cyclic small molecule compound with hexa-penta-aromatic heterocycle and application of the cyclic small molecule compound with hexa-penta-aromatic heterocycle. The compound is an effective cyclin dependent kinase, and especially can be used as a CDK2 inhibitor. # imgabs0 #

Description

Technical Field

[0001] The present invention relates to the field of medicinal chemistry, and particularly to a class of cyclic small molecule compounds having a six-fused five-membered heteroaromatic ring and their applications. Background Art

[0002] Cyclin-Dependent Kinases (CDKs) belong to the serine / threonine protein kinase family and are directly involved in the regulation of the cell cycle, promoting the orderly growth, proliferation, and apoptosis of cells. Cell cycle disorder is one of the important characteristics in the occurrence and development of various cancers. Currently, small molecule inhibitors targeting CDK4 / 6 have achieved great success in the market. Therefore, regulating the cell cycle of cancer cells by modulating CDK to achieve anti-cancer effects is an effective means for treating cancer.

[0003] Currently, 13 family members have been discovered. Among them, CDK1, 2, 3, 4, and 6 are directly involved in the regulation of the cell cycle, while CDK8, 9, 10, and 11 play key roles in cell apoptosis, transcription, differentiation, etc. CDK monomers are enzymatically inactive and must bind to cyclin to form a dimer to exert enzymatic activity. Among them, CDK is the catalytic subunit and cyclin is the regulatory subunit. The CDK / cyclin complex participates in the general process of the cell cycle: under the stimulation of growth factors, CDK4 / cyclin D and CDK6 / cyclin D jointly promote the orderly progression from the G0 phase to the G1 phase. Subsequently, CDK2 / cyclin E phosphorylates the retinoblastoma protein (RB), and the transcription factor E2F dissociates from RB, activating the synthesis of DNA by related genes. Then CDK2 binds to cyclin A to jointly promote the transition from the G1 phase to the S phase. The appearance of CDK2 / cyclin A and the unactivated complexes CDK1 / cyclin A and CDK1 / cyclin B marks the completion of the S phase. In the G2 to M phases, CDC25 activates CDK1 / cyclin B, the nuclear membrane ruptures, and chromatin condenses, and the cell transitions from the G2 phase to the M phase.

[0004] CDK2 is a key regulator of various oncogenic signaling pathways, and the increased activity of CDK2 is an important reason for the fast proliferation rate of tumor cells. In addition, experiments have shown that overexpression of cyclin A / E has been observed in key oncogenic processes in various cancers. Therefore, due to the relative specificity of cyclin E for CDK2 and its dysregulation in certain types of cancers, CDK2 is an attractive target for treating specific genotype tumors.

[0005] For a long time, the discovery of CDK inhibitors has been a goal pursued by the academic and industrial communities. Although the early first-generation pan-CDK inhibitors had good anti-tumor activity in vitro, due to low selectivity and large toxic side effects, their clinical applications were developed. Among the currently developed second-generation selective CDK inhibitors, the most studied are CDK4 / 6 inhibitors. Research has shown that CDK2 mediates the drug resistance of CDK4 / 6 inhibitors. Therefore, the research on drugs that can selectively inhibit the activity of CDK2 and exert efficacy in vivo is of great significance for the treatment of tumors.

[0006] Therefore, there is an urgent need in this field to develop drugs that can selectively inhibit the activity of CDK2 and exert efficacy in vivo. Summary of the Invention

[0007] The object of the present invention is to develop drugs that can selectively inhibit the activity of CDK2 and exert efficacy in vivo, and specifically relates to a class of cyclic small molecule compounds with a six-fused five-membered heteroaromatic ring and their applications.

[0008] In the first aspect of the present invention, a compound represented by Formula I is provided.

[0009]

[0010] Wherein,

[0011] Ring A is selected from the following groups: a substituted or unsubstituted C6-C10 aromatic ring (preferably a benzene ring), a substituted or unsubstituted 5-12 membered aromatic heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen, a substituted or unsubstituted 7-12 membered aromatic fused ring, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted heterocycloalkyl containing 1-4 heteroatoms selected from oxygen, sulfur, and nitrogen; wherein, the substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the following group: C1-C6 alkoxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl, sulfonyl (S(O) 2 CH 3 )), hydroxyl, carboxyl, nitro, cyano, amino;

[0012] R 2 is selected from the following groups: a substituted or unsubstituted C1-C6 alkyl, a substituted or unsubstituted C1-C6 cycloalkyl, halogen, hydroxyl; wherein, the substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the following group: hydroxyl, carboxyl, nitro, cyano, amino;

[0013] R 3Selected from the following group: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 cycloalkyl, C1-C6 alkyl-(4-8 membered heterocycloalkyl), substituted or unsubstituted C6-C10 aromatic ring (preferably benzene ring), substituted or unsubstituted 5-12 membered aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted 7-12 membered aromatic fused ring, halogen, hydroxyl; wherein, the said substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the following group: hydroxyl, carboxyl, nitro, cyano, amino;

[0014] Wherein, unless otherwise specified, each of the said heteroaryl, heterocycle, heterocycloalkyl or heteroaromatic ring independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; the said aromatic ring or heteroaromatic ring includes monocyclic, fused or condensed rings;

[0015] The said halogen is F, Cl, Br or I.

[0016] In another preferred example, the said ring A is selected from the following group: substituted or unsubstituted benzene ring, substituted or unsubstituted 5-6 membered aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; wherein, the said substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the following group: C1-C6 alkoxy, halogen, C1-C6 alkyl, sulfonyl.

[0017] In another preferred example, the said ring A is selected from the following group:

[0018] In another preferred example, the said R 2 is selected from the following group: -CH(CH 2 ) 2 , -(CH 2 ) 2 , Br.

[0019] In another preferred example, R 3 is selected from the following group:

[0020] In another preferred example, R 3 is selected from the following group: C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkyl-(4-8 membered heterocycloalkyl), substituted or unsubstituted benzene ring, substituted or unsubstituted 5-10 membered aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted 7-10 membered aromatic fused ring, halogen, hydroxyl; wherein, the said substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the following group: hydroxyl, carboxyl, nitro, cyano, amino.

[0021] In another preferred example, the compound has a structure selected from the following table:

[0022]

[0023]

[0024]

[0025] In a second aspect of the present invention, there is provided a pharmaceutical composition comprising: the compound of formula I as described in the first aspect, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients and / or diluents.

[0026] In a third aspect of the present invention, there is provided the use of the compound of formula I as described in the first aspect for preparing a pharmaceutical composition for treating a disease associated with the inhibition of CDK2 activity.

[0027] In another preferred example, the disease is a cell cycle disorder disease associated with CDK2.

[0028] In another preferred example, the disease is selected from the group consisting of: malignant tumors, essential thrombocythemia, psoriasis, liver cancer, malignant hematological tumors, breast cancer, bladder cancer, lung cancer, glioma, tracheoesophageal fistula, atrial (form) septal defect, thyroglossal cyst, Alzheimer's disease, multiple sclerosis, immunodeficiency, or a combination thereof.

[0029] It should be understood that within the scope of the present invention, the above technical features of the present invention and the technical features specifically described below (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. Detailed Description

[0030] Through extensive and in-depth research and a large number of experimental screenings, the present inventors unexpectedly developed for the first time a class of cyclic small molecule compounds with a six-fused five-membered heteroaromatic ring. The compound can inhibit the activity of CDK2 and can exert a pharmacological effect in vivo, thereby achieving an anti-cancer effect. The present invention was completed on this basis.

[0031] Term Explanation

[0032] In the present invention, the alkyl includes linear or branched alkyl, and the halogen is F, Cl, Br or I, preferably F or Br.

[0033] In particular, in this text, unless otherwise specified, the atoms mentioned include all isotopic forms thereof. For example, when referring to a "hydrogen atom", it refers to a hydrogen atom, a deuterium atom, a tritium atom, or a combination thereof. In the present invention, the abundances of various isotopic atoms of an element can be the natural state in which the element exists in nature or a state in which a certain isotope is enriched.

[0034] The term "C1-C6 alkyl" refers to a straight-chain or branched-chain alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, or a similar group.

[0035] In particular, unless otherwise specified, in the present invention, when the number of carbon atoms of a group is not limited, it refers to a group having 1 to 10 carbon atoms, preferably 1 to 4 carbon atoms.

[0036] The term "5-7 membered heterocycle" refers to a heterocyclic group having 5 to 7 carbon atoms or heteroatoms (selected from N, O, S), which can be a saturated or partially unsaturated cyclic group, such as a pyrrolidinyl group, a piperidinyl group, or a similar group.

[0037] CDK2 inhibitor

[0038] CDK2 mediates the resistance of CDK4 / 6 inhibitor drugs. The compound of formula I of the present invention can selectively inhibit CDK2 and can exert a pharmacological effect in vivo, thereby achieving an anti-cancer effect. In the present invention, a preferred CDK2 inhibitor has the structure shown in formula I as follows:

[0039]

[0040] Wherein,

[0041] Ring A is selected from the group consisting of: a substituted or unsubstituted C6-C10 aromatic ring (preferably a benzene ring), a substituted or unsubstituted 5-12 membered aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen, a substituted or unsubstituted 7-12 membered aromatic fused ring, a substituted or unsubstituted C3-C8 cycloalkyl group, a substituted or unsubstituted heterocycloalkyl group containing 1 to 4 heteroatoms selected from oxygen, sulfur, and nitrogen; wherein, the substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the group consisting of: C1-C6 alkoxy, halogen, C1-C6 alkyl, sulfonyl, hydroxyl, carboxyl, nitro, cyano, amino;

[0042] R 2 is selected from the group consisting of: a substituted or unsubstituted C1-C6 alkyl group, a substituted or unsubstituted C1-C6 cycloalkyl group, halogen, hydroxyl; wherein, the substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the group consisting of: hydroxyl, carboxyl, nitro, cyano, amino;

[0043] R 3 Selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 cycloalkyl, C1-C6 alkyl heterocycloalkyl, substituted or unsubstituted C6-C10 aromatic ring (preferably benzene ring), substituted or unsubstituted 5-12 membered aromatic heterocycle containing 1-4 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted 7-12 membered aromatic fused ring, halogen, hydroxyl; wherein, the said substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the group consisting of: hydroxyl, carboxyl, nitro, cyano, amino;

[0044] Wherein, unless otherwise specified. Each of the heteroaryl, heterocycle, heterocycloalkyl or heteroaromatic ring independently contains 1-4 heteroatoms selected from oxygen, sulfur and nitrogen; the said aromatic ring or heteroaromatic ring includes monocyclic, fused ring or condensed ring;

[0045] The said halogen is F, Cl, Br or I.

[0046] In a more preferred embodiment of the present invention, the compound of general formula I of the present invention is preferably the following specific compounds:

[0047]

[0048]

[0049]

[0050] Preparation method of the compound of formula I

[0051] The method for preparing the compound of formula I is described in the following schemes and examples, where A is I-1 to I-18. The starting materials and intermediates are purchased from commercial sources, prepared by known procedures, or otherwise described. In some cases, the order of steps for carrying out the reaction scheme can be changed to facilitate the reaction or avoid unwanted side reaction products.

[0052] Generally, in the preparation process, each reaction is usually carried out in an inert solvent at room temperature to reflux temperature (such as 0 °C to 150 °C, preferably 10 °C to 100 °C). The reaction time is usually 0.1 hour to 60 hours, preferably 0.5 to 48 hours.

[0053] Preferably, the compound of the present invention can be prepared by the following steps:

[0054]

[0055] s1) In an inert solvent (such as DCM), in the presence of a base (such as DIPEA), compound A-1 and compound A-2 react to obtain compound A-3;

[0056] s2) In an inert solvent (such as acetonitrile), in the presence of a base (such as potassium carbonate), compound A-3 reacts with an amino protecting reagent (such as 4-methoxybenzyl chloride) to obtain compound A-4;

[0057] s3) In an inert solvent (such as acetonitrile), in the presence of an oxidizing agent (such as potassium monopersulfate), compound A-4 reacts to obtain compound A-5;

[0058] s4) In an inert solvent (such as acetonitrile), in the presence of a base (such as DIPEA), compound A-5 reacts with compound A-6 to obtain compound A-7;

[0059] s5) In an inert solvent (such as DMSO), in the presence of a catalyst (such as Grubbs II catalyst), compound A-7 reacts to obtain compound A-8;

[0060] s6) In an inert solvent (such as methanol), in the presence of a catalyst (such as palladium on carbon), compound A-8 reacts with H 2 to obtain compound A-9;

[0061] s7) In an inert solvent (such as methanol), in the presence of an acid (such as trifluoroacetic acid), compound A-9 reacts to obtain compound A-10.

[0062] Preferably, in step s1), the reaction temperature is 0 °C to 50 °C, preferably 20 °C to 30 °C.

[0063] Preferably, in step s2), the reaction temperature is 60 °C to 100 °C, preferably 70 °C to 80 °C.

[0064] Preferably, in step s3), the reaction temperature is 0 °C to 50 °C, preferably 20 °C to 30 °C.

[0065] Preferably, in step s4), the reaction temperature is 90 °C to 130 °C, preferably 100 °C to 110 °C.

[0066] Preferably, in step s5), the reaction temperature is 30 °C to 50 °C, preferably 40 °C.

[0067] Preferably, in step s6), the reaction temperature is 0 °C to 50 °C, preferably 20 °C to 30 °C.

[0068] Preferably, in step s7), the reaction temperature is 0 °C to 50 °C, preferably 20 °C to 30 °C.

[0069] Use of the compound of formula I

[0070] Upon research, the compound of formula I described in the present invention has inhibitory activity against cyclin-dependent kinases (CDKs). Therefore, any one or a mixture of several of the tautomer, racemate, enantiomer, diastereoisomer, pharmaceutically acceptable salt, and pharmaceutically acceptable solvate of the compound of formula I or the derivative described in the present invention can be applied to the preparation of cyclin-dependent kinases, and in particular, can be applied to the preparation of CDK2 inhibitors.

[0071] Meanwhile, the said inhibitor can be applied to the preparation of a drug for preventing or treating diseases related to CDK2. Specifically, it can be applied to the preparation of a drug for preventing or treating cell cycle disorder diseases related to CDK2.

[0072] In addition, the said inhibitor can be applied to the preparation of a drug for treating or preventing cell cycle disorders related to the cyclin-dependent kinase CDK2.

[0073] The active ingredient of the inhibitor described in this patent is preferably the specific compound shown in the present invention, or any one or a mixture of several of the tautomer, racemate, enantiomer, diastereoisomer, pharmaceutically acceptable salt, and pharmaceutically acceptable solvate of the shown compound.

[0074] Pharmaceutical compositions and their uses

[0075] On the other hand, the present invention provides a pharmaceutical composition which contains a therapeutically effective amount of one or more selected from the compounds of the above general formula (I), their pharmaceutically acceptable salts, enantiomers, diastereoisomers or racemates, and optionally, one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliary materials and / or diluents. The auxiliary materials are, for example, odorants, flavorants, sweeteners, etc.

[0076] The pharmaceutical composition provided by the present invention preferably contains 1 - 99% by weight of the active ingredient, and its preferred ratio is that the compound of general formula I as the active ingredient accounts for 65wt% - 99% of the total weight, and the remaining part is a pharmaceutically acceptable carrier, diluent or solution or salt solution.

[0077] The compounds and pharmaceutical compositions provided by the present invention can be in various forms, such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, etc., and can exist in a suitable solid or liquid carrier or diluent and a suitable sterilized apparatus for injection or infusion.

[0078] The various dosage forms of the pharmaceutical composition of the present invention can be prepared according to the conventional preparation methods in the pharmaceutical field. The unit dosage of its formulation contains 0.05 - 200 mg of the compound of general formula I, and preferably, the unit dosage of the formulation contains 0.1 mg - 100 mg of the compound of general formula I.

[0079] The compounds and pharmaceutical compositions of the present invention can be clinically used in mammals, including humans and animals, and can be administered through routes such as oral, nasal, dermal, pulmonary, or gastrointestinal. The most preferred is oral administration. The most preferred daily dose is 0.01 - 200 mg / kg body weight, taken once, or 0.01 - 100 mg / kg body weight taken in divided doses. Regardless of the administration method, the optimal dose for an individual should be determined according to the specific treatment. Usually, it starts with a small dose and gradually increases until the most suitable dose is found.

[0080] Another aspect of the present invention provides a CDK2 inhibitor, which comprises one or more selected from the compounds represented by the above general formula I, their pharmaceutically acceptable salts, isomers, or mixtures thereof, and optionally one or more pharmaceutically acceptable carriers, excipients, adjuvants, auxiliaries, and / or diluents.

[0081] The compounds and compositions of the present invention are used for the treatment and prevention of cell cycle disorder diseases related to CDK2, and the diseases include, but are not limited to, malignant tumors, essential thrombocythemia, psoriasis, liver cancer, malignant hematological tumors, breast cancer, bladder cancer, lung cancer, glioma, tracheoesophageal fistula, atrial septal defect, thyroglossal duct cyst, Alzheimer's disease, multiple sclerosis, immunodeficiency diseases, etc.

[0082] Therefore, another aspect of the present invention provides the use of the compounds represented by the above general formula I, their pharmaceutically acceptable salts, isomers, or mixtures thereof in the preparation of drugs for the treatment of cell cycle disorder diseases related to CDK2, such as: malignant tumors, essential thrombocythemia, psoriasis, liver cancer, malignant hematological tumors, breast cancer, bladder cancer, lung cancer, glioma, tracheoesophageal fistula, atrial septal defect, thyroglossal duct cyst, Alzheimer's disease, multiple sclerosis, immunodeficiency diseases, etc.

[0083] Another aspect of the present invention provides a method for treating cell cycle disorder diseases related to CDK2 activity or expression level, such as: malignant tumors, essential thrombocythemia, psoriasis, liver cancer, malignant hematological tumors, breast cancer, bladder cancer, lung cancer, glioma, tracheoesophageal fistula, atrial septal defect, thyroglossal duct cyst, Alzheimer's disease, multiple sclerosis, immunodeficiency diseases, etc., which comprises administering to a patient in need of such treatment one or more selected from the compounds represented by the above general formula I, their pharmaceutically acceptable salts, isomers, or mixtures thereof.

[0084] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0085] 1. A class of cyclic small molecule compounds with a six-fused five-membered heteroaromatic ring is provided, and the compounds have an inhibitory effect on the activity of cyclin-dependent kinase CDK2.

[0086] 2. The compounds of the present invention have a different mechanism of action from existing compounds and are therefore expected to be used as lead compounds for the development of more CDK2 inhibitor molecules.

[0087] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are generally carried out under conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are by weight.

[0088] Example 1, Synthesis and Characterization of Compound II-1

[0089]

[0090] Step 1: The synthesis of compound II-1-1 was referenced from (European Journal of Medicinal Chemistry, 2018, 158, 1-6).

[0091] Step 2: Synthesis of compound II-1-2

[0092]

[0093] To a solution of 4-fluoro-2-hydroxybenzaldehyde (5 g, 35.5 mmol, 1 eq, CAS: 348-28-7) in acetonitrile (120 mL), 4-bromo-1-butene (11 ml, 106.5 mmol, 3 eq, CAS: 5162-44-7) and potassium carbonate (10 g, 71 mmol, 2 eq) were added successively. After purging with nitrogen three times, the reaction was stirred in an oil bath at 90 °C for 18 hours. TLC was used to detect until the raw materials were completely reacted. The reaction solution was concentrated by rotary evaporation to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (PE:EA = 5:1) to obtain a colorless oily liquid II-1-2-2 (5.59 g).

[0094] To a solution of II-1-2-2 (5.5 g, 28.5 mmol, 1 eq) in ethanol (120 mL), sodium carbonate (9.2 g, 85.67 mmol, 3 eq) and hydroxylamine hydrochloride (3.17, 42.84 mmol, 1.5 eq, CAS: 5470-11-1) were added successively. The reaction was carried out at room temperature for 6 hours. TLC and LCMS were used to detect until the raw materials were completely reacted. The reaction solution was concentrated by rotary evaporation to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (PE:EA = 5:1) to obtain a colorless oily liquid II-1-2-3 (5.8 g).

[0095] To a solution of II-1-2-3 (3g, 14.3 mmol, 1 eq) in tetrahydrofuran (70 mL), hydrochloric acid (11.4 mL, 12 M, 143 mmol, 8 eq) and zinc powder (9.3 g, 143 mmol, 8 eq) were successively added. The reaction was carried out at room temperature for 12 hours. TLC and LCMS were used to detect the complete reaction of the starting materials. The reaction mixture was filtered and concentrated in vacuo to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (DCM:MeOH = 15:1) to obtain a colorless oily liquid II-1-2 (1.94 g).

[0096] Step 3: Synthesis of compound II-1-3

[0097] To a solution of II-1-1 (1.6 g, 6.6 mmol, 1 eq) in N,N-dimethylformamide (30 mL), II-1-2 (1.28 g, 6.6 mmol, 1 eq) and potassium carbonate (3.6 g, 23.7 mmol, 3 eq) were successively added. The reaction was carried out at room temperature for 8 hours. TLC was used to detect the complete reaction of the starting materials. A large amount of water (500 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain the crude product. The crude product was purified by column chromatography (PE:EA = 10:1) to obtain a colorless oily liquid II-1-3 (0.9 g).

[0098] Step 4: Synthesis of compound II-1-4

[0099] To a solution of II-1-3 (0.9 g, 2.3 mmol, 1 eq) in N,N-dimethylformamide (8 mL), 4-methoxybenzyl chloride (0.57 ml, 2.3 mmol, 1.5 eq) and potassium carbonate (1.14 g, 4.6 mmol, 4.6 eq) were successively added. The reaction was stirred in an oil bath at 70 °C for 3 hours. TLC was used to detect the complete reaction of the starting materials. A large amount of water (500 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a colorless oily crude product II-1-4 (1.5 g).

[0100] Step 5: Synthesis of compound II-1-5

[0101] To a mixed solution of II-1-4 (1.5 g, 2.8 mmol, 1 eq) in acetonitrile (10 mL) / water (5 mL), potassium monopersulfate (5.5 g, 8.6 mmol, 3 eq) was added. The reaction was carried out at room temperature for 12 hours, and TLC was used to detect the complete reaction of the starting materials. 100 mL of water was added to the reaction solution, and then it was extracted with dichloromethane (50 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE:EA = 5:1) to obtain a yellow oily liquid II-1-5 (386 mg).

[0102] Step 6: Synthesis of compound II-1-6

[0103]

[0104] Compound 1-Boc-3-aminomethylazetidine (5 g, 26.8 mmol, 1 eq) and triethylamine (7.5 mL, 53.6 mmol, 2 eq) were dissolved in dry tetrahydrofuran solution (100 mL). A mixed solution of 3-bromopropene (2.3 mL, 26.8 mmol, 1 eq) and dry tetrahydrofuran solution (10 mL) was added dropwise. The reaction was carried out at room temperature for 12 hours, and TLC and LCMS were used to detect the complete reaction of the starting materials. The reaction solution was concentrated to dryness to obtain a crude product. The crude product was separated and purified by silica gel column chromatography (DCM:MeOH = 15:1) to obtain a colorless oily liquid II-1-6 (4.5 g).

[0105] Step 7: Synthesis of compound II-1-7

[0106] To a solution of II-1-5 (386 mg, 0.69 mmol, 1 eq) in N-methylpyrrolidone (1.2 mL), II-1-6 (500 mg, 2.07 mmol, 3 eq) and N,N-diisopropylethylamine (1.2 mL, 6.9 mmol, 10 eq) were added in sequence. After replacing the nitrogen three times, the reaction was placed in an oil bath at 150 °C and stirred for 48 hours. TLC and LCMS were used to detect the complete reaction of the starting materials. A large amount of water (300 mL) was added to the reaction solution, and it was extracted with ethyl acetate (50 mL×3). The combined organic phases were washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography (PE:EA = 5:1) to obtain a colorless oily liquid II-1-7 (185 mg).

[0107] Step 8: Synthesis of compound II-1-8

[0108] To a dry dichloromethane solution (260 mL) of II-1-7 (185 mg, 0.26 mmol, 1 eq) was added Grubbs II catalyst (72 mg, 0.078 mmol, 0.3 eq). After purging with nitrogen three times, the reaction was stirred in an oil bath at 40 °C for 12 hours. TLC and LCMS were used to detect until the raw materials were completely reacted. The reaction solution was filtered and concentrated in vacuo to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (PE:EA = 5:1) to obtain a colorless oily liquid II-1-8 (85 mg).

[0109] Step 9: Synthesis of compound II-1-9

[0110] To a dry tetrahydrofuran solution (2 mL) of II-1-8 (85.5 mg, 0.13 mmol, 1 eq) was added palladium on carbon (85.5 mg, 30% Wt). After purging with hydrogen three times, the reaction was stirred at room temperature for 12 hours. TLC and LCMS were used to detect until the raw materials were completely reacted. The reaction solution was filtered and concentrated in vacuo to obtain the crude product. The crude product was separated and purified by silica gel column chromatography (PE:EA = 5:1) to obtain a colorless oily liquid II-1-9 (97 mg).

[0111] Step 10: Synthesis of compound II-1

[0112] To a dichloromethane solution (1 mL) of compound II-1-9 (97 mg, 0.14 mmol, 1 eq) was added trifluoroacetic acid (3 mL). The reaction was stirred at room temperature for 12 hours. TLC and LCMS were used to detect until the raw materials were completely reacted. The reaction solution was adjusted to pH neutral with saturated sodium bicarbonate solution and extracted with ethyl acetate (20 mL × 3). The organic phase was washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a colorless oily crude product. The crude product was separated and purified by pre-HPLC (FA) to obtain a white solid II-1 (10.3 mg). 1H NMR (400 MHz, CD3OD-d4) δ = 8.00 (s, 1H), 7.48 - 7.44 (m, 1H), 6.80 - 6.77 (m, 1H), 6.70 - 6.65 (m, 1H), 4.50 - 4.46 (m, 1H), 4.13 - 4.10 (m, 3H), 3.86 - 3.81 (m, 3H), 3.60 - 3.54 (m, 1H), 3.40 - 3.35 (m, 1H), 3.22 - 3.15 (m, 2H), 2.74 - 2.70 (m, 1H), 1.98 - 1.90 (m, 4H), 1.81 - 1.79 (m, 2H), 1.35 - 1.32 (m, 6H); LCMS (M+1): 454.41

[0113] Example 2, Synthesis and characterization of compound II-2

[0114] Refer to the synthetic route of Compound II-1, where II-1-2-1 is replaced with II-2-2-1 (CAS: 210039-65-9). The final product was separated and purified by pre-HPLC (FA) to obtain II-2. LCMS (M+1): 504.26. 1 H NMR(400MHz,CD 3 OD-d4) δ = 8.03(s, 1H), 7.82 - 7.81(m, 1H), 7.59 - 7.56(m, 1H), 7.16 - 7.18(m, 1H), 4.47 - 4.43(m, 1H), 4.25 - 4.23(m, 2H), 4.10 - 4.05(m, 1H), 3.86 - 3.81(m, 2H), 3.79 - 3.78(m, 2H), 3.56 - 3.49(m, 1H), 3.38 - 3.36(m, 1H), 3.14 - 3.06(m, 2H), 2.64 - 2.62(m, 1H), 2.01 - 2.00(m, 2H), 1.99 - 1.91(m, 2H), 1.84 - 1.81(m, 2H), 1.35 - 1.32(m, 6H).

[0115] Example 3, Synthesis and Characterization of Compound II-3

[0116] Refer to the synthetic route of Compound II-1, where II-1-2-1 is replaced with II-3-2-1 (CAS: 632628-02-5). The final product was separated and purified by pre-HPLC (FA) to obtain II-8. LCMS (M+1): 514.25.

[0117] Example 4, Synthesis and Characterization of Compound II-4

[0118] Refer to the synthetic route of Compound II-1, where II-1-2-1 is replaced with II-4-2-1 (CAS: 74901-29-4). The final product was separated and purified by pre-HPLC (FA) to obtain II-4. 1 H NMR(400MHz,CD 3OD-d4) δ = 8.03 (s, 1H), 7.82 - 7.81 (m, 1H), 7.66 - 7.63 (m, 1H), 7.18 - 7.16 (m, 1H), 4.50 - 4.46 (m, 1H), 4.26 - 4.24 (m, 2H), 4.15 - 4.09 (m, 1H), 3.85 - 3.81 (m, 2H), 3.75 - 3.73 (m, 1H), 3.59 - 3.53 (m, 1H), 3.40 - 3.38 (m, 1H), 3.36 - 3.30 (m, 4H), 3.19 - 3.16 (m, 2H), 2.00 - 1.97 (m, 2H), 1.91 - 1.82 (m, 2H), 1.81 - 1.79 (m, 2H), 1.35 - 1.32 (m, 6H); LCMS (M+1): 461.27。

[0119] Example 5, Synthesis and Characterization of Compound II-5

[0120] Referring to the synthetic route of Compound II-1, wherein II-1-2-1 is replaced with II-5-2-1 (CAS: 1194-98-5). The final product was separated and purified by pre-HPLC (FA) to obtain II-5. LCMS (M+1): 450.29。 1 H NMR (400 MHz, CD 3 OD-d4) δ = 8.01 (s, 1H), 7.33 - 7.31 (m, 1H), 6.81 (s, 1H), 6.77 - 6.75 (m, 1H), 4.48 - 4.44 (m, 2H), 4.14 - 4.13 (m, 1H), 4.12 - 4.10 (m, 3H), 4.09 - 4.06 (m, 1H), 3.82 (m, 1H), 3.80 - 3.78 (m, 2H), 3.56 - 3.53 (m, 2H), 3.50 - 3.48 (m, 1H), 3.18 - 3.15 (m, 2H), 3.14 - 3.13 (m, 2H), 2.30 (s, 1H), 1.96 - 1.90 (m, 4H), 1.81 - 1.79 (m, 2H), 1.64 - 1.61 (m, 1H), 1.36 - 1.31 (m, 6H)。

[0121] Example 6, Synthesis and Characterization of Compound II-6

[0122] Referring to the synthetic route of Compound II-1, wherein II-1-2-1 is replaced with II-6-2-1 (CAS: 1761-61-1). The final product was separated and purified by pre-HPLC (FA) to obtain II-6. LCMS (M+1): 514.19。 1 H NMR (400 MHz, CD 3OD-d4) δ = 8.03 (s, 1H), 7.61 - 7.60 (m, 1H), 7.38 - 7.35 (m, 1H), 6.95 - 6.93 (m, 1H), 4.48 - 4.44 (m, 1H), 4.16 - 4.09 (m, 2H), 3.84 - 3.82 (m, 1H), 3.80 - 3.74 (m, 2H), 3.56 - 3.51 (m, 2H), 3.21 - 3.12 (m, 2H), 2.68 - 2.66 (m, 1H), 1.96 - 1.94 (m, 2H), 1.91 - 1.87 (m, 2H), 1.82 - 1.78 (m, 2H), 1.35 - 1.32 (m, 6H).

[0123] Example 7, Synthesis and Characterization of Compound II-7

[0124] Referring to the synthetic route of Compound II-1, wherein II-1-2-1 is replaced with II-7-2-1 (CAS: 673-22-3). The final product was separated and purified by pre-HPLC (FA) to obtain II-7. LCMS (M+1): 466.29.

[0125] Example 8, Synthesis and Characterization of Compound II-8

[0126] Referring to the synthetic route of Compound II-1, wherein II-1-2-1 is replaced with II-8-2-1 (CAS: 613-84-3). The final product was separated and purified by pre-HPLC (FA) to obtain II-8. LCMS (M+1): 450.29. 1 H NMR (400 MHz, CD 3 OD-d4) δ = 8.01 (s, 1H), 7.27 - 7.26 (m, 1H), 7.07 - 7.04 (m, 1H), 6.88 - 6.87 (m, 1H), 4.46 - 4.41 (m, 2H), 4.12 - 4.06 (m, 4H), 3.88 - 3.84 (m, 2H), 3.80 - 3.76 (m, 3H), 3.53 - 3.48 (m, 2H), 3.08 - 3.05 (m, 2H), 2.58 (s, 2H), 2.25 (s, 3H), 1.97 - 1.94 (m, 4H), 1.80 - 1.79 (m, 2H), 1.64 - 1.61 (m, 1H), 1.34 - 1.32 (m, 6H).

[0127] Example 9, Synthesis and Characterization of Compound II-9

[0128] Refer to the synthetic route of compound II-1, where II-1-2-1 is replaced with II-9-2-1 (CAS: 32768-36-8). The final product was separated and purified by pre-HPLC (FA) to obtain II-9. LCMS (M+1): 437.27. 1 H NMR(400MHz,CD 3 OD-d4)δ=8.07-8.04(m,1H),8.04(s,1H),7.83-7.81(m,1H),6.98-6.95(m,1H),4.53-4.44(m,2H),4.12-4.06(m,2H),3.82-3.77(m,3H),3.57-3.48(m,2H),3.20-3.13(m,3H),2.67(s,1H),1,97-1.96(m,2H),1.90-1.88(m,2H),1.81-1.76(m,2H),1.36-1.33(m,6H).

[0129] Example 10, Synthesis and Characterization of Compound II-10

[0130] Refer to the synthetic route of compound II-1, where II-1-2-1 is replaced with II-10-2-1 (CAS: 1423547-16-3) and II-1-6-1 is replaced with II-10-6-1 (CAS: 144222-22-0). The final product was separated and purified by pre-HPLC (FA) to obtain II-10. LCMS (M+1): 542.28.

[0131] Example 11, Synthesis and Characterization of Compound II-11

[0132] Refer to the synthetic route of compound II-1, where II-1-2-1 is replaced with II-11-2-1 (CAS: 1849-54-3). The final product was separated and purified by pre-HPLC (FA) to obtain II-11. LCMS (M+1): 437.27.

[0133] Example 12, Synthesis and Characterization of Compound II-12

[0134] Refer to the synthetic route of compound II-1, where II-1-2-1 is replaced with II-12-2-1 (CAS: 1255352-02-3). The final product was separated and purified by pre-HPLC (FA) to obtain II-12. LCMS (M+1): 440.28. 1 H NMR(400MHz,CD 3OD-d4) δ = 8.02 (m, 1H), 7.45 (m, 1H), 4.26 - 4.24 (m, 2H), 3.84 - 3.82 (m, 2H), 3.70 (s, 3H), 3.59 - 3.56 (m, 2H), 3.45 - 3.44 (m, 2H), 3.23 - 3.20 (m, 2H), 3.17 - 3.14 (m, 2H), 2.38 - 2.36 (m, 1H), 1.94 - 1.92 (m, 2H), 1.87 - 1.84 (m, 2H), 1.80 - 1.77 (m, 2H), 1.65 - 1.63 (m, 2H), 1.36 - 1.34 (m, 6H).

[0135] Example 13, Synthesis and Characterization of Compound II-13

[0136] Referring to the synthetic route of Compound II-1, where II-1-2-1 is replaced by II-13-2-1 (CAS: 90-02-8) and II-1-1 is replaced by II-13-1. The synthesis of Compound II-13-1 was referenced from (Bioorganic & Medicinal Chemistry Letters, 2016, 26, 3562–3566). The final product was separated and purified by pre-HPLC (FA) to obtain II-13. LCMS (M+1): 472.14. 1 H NMR (400 MHz, CD 3 OD-d4) δ = 7.98 (m, 1H), 7.50 - 7.46 (m, 1H), 7.37 - 7.34 (m, 1H), 7.27 - 7.23 (m, 1H), 7.00 - 6.91 (m, 2H), 4.81 - 4.77 (m, 1H), 4.31 - 4.25 (m, 1H), 4.14 - 4.12 (m, 2H), 3.88 - 3.84 (m, 3H), 3.60 - 3.55 (m, 1H), 3.17 - 3.13 (m, 2H), 2.71 (s, 1H), 1.99 - 1.96 (m, 4H), 1.81 - 1.78 (m, 2H)

[0137] Example 14, Synthesis and Characterization of Compound II-14

[0138] Refer to the synthetic route of Compound II-1, where II-1-2-1 is replaced by II-14-2-1 (CAS: 90-02-8), and II-1-1 is replaced by II-14-1. The synthesis of Compound II-14-1 is referred to (Bioorganic & Medicinal Chemistry Letters, 2016, 26, 3562–3566). The final product was separated and purified by pre-HPLC (FA) to obtain II-14. LCMS (M+1): 434.26. 1 H NMR(400MHz,CD 3 OD-d4)δ=7.67(m,1H),7.35-7.33(m,1H),7.16-7.14(m,1H),6.89-6.87(m,1H),6.84-6.80(m,1H),4.72-4.67(m,2H),4.22-4.02(m,1H),4.05-4.02(m,2H),3.79-3.75(m,2H),3.73-3.71(m,2H),3.47-3.44(m,1H),3.09-3.03(m,3H),2.59-2.58(m,3H),1.89-1.81(m,4H),1.81-1.70(m,2H),1.22-1.19(m,3H),0.91-0.88(m,2H),0.66-0.62(m,2H).

[0139] Example 15, Synthesis and Characterization of Compound II-15

[0140] Refer to the synthetic route of Compound II-1, where II-1-2-1 is replaced by II-15-2-1 (CAS: 90-02-8), and II-1-1 is replaced by II-15-1. The synthesis of Compound II-15-1 is referred to (Bioorganic & Medicinal Chemistry Letters, 2016, 26, 3562–3566). The final product was separated and purified by pre-HPLC (FA) to obtain Ⅰ-25. LCMS (M+1): 422.26. 1 HNMR(400MHz,CD 3OD-d4) δ = 7.89 (s, 1H), 7.50 - 7.44 (m, 1H), 7.37 - 7.34 (m, 1H), 7.27 - 7.22 (m, 1H), 6.99 - 6.91 (m, 1H), 4.51 - 4.46 (m, 1H), 4.14 - 4.10 (m, 3H), 3.89 - 3.83 (m, 1H), 3.82 - 3.79 (m, 2H), 3.56 - 3.51 (m, 1H), 3.17 - 3.12 (m, 2H), 2.86 - 2.80 (m, 2H), 1.98 - 1.92 (m, 4H), 1.82 - 1.78 (m, 2H), 1.32 - 1.28 (m, 4H).

[0141] Example 16, Synthesis and Characterization of Compound II-16

[0142] Refer to the synthetic route of Compound II-1, where II-1-2-1 is replaced with II-16-2-1 (CAS: 90-02-8) and II-1-6-1 is replaced with II-16-6-1 (CAS: 871014-19-6). The final product was separated and purified by pre-HPLC (FA) to obtain II-16. LCMS (M+1): 436.27. 1 H NMR (400 MHz, CD 3 OD-d4) δ = 7.74 (s, 1H), 7.46 - 7.43 (m, 1H), 7.24 - 7.19 (m, 1H), 6.98 - 6.90 (m, 2H), 5.08 - 5.04 (m, 1H), 4.89 (s, 1H), 4.17 - 4.15 (m, 2H), 3.91 - 3.87 (m, 1H), 3.65 - 3.63 (m, 2H), 3.15 - 3.09 (m, 1H), 2.93 - 2.85 (m, 2H), 2.57 - 2.52 (m, 2H), 1.94 - 1.91 (m, 2H), 1.80 - 1.79 (m, 4H), 1.29 - 1.28 (m, 6H).

[0143] Example 17, Synthesis and Characterization of Compound II-17

[0144] Refer to the synthetic route of Compound II-1, where II-1-2-1 is replaced with II-17-2-1 (CAS: 90-02-8) and II-1-6-1 is replaced with II-17-6-1 (CAS: 130290-79-8). The final product was separated and purified by pre-HPLC (FA) to obtain I-38. LCMS (M+1): 533.28.

[0145] Example 18, Synthesis and Characterization of Compound II-18

[0146] Refer to the synthetic route of Compound II-1, where II-1-2-1 is replaced with II-18-2-1 (CAS: 90-02-8) and II-1-6-1 is replaced with II-18-6-1 (CAS: 645400-44-8). The final product was separated and purified by pre-HPLC (FA) to obtain II-18. LCMS (M+1): 450.29. 1 H NMR (400 MHz, CD 3 OD-d4) δ = 7.74 (s, 1H), 7.46 - 7.43 (m, 1H), 7.33 - 7.29 (m, 1H), 7.23 - 7.19 (m, 1H), 6.98 - 6.90 (m, 1H), 4.89 - 4.86 (m, 1H), 4.18 - 4.15 (m, 1H), 4.09 - 4.03 (m, 1H), 3.96 - 3.92 (m, 1H), 3.60 - 3.55 (m, 1H), 3.53 - 3.48 (m, 1H), 3.15 - 3.13 (m, 1H), 2.38 - 2.28 (m, 2H), 2.10 - 2.00 (m, 2H), 1.91 (m, 2H), 1.78 (m, 2H), 1.69 - 1.61 (m, 2H), 1.32 - 1.28 (m, 6H).

[0147] Biological test examples

[0148] Test Example 1: Biochemical test for the inhibition of CDK2 / cyclinE kinase protein activity by the compound

[0149] The GST-tagged CDK2 / cyclinE kinase protein complex and Eu-anti-GST were prepared as 2X solutions in a buffer system consisting of 50 mL HEPES pH 7.5, 0.01% BRIJ-35, 10 mM MgCl 2 and 1 mM EGTA.

[0150] The AlexaFluor-labeled Tracer was prepared as a 2X solution in the Kinase buffer.

[0151] In a 384-well plate (Greiner #784207), the solutions were added or the corresponding operations were performed in the following steps in sequence:

[0152] 1. 3.84 uL of Kinase buffer

[0153] 2. 160 nL - 100X DMSO solution of the test compound

[0154] 3. 8.0 uL - 2X CDK2 / cyclinE kinase protein complex and Eu-anti-GST solution

[0155] 4. 4.0 uL – 4X AlexaFluor-labeled Tracer solution

[0156] 5. Shake the microplate for 30 seconds

[0157] 6. Incubate at room temperature for 60 minutes for equilibration

[0158] 7. Read the fluorescence value

[0159] In the final incubation system, it contains 2.5 nM CDK2 / cyclinE kinase protein complex, 2 nM Eu-anti-GST, and 100 nM AlexaFluor-labeled Tracer. The test compound is serially diluted 3-fold starting from the highest concentration of 10 uM, with a total of 11 concentration points. Set 2 replicates. Calculate the inhibition rate of each well based on the fluorescence reading, plot the dose-response curve, and calculate the half-maximal inhibitory concentration IC 50 , and the results are shown in Table 1 below.

[0160] Table 1: Half-maximal inhibitory concentration IC 50

[0161]

[0162] The experimental results show that some compounds exhibit good inhibitory ability against CDK2 enzyme activity.

[0163] All documents mentioned in this invention are cited in this application for reference as if each document was cited separately for reference. In addition, it should be understood that after reading the above teachings of this invention, those skilled in the art can make various changes or modifications to this invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. A compound represented by Formula I, wherein, Ring A is selected from the following groups: a substituted or unsubstituted C6-C10 aromatic ring (preferably a benzene ring), a substituted or unsubstituted 5-12 membered aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, a substituted or unsubstituted 7-12 membered aromatic fused ring, a substituted or unsubstituted C3-C8 cycloalkyl, a substituted or unsubstituted heterocycloalkyl containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; wherein, the said substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the following groups: C1-C6 alkoxy, halogen, C1-C6 alkyl, C1-C6 haloalkyl, sulfonyl (S(O) 2 CH 3 )), hydroxyl, carboxyl, nitro, cyano, amino; R 2 selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 cycloalkyl, halogen, hydroxy; wherein said substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the group consisting of: hydroxy, carboxy, nitro, cyano, amino; R 3 selected from the group consisting of: substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C1-C6 cycloalkyl, C1-C6 alkyl-(4-8 membered heterocycloalkyl), substituted or unsubstituted C6-C10 aromatic ring (preferably benzene ring), substituted or unsubstituted 5-12 membered aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted 7-12 membered aromatic fused ring, halogen, hydroxyl; wherein, the said substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the group consisting of: hydroxyl, carboxyl, nitro, cyano, amino; wherein, unless otherwise specified, each of the heteroaryl, heterocycle, heterocycloalkyl or heteroaromatic ring independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; the aromatic ring or heteroaromatic ring includes a monocyclic, fused-ring or condensed-ring; the halogen is F, Cl, Br or I.

2. The compound of Formula I according to claim 1, characterized in that, ring A is selected from the group consisting of: a substituted or unsubstituted benzene ring, a substituted or unsubstituted 5- to 6-membered aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen; wherein, the substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the group consisting of: C1-C6 alkoxy, halogen, C1-C6 alkyl, sulfonyl.

3. The compound of Formula I according to claim 1, characterized in that, The ring A described above is selected from the following group:

4. The compound of Formula I according to claim 1, characterized in that, The described R 2 is selected from the group consisting of: -CH(CH 2 ) 2 , -(CH 2 ) 2 , Br.

5. The compound of Formula I according to claim 1, characterized in that, R 3 Selected from the group consisting of:

6. The compound of Formula I according to claim 1, characterized in that, R 3 Selected from the following group: C1-C6 alkyl, C1-C6 cycloalkyl, C1-C6 alkyl-(4-8 membered heteroalkyl), substituted or unsubstituted benzene ring, substituted or unsubstituted 5-10 membered aromatic heterocycle containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen, substituted or unsubstituted 7-10 membered aromatic fused ring, halogen, hydroxyl; wherein, the said substitution means that one or more hydrogen atoms on the group are substituted by substituents selected from the following group: hydroxyl, carboxyl, nitro, cyano, amino.

7. The compound according to claim 1, characterized in that, the compound has a structure selected from the following table:

8. A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises: the compound of Formula I according to claim 1, and one or more pharmaceutically acceptable carriers, excipients, adjuvants, excipients and / or diluents.

9. Use of the compound of Formula I according to claim 1, characterized in that, for preparing a pharmaceutical composition for treating diseases related to the inhibition of CDK2 activity.

10. The use according to claim 9, characterized in that, the disease is a cell cycle disorder disease related to CDK2.

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