CN116253735A

CN116253735A - Pyrimidopyrimidinone compounds and uses thereof

Info

Publication number: CN116253735A
Application number: CN202111514537.6A
Authority: CN
Inventors: 燕立波; 魏松; 胡诗合; 金永华; 刘宇
Original assignee: Skyrun Pharma Co ltd
Current assignee: Skyrun Pharma Co ltd
Priority date: 2021-12-10
Filing date: 2021-12-10
Publication date: 2023-06-13

Abstract

The invention discloses a pyrimidopyrimidinone compound and application thereof, wherein the pyrimidopyrimidinone compound has good inhibitory activity on cyclin dependent kinase 2/4/6 (CDK 2/4/6), can be used as a CDK2/4/6 inhibitor, and is used for preparing medicines for preventing and/or treating diseases related to CDK2/4/6 overexpression mediation in organisms and medicines for treating diseases related to angiogenesis or cancer metastasis.

Description

Pyrimidopyrimidinone compounds and uses thereof

Technical Field

The invention belongs to the technical field of medicines, and in particular relates to a pyrimidone compound and application thereof in preparing a medicine for preventing and/or treating diseases related to cyclin-dependent kinase (cyclin-dependent kinase) overexpression or cancer metastasis in organisms.

Background

Breast cancer is one of the global high-frequency malignant tumors of women. Statistics by the international cancer research center (IARC) of the world health organization: the new cases of the global female breast cancer reach 138 ten thousand in 2008, and account for 22.9% of the new cases of all female malignant tumors in the current year. About 45.8 ten thousand people die from breast cancer annually worldwide. It is counted that about 16.9 ten thousand women in China diagnose breast cancer each year, and 4.5 ten thousand women die from breast cancer each year. The current global breast cancer drug market is about $200 billion, with a predicted compound growth rate of about 11% in 2025 years, expanding to $384 billion. Cyclin-dependent kinases (Cyclin-DependentKinase, CDK), which belong to the serine/threonine protein kinase family, are heterodimeric complexes composed of cell cycle catalytic kinase subunits and regulatory subunits, are key kinases involved in cell cycle regulation, and are also involved in transcriptional regulation. Wherein CDK1, CDK2, CDK4 and CDK6 are major subtypes involved in the regulation of the cell growth cycle in humans, CDK1 mainly regulates the M phase of the cell life cycle, CDK2 mainly regulates the G1, S, M phases, CDK4/6 is mainly involved in the regulation of the G1 phase activity. CDK inhibitors play a vital role in cell cycle control, and can block cell cycle and control cell proliferation, thereby achieving the purpose of resisting tumor.

Currently, CDK inhibitors marketed at home and abroad are CDK4/6 inhibitors such as piperaquine Bai Xili, reboxetine, abbe selinide and the like. CDK4/6 is highly expressed in many malignant tumors, particularly Hormone Receptor (HR) positive breast cancers, and CDK4/6 inhibitors primarily block the transition of tumor cells from the anagen phase to the DNA replication phase, which in combination with endocrine therapy can greatly increase the progression-free survival and overall survival of metastatic breast cancer patients, and have been the treatment of choice in HR positive/HER 2 negative advanced breast cancer patients. Recent studies indicate that CDK4/6 inhibitors have a certain therapeutic effect in cancer treatment, but cancer cells can still evade the effects of CDK4/6 inhibitors by enhancing CDK2 signaling, while targeting cyclin dependent kinases CDK2, CDK4 and CDK6 can overcome the resistance to CDK4/6 inhibition. Therefore, the development of new CDK2/4/6 inhibitors with high inhibitory activity and excellent pharmacokinetic properties has become key to the development of novel antitumor drugs.

Disclosure of Invention

In view of the above-mentioned shortcomings of the prior art, it is an object of the present invention to provide a class of pyrimidopyrimidinone compounds which have a good inhibitory activity on CDK2/4/6 kinases and are useful as CDK2/4/6 inhibitors, providing the possibility for the treatment of CDK2/4/6 mediated diseases.

In order to achieve the above object, the present invention adopts the following technical means:

a compound of formula I or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof:

in the formula I, the compound (I),

x is selected from-CR ⁵ R ⁶ -、-NR ⁵ -, O or S, wherein R ⁵ 、R ⁶ Each independently represents hydrogen, deuterium, halogen, alkyl, aryl or Het;

y is selected from O or S;

q is selected from-NR ⁷ CONR ⁸ -、-CONR ⁷ -、-NR ⁷ CO-、-CO-、-NR ⁷ SO ₂ NR ⁸ -、-SO ₂ NR ⁷ -、-NR ⁷ SO ₂ -、-SO ₂ -、-NR ⁷ -、-NR ⁷ (CH ₂ ) _n N-、-NR ⁷ (CH ₂ ) _n O-or-CR ⁷ R ⁸ Wherein n=1, 2,3, 4 or 5, r ⁷ 、R ⁸ Each independently represents hydrogen, deuterium, alkyl, aryl or Het;

ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl;

R ¹ selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl or Het;

R ² selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl or Het;

R ³ selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl or Het;

R ⁴ selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl or Het;

the dotted line indicates that there may be a single bond or a double bond, where when the dotted line indicatesR is, in the case of double bonds ³ Absence of;

alkyl is a straight or branched saturated hydrocarbon group of 1 to 6 carbon atoms, a cyclic saturated hydrocarbon group of 3 to 6 carbon atoms, or a cyclic saturated hydrocarbon group of 3 to 6 carbon atoms to which a straight or branched saturated hydrocarbon group of 1 to 6 carbon atoms is attached;

in the above groups, aryl is a carbocyclic ring selected from phenyl, naphthyl, acenaphthylenyl or tetrahydronaphthyl, each of which is optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from hydrogen, alkyl, cyano, halogen, nitro, haloalkyl, hydroxy, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl or Het;

het is a monocyclic heterocycle selected from piperidinyl, pyrrolyl, pyrazolyl, imidazolyl, furanyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl; or a bicyclic heterocycle selected from quinolinyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2, 3-dihydrobenzo [1,4] dioxanyl or benzo [1,3] dioxolyl; each monocyclic or bicyclic heterocycle is optionally substituted with 1, 2 or 3 substituents, each substituent being independently selected from halogen, haloalkyl, hydroxy, alkyl or alkoxy;

halogen is selected from fluorine, chlorine, bromine or iodine.

Further, in the formula I,

x is-NR ⁵ -or O, wherein R ⁵ Selected from hydrogen, deuterium, halogen, alkyl, aryl or Het;

y is selected from O or S;

q is selected from-NR ⁷ CONR ⁸ -、-CONR ⁷ -、-NR ⁷ CO-、-CO-、-NR ⁷ SO ₂ NR ⁸ -、-SO ₂ NR ⁷ -、-NR ⁷ SO ₂ -、-SO ₂ -or-CR ⁷ R ⁸ Wherein R is ⁷ 、R ⁸ Each independently represents hydrogen, deuterium, alkyl, aryl or Het;

ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl;

R ¹ selected from hydrogen, alkoxy, alkyl, aryl or Het;

R ² selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl or Het;

R ³ selected from hydrogen, halogen, alkoxy, alkyl, aryl or Het;

R ⁴ selected from hydrogen, hydroxy, alkoxy, alkyl, aryl or Het.

Further, in the formula I,

x is-NR ⁵ -, wherein R is ⁵ Selected from hydrogen, deuterium or alkyl;

y is selected from O;

q is selected from-CO-or-SO ₂ -；

Ring A is selected from 3-10 membered cycloalkyl, 6-10 membered aryl;

R ¹ selected from hydrogen, alkoxy, alkyl or aryl;

R ² selected from hydrogen, halogen, hydroxy, alkoxy or alkyl;

R ³ selected from hydrogen, alkoxy or alkyl;

R ⁴ selected from hydrogen, alkoxy, alkyl, aryl or Het.

Further, in the formula I,

x is-NH-;

y is selected from O;

q is selected from-CO-or-SO ₂ -；

Ring a is selected from 3-10 membered cycloalkyl;

R ¹ is hydrogen or alkyl;

R ² selected from hydrogen, halogen or alkyl;

R ³ selected from hydrogen, alkoxy or alkyl;

R ⁴ selected from hydrogen, alkoxy, alkyl, aryl or Het.

Further, the pharmaceutically acceptable salts include acid addition salts of compounds of formula I with: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid; also included are the acid salts of the compounds of formula I with inorganic bases.

Further, the pharmaceutically acceptable salts include basic metal cation salts, alkaline earth metal cation salts, and ammonium cation salts.

Further, the compound of formula I is one of the following compounds:

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a pharmaceutical composition comprising a compound as described above or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

Use of a compound as described above in the manufacture of a medicament for the prophylaxis and/or treatment of a CDK2/4/6 associated disorder.

Further, the CDK2/4/6 associated disorder is selected from, but not limited to, hyperlipidemia or cancer; such cancers include lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal breast cancer, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, renal pelvis cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, cancer of the female reproductive system, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-hodgkin's lymphoma, large intestine villous adenoma, melanoma, cytoma and sarcoma, and myelodysplastic syndrome.

The beneficial effects are that: the compound of the general formula I and pharmaceutically acceptable salts, prodrugs, crystal forms, stereoisomers, tautomers, hydrates or solvates thereof provided by the invention are used as receptor tyrosine kinase inhibitors, and particularly have excellent inhibitory activity on CDK2/4/6 kinase. Therefore, the compound can be used for preparing medicines for treating clinical symptoms related to CDK2/4/6, such as medicines for preventing and/or treating diseases related to abnormal proliferation, morphological change, hyperkinesia and the like of cells related to CDK2/4/6 in organisms and medicines for treating diseases related to angiogenesis or cancer metastasis.

Detailed Description

The present invention provides compounds of formula I:

pharmacological test results show that the compound has good inhibitory activity on CDK2/4/6, can be used as a novel CDK2/4/6 inhibitor, and provides possibility for treating diseases mediated by CDK 2/4/6.

In the present invention, the compounds of formula I may also exist in the form of salts, hydrates, solvates thereof, which are converted in vivo to the compounds of formula I. For example, within the scope of the present invention, the compounds of the present invention are converted to pharmaceutically acceptable salt forms and used in salt form according to procedures known in the art.

Meanwhile, the compound of formula I may also exist in a polycrystalline or amorphous form.

In addition, the compounds of formula I may also exist in specific geometric or stereoisomeric forms. Additional asymmetric carbon atoms may be present in the substituents such as alkyl groups, and all such isomers and mixtures thereof are included within the scope of the present invention.

As used herein, "prodrug" refers to any covalently bound carrier that releases the active parent drug when administered to a mammalian patient. Prodrugs can be prepared by conventional procedures or in vivo by modifying functional groups present in the compound in a manner that they decompose to the parent compound. Prodrugs include those which, when administered to a mammalian patient, wherein, for example: and (3) decomposing the hydroxyl, amino, mercapto or carboxyl groups to form free hydroxyl, amino, mercapto or carboxyl groups, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohols in the compounds of the present invention, or amine functional methyl amine, ethyl amine derivatives.

The pharmaceutical compositions contemplated in the present invention include a compound of formula I or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

The pharmaceutical compositions of the present invention may be administered in a variety of known ways, such as orally, parenterally, by inhalation spray, or via an implanted reservoir. The pharmaceutical composition of the invention can be administered alone or in combination with other antitumor drugs. The oral composition may be any orally acceptable dosage form including, but not limited to, tablets, capsules, emulsions, suspensions, dispersions, and solutions. Common pharmaceutically acceptable carriers or excipients include stabilizers, diluents, surfactants, lubricants, antioxidants, binders, colorants, fillers, emulsifiers, and the like.

Sterile injectable compositions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. Pharmaceutically acceptable carriers and solvents that can be used include water, mannitol, sodium chloride solution, and the like.

Topical compositions may be formulated as oils, lotions, creams and the like. Carriers for the compositions include vegetable or mineral oils, animal fats, and high molecular weight alcohols, among others. A pharmaceutically acceptable carrier is a carrier in which the active ingredient is soluble.

The actual dosage level of the active ingredient in the pharmaceutical compositions of the present invention may be varied to obtain an amount of active ingredient that is effective to achieve the desired therapeutic response for the particular patient, composition and mode of administration, and that is non-toxic to the patient. The dosage level selected will depend on a variety of factors including the activity of the particular compound of the invention or salt thereof employed, the route of administration, the time of administration, the rate of excretion of the particular composition employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular composition employed, the age, sex, weight, general health and past medical history of the patient being treated, and like factors well known in the medical arts.

The invention also provides the use of a compound of formula I, or a pharmaceutically acceptable salt, prodrug, crystalline form, stereoisomer, tautomer, hydrate or solvate thereof, in the manufacture of a medicament for the prophylaxis and/or treatment of a CDK2/4/6 associated disorder. Such as: the application of the composition in preparing medicines for preventing and/or treating diseases related to abnormal proliferation, morphological change, hyperkinesia and the like of CDK2/4/6 in organisms and diseases related to angiogenesis or cancer metastasis.

The CDK2/4/6 associated disorder is selected from, but not limited to, hyperlipidemia or cancer; the cancers include lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal carcinoma of the breast, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, renal pelvis cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, cancer of the female reproductive system, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-hodgkin's lymphoma, large intestine villous adenoma, melanoma, cytoma and sarcoma, myelodysplastic syndrome.

The process for the preparation of the compounds of the general formula I according to the invention is described below in connection with specific examples, which, however, do not constitute any limitation of the invention. The compounds of the present invention may also be conveniently prepared by optionally combining the various synthetic methods described in this specification or known in the art, such combinations being readily apparent to those skilled in the art to which the present invention pertains.

The starting materials, reagents, etc. used in the examples of the present invention are all commercially available. The present invention may be prepared in salt form using salt forming methods commonly used in the art.

Example 1

1-cyclopentyl-3-methyl-7- [ (1-methanesulfonyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-1)

The synthetic route is as follows:

synthesis of Compound I-1-1:

to a 100mL single-necked flask was added 2, 4-dichloro-5-pyrimidine-carbaldehyde (2.00 g,11 mmol), THF (10 mL), the temperature was lowered to 0℃and sodium borohydride (1.25 g,14 mmol) was added in portions, the reaction was completed at 0℃for 3 hours, and TLC was monitored. Pouring the reaction solution into 15mL ice water, extracting with EA (5 mL. Times.3) until the water layer is free of product, stopping extraction, concentrating to obtain crude product, and performing column Chromatography (CH) ₂ Cl ₂ MeOH=100:1) to yield 0.45g of a yellow solid, 22% yield, MS m/z:179.1[ M+H] ⁺ 。

Synthesis of Compound I-1-2:

to a 100mL single port flask, compound I-1-1 (0.45 g,2.51 mmol), cyclopentylamine (0.321 g,3.77 mmol), DIPEA (0.647 g,5.02 mmol) and acetonitrile 10mL were added, the reaction was warmed to 60℃for 5h, TLC (PE: EA=2:1) monitored the reaction was completed, the reaction solution was poured into 10mL ice water, EA (20 mL. Times.3) extracted, dried over sodium sulfate, and column chromatography (PE: EA=2:1) gave 0.37g, yield 65%, MS m/z:228.2[ M+H ]] ⁺ 。

Synthesis of Compound I-1-3:

direction 1In a 00mL single vial was added Compound I-1-2 (0.37 g,1.63 mmol), CH ₂ Cl ₂ 10mL, cooling to 0deg.C, adding dessmartin oxidant (1.04 g,2.45 mmol), reacting at room temperature for 4h, monitoring the reaction by TLC (PE: EA=2:1), pouring the reaction solution into 10mL ice water, adding sodium bicarbonate water solution 5mL, stirring at room temperature for 0.5h, CH ₂ Cl ₂ (10 ml. Times.3) extraction, washing with sodium chloride solution once, drying with sodium sulfate, concentrating to dryness, column chromatography (PE: EA=2:1) gives 0.40g, yield 100%, MS m/z:226.4[ M+H] ⁺ . Synthesis of Compound I-1-4:

to a 50mL single vial was added compound I-1-3 (0.37 g,1.64 mmol), methylamine hydrochloride (0.56 g,8.2 mmol), sodium acetate (0.67 g,8.2 mmol), methanol 10mL, and heated to 70℃for 3h, TLC monitored the reaction, cooled to room temperature, sodium borohydride (0.13 g,3.28 mmol) was added, reacted at room temperature for 2h, post-treatment added with 10mL of water, EA (15 mL. Times.3) extracted, dried over sodium sulfate, concentrated to give 0.055g by column chromatography (DCM: MEOH=20:1), yield 14%, MS m/z:241.2[ M+H ]] ⁺ 。

Synthesis of Compound I-1-5:

to a 100mL single port flask, compound I-8-4 (0.18 g,0.71 mmol), DIEA (0.37 g,2.84 mmol), triphosgene (0.076 g,0.26 mmol), THF 5mL, reacted at room temperature for 4h, after TLC monitoring the reaction, the reaction solution was poured into ice water, 5mL of aqueous sodium bicarbonate was added with stirring, EA (10 mL. Times.3) was extracted, sodium chloride solution was washed once, dried over sodium sulfate, concentrated to give 0.15g by column chromatography (DCM: MEOH=20:1), yield 79%, MS m/z:267.2[ M+H ]] ⁺ 。

Synthesis of Compound I-1:

to a 50mL single vial was added I-8-5 (0.09 g,0.34 mmol), 1-methanesulfonyl-4-aminopiperidine (0.072 g,0.41 mmol), cs ₂ CO ₃ (0.33 g,1.02 mmol) and 5mL of 1, 4-dioxane, pd was added under nitrogen ₂ (dba) ₃ (0.02 g,0.034 mmol) and BINAP (0.043 g,0.068 mmol), nitrogen substitution 3 times, heating to 120 ℃ for reaction 5h, TLC (DCM: MEOH=20:1) monitoring the reaction completion, cooling the reaction solution to room temperature, adding ice water 5mL, EA (5 mL. Times.3) for extraction, concentrating the organic phase by dryness, obtaining white solid 0.04g by column chromatography (DCM: meOH=50:1), yield 29％，MS m/z:409.1[M+H] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(ppm):7.91(s,1H),6.98(s,1H),4.16(s,2H),3.85-3.72(m,1H),3.53(d,J＝10.4Hz,2H),2.87(s,6H),2.83-2.76(m,2H),2.10(s,2H),2.02-1.80(m,5H),1.76-1.64(m,2H),1.60-1.45(m,4H),1.29-1.05(m,2H)。

Example 2

(R) -1- (2-hydroxy-2-methylcyclopentyl) -3-methyl-7- [ (1-methanesulfonyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-2)

Preparation method referring to example 1, starting with 2, 4-dichloro-5-pyrimidinecarboxaldehyde, 40mg of a white solid was obtained in 17% yield, MS m/z 439.2[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(ppm):7.93(s,1H),7.04(s,1H),5.04(t,J＝8.6Hz,1H),4.17(d,J＝3.8Hz,2H),4.13(s,1H),3.80(s,1H),3.53(t,J＝10.4Hz,2H),2.87(s,6H),2.85-2.78(m,2H),2.36-2.24(m,1H),2.17-1.99(m,2H),1.96-1.82(m,2H),1.76-1.65(m,2H),1.62-1.50(m,2H),1.05(s,3H)。

Example 3

1-cycloheptyl-3-methyl-7- [ (1-methanesulfonyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-3)

Preparation method referring to example 1, using 2, 4-dichloro-5-pyrimidine-carbaldehyde as a starting material gave 140mg of a white solid with a yield of 49%, MS m/z:437.5[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(ppm):7.89(s,1H),7.01(s,1H),4.75(t,J＝10.0Hz,1H),4.15(s,2H),3.78(s,1H),3.62-3.52(m,2H),2.88(s,3H),2.87(s,3H),2.84-2.77(m,2H),2.40-2.27(m,2H),1.95(t,J＝13.9Hz,2H),1.79-1.39(m,14H)。

Example 4

1-phenyl-3-isopropyl-7- [ (1-acetyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-4)

Preparation method referring to example 1, using 2, 4-dichloro-5-pyrimidine-carbaldehyde as a starting material gave 150mg of a white solid with a yield of 74%, MS m/z:409.1[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):8.03-7.87(s,1H),7.51-7.42(t,J＝7.5Hz,2H),7.42-7.35(t,J＝7.3Hz,1H),7.27-7.20(d,J＝7.4Hz,2H),5.09-4.90(m,1H),4.84-4.72(p,J＝6.8Hz,1H),4.49-4.37(d,J＝13.1Hz,1H),4.35-4.26(s,2H),3.75-3.60(d,J＝13.0Hz,1H),3.58-3.27(m,1H),3.11-2.81(m,1H),2.69-2.42(m,1H),2.15-2.04(m,3H),1.99-1.77(m,4H),1.29-1.25(d,J＝6.8Hz,6H)。

Example 5

1-phenyl-3-isopropyl-7- [ (1-methyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-5)

Preparation method referring to example 1, starting with 2, 4-dichloro-5-pyrimidinecarboxaldehyde, 36mg of a white solid was obtained in 19% yield, MS m/z 381.3[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):7.98-7.90(br,1H),7.50-7.41(t,J＝7.5Hz,2H),7.40-7.34(t,J＝7.3Hz,1H),7.27-7.20(m,2H),5.11-4.91(m,1H),4.84-4.68(dt,J＝13.6,6.8Hz,1H),4.32-4.19(m,2H),2.80-2.62(m,2H),2.40-2.27(m,2H),2.27-2.14(m,3H),2.05(s,3H),1.47-1.32(m,2H),1.28-1.20(d,J＝6.9Hz,6H)。

Example 6

1-phenyl-3-isopropyl-7- [ (1-isopropyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-6)

Preparation method referring to example 1, starting with 2, 4-dichloro-5-pyrimidinecarboxaldehyde, 130mg of a white solid was obtained in 64% yield, MS m/z 409.1[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):8.02(s,1H),7.55-7.41(m,2H),7.40-7.31(m,1H),7.27(d,J＝7.5Hz,2H),5.45-4.92(m,1H),4.85-4.67(m,1H),4.38(s,2H),3.08(s,1H),2.87-2.65(m,3H),2.39(s,2H),1.96-1.67(m,2H),1.49-1.35(m,2H),1.33-1.18(m,6H)。

Example 7

1-phenyl-3-isopropyl-7- [ (1-methanesulfonyl-piperidin) -3-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-7)

Preparation method referring to example 1, using 2, 4-dichloro-5-pyrimidine-carbaldehyde as a starting material gave 140mg of a white solid with a yield of 63%, MS m/z:445.3[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):8.02(s,1H),7.52(t,J＝7.6Hz,2H),7.41(t,J＝7.3Hz,1H),7.27(d,J＝7.6Hz,2H),5.21(s,1H),4.83-4.70(m,1H),4.37-4.22(m,2H),3.92(s,1H),3.49(d,J＝17.7Hz,1H),3.31(s,1H),3.06-2.95(m,1H),2.94-2.83(m,1H),2.75(s,3H),1.98-1.84(m,1H),1.83-1.67(m,2H),1.64-1.52(m,1H),1.35-1.21(m,7H)。

Example 8

1-phenyl-3-isopropyl-7- [ (1-propionyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-8)

Preparation method reference example 1, 2,4-dichloro-5-pyrimidinecarboxaldehyde as starting material, giving 70mg of a white solid, yield 52%, MS m/z 423.2[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):7.99(s,1H),7.49(t,J＝7.5Hz,2H),7.39-7.32(m,1H),7.18(d,J＝7.5Hz,2H),5.46-5.04(m,1H),4.84-4.68(m,1H),4.49-4.37(m,1H),4.34(s,2H),3.78-3.62(m,1H),3.60-3.15(m,1H),3.03-2.41(m,2H),2.38-2.27(m,2H),2.02(s,2H),1.34-1.23(m,6H),1.22-1.16(m,1H),1.09(t,J＝7.4Hz,3H)。

Example 9

1-phenyl-3-isopropyl-7- [ (1-cyclopropanecarbonyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-9)

Preparation method referring to example 1, starting with 2, 4-dichloro-5-pyrimidinecarboxaldehyde, 82mg of a white solid was obtained in 59% yield, MS m/z 435.1[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):8.04(s,1H),7.53(t,J＝7.5Hz,2H),7.41(t,J＝7.3Hz,1H),7.27-7.18(m,2H),5.30(s,1H),4.87-4.71(m,1H),4.53-4.36(m,1H),4.33(s,2H),3.95(s,1H),3.82-3.70(m,1H),3.65(s,1H),3.19-2.81(m,1H),2.77-2.41(m,1H),2.30-2.09(m,1H),2.00-1.79(m,3H),1.76-1.66(m,1H),1.28-1.25(m,6H),1.03-0.92(m,2H),0.80-0.68(m,2H)。

Example 10

1-phenyl-3-isopropyl-7- [ (1-cyclopropanemethanesulfonyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-10)

Preparation method referring to example 1, starting with 2, 4-dichloro-5-pyrimidinecarboxaldehyde, 130mg of a white solid was obtained in 86% yield, MS m/z 471.2[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):8.01(s,1H),7.51-7.41(m 2H),7.40-7.32(m,1H),7.27-7.17(m,2H),5.45-.04(m,1H),4.86-4.71(m,1H),4.40(s,2H),3.78-3.57(m,2H),3.52-3.16(m,1H),2.92(s,2H),2.35-2.17m,1H),2.14(s,1H),1.98-1.76(m,2H),1.49-1.36(m,2H),1.29-1.24(m,6H),1.20-1.12(m,2H),1.04-0.93(m,2H)。

Example 11

1-phenyl-3-ethyl-7- [ (1-acetyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-11)

Preparation method referring to example 1, starting with 2, 4-dichloro-5-pyrimidinecarboxaldehyde, 12mg of a white solid was obtained in 8% yield, MS m/z:395.3[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):8.12(s,1H),7.44(t,J＝7.5Hz,2H),7.37(d,J＝7.0Hz,1H),7.23(d,J＝7.2Hz,2H),4.46(s,2H),3.54(dd,J＝14.3,7.2Hz,2H),3.42-3.33(m,2H),3.27(s,2H),2.25-2.15(m,6H),1.39(d,J＝6.6Hz,6H),1.24(d,J＝7.2Hz,3H)。

Example 12

1-phenyl-3-ethyl-7- [ (1-methyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-12)

Preparation method referring to example 1, starting with 2, 4-dichloro-5-pyrimidinecarboxaldehyde, 34mg of a white solid was obtained in 24% yield, MS m/z:337.2[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):8.02(s,1H),7.43(t,J＝7.4Hz,2H),7.37(d,J＝7.1Hz,1H),7.22(d,J＝7.4Hz,2H),4.44(s,2H),4.40(s,1H),4.11(dd,J＝15.0,8.0Hz,1H),3.54(q,J＝7.1Hz,2H),3.25(s,2H),2.67(s,3H),2.61(s,1H),2.06-1.87(m,4H),1.25(t,J＝7.1Hz,3H)。

Example 13

1-phenyl-3-ethyl-7- [ (1-isopropyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-13)

Preparation method referring to example 1, starting with 2, 4-dichloro-5-pyrimidinecarboxaldehyde, 76mg of a white solid was obtained in 49% yield, MS m/z:395.1[ M+H ]] ⁺ 。

Example 14

1-phenyl-3-ethyl-7- [ (1-propionyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-14)

Preparation method referring to example 1, starting with 2, 4-dichloro-5-pyrimidinecarboxaldehyde, 25mg of a white solid was obtained in 37% yield, MS m/z 409.5[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):7.93(s,1H),7.45(t,J＝7.5Hz,2H),7.39(d,J＝7.3Hz,1H),7.24(dd,J＝5.3,3.3Hz,2H),5.03(s,1H),4.43(s,3H),3.71(d,J＝11.8Hz,1H),3.55(t,J＝7.2Hz,2H),2.88(s,1H),2.56(d,J＝5.4Hz,1H),2.33(q,J＝7.5Hz,2H),2.05-1.92(m,5H),1.26(t,J＝7.1Hz,3H),1.14(t,J＝7.5Hz,3H)。

Example 15

1-phenyl-3-ethyl-7- [ (1-cyclopropanecarbonyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-15)

Preparation method referring to example 1, using 2, 4-dichloro-5-pyrimidine-carbaldehyde as a starting material gave 36mg of a white solid with a yield of 20%, MS m/z:421.2[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):7.93(s,1H),7.46(t,J＝7.4Hz,2H),7.38(t,J＝7.3Hz,1H),7.25(dd,J＝5.3,3.3Hz,2H),5.12(s,1H),4.43(s,3H),4.09(d,J＝14.8Hz,1H),3.56(q,J＝7.2Hz,2H),2.98(s,1H),2.58(d,J＝5.8Hz,1H),2.04(d,J＝14.5Hz,2H),1.85(s,2H),1.72(ddd,J＝12.7,8.1,4.7Hz,1H),1.27(t,J＝7.2Hz,3H),1.00-0.93(m,2H),0.75(dd,J＝7.9,3.1Hz,2H)。

Example 16

1-phenyl-3-ethyl-7- [ (1-cyclopropanemethanesulfonyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-16)

Preparation method referring to example 1, using 2, 4-dichloro-5-pyrimidine-carbaldehyde as a starting material gave 17mg of a white solid with a yield of 9%, MS m/z:457.2[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):7.93(s,1H),7.46(t,J＝7.5Hz,2H),7.38(t,J＝7.3Hz,1H),7.25(dd,J＝5.3,3.3Hz,2H),5.09(s,1H),4.43(s,2H),3.66(d,J＝11.1Hz,2H),3.55(t,J＝7.2Hz,2H),2.77(s,1H),2.24(ddd,J＝9.7,6.4,4.0Hz,1H),1.87(d,J＝24.5Hz,4H),1.43(d,J＝11.7Hz,2H),1.27(t,J＝7.2Hz,3H),1.19-1.13(m,2H),1.03-0.94(m,2H)。

Example 17

1-phenyl-3-ethyl-7- [ (1-methanesulfonyl-piperidin) -3-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-17)

Preparation method referring to example 1, 2, 4-dichloro-5-pyrimidine-carbaldehyde was used as starting material49mg of yellow solid was obtained in 16% yield, MS m/z:431.2[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):7.94(s,1H),7.47(t,J＝7.6Hz,2H),7.38(t,J＝7.4Hz,1H),7.25(d,J＝7.4Hz,2H),4.42(s,2H),3.56(q,J＝7.2Hz,2H),3.25(s,1H),3.05-2.99(m,1H),2.92-2.86(m,1H),2.73(s,3H),2.03(s,1H),1.76(s,2H),1.59(s,1H),1.46(dd,J＝8.4,4.1Hz,1H),1.34-1.30(m,1H),1.26(t,J＝7.1Hz,3H)。

Example 18

1- (pyridin-4-yl) -3-isopropyl-7- [ (1-acetyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-18)

Preparation method referring to example 1, using 2, 4-dichloro-5-pyrimidine-carbaldehyde as a starting material gave 79mg of a white solid with a yield of 45%, MS m/z:410.2[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):8.78-8.57(m,2H),8.04(s,1H),7.27(d,J＝5.8Hz,2H),5.40(s,1H),4.81-4.67(m,1H),4.49(t,J＝11.3Hz,1H),4.34-4.23(m,2H),3.78(d,J＝12.8Hz,1H),3.13-2.80(m,1H),2.75-2.49(m,1H),2.46-2.18(m,1H),2.10(s,3H),1.96-1.71(m,2H),1.28-1.25(m,6H)。

Example 19

1- (pyridin-4-yl) -3-isopropyl-7- [ (1-isopropyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-19)

Preparation method referring to example 1, using 2, 4-dichloro-5-pyrimidine-carbaldehyde as a starting material gave 100mg of a white solid with a yield of 56% and MS m/z:410.1[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):8.73-8.59(m,2H),8.03(s,1H),7.27(d,J＝6.0Hz,2H),5.39(s,1H),4.82-4.67m,1H),4.32(s,2H),2.82-2.73(m,2H),2.70-2.62(m,1H),2.38-1.57(m,4H),1.43-1.30(m 2H),1.26-1.14(m,6H),1.03-0.95(m,6H)。

Example 20

1- (pyridin-4-yl) -3-isopropyl-7- [ (1-methyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-20)

Preparation method referring to example 1, starting with 2, 4-dichloro-5-pyrimidinecarboxaldehyde, 80mg of a white solid was obtained in 48% yield, MS m/z 382.2[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,CDCl ₃ )δ(ppm):8.82-8.62(m,2H),8.09(s,1H),7.27-7.19(m,2H),5.59-5.05(m,1H),4.86-4.66(m,1H),4.41(s,2H),2.82-2.60(m,2H),2.31(s,3H),2.08-1.64(m,4H),1.51-1.38(m,2H),1.27-1.23(m,6H)。

Example 21

1-cyclopentyl-3-methyl-7- [ (1-methanesulfonyl-piperidin) -4-ylamino ] -pyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-21)

Preparation method referring to example 1, starting with 2, 4-dichloro-5-pyrimidinecarboxaldehyde, a white solid was obtained in 15mg, yield 22%, MS m/z 393.2[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(ppm):7.92(s,1H),7.29(s,2H),6.95(s,1H),3.85-3.72(m,1H),3.53(d,J＝10.4Hz,2H),2.89(s,3H),2.83-2.76(m,2H),2.10(s,2H),2.02-1.82(m,5H),1.77-1.63(m,2H),1.61-1.44(m,4H),1.29-1.07(m,2H)。

Example 22

1- (pyridin-4-yl) -3-methyl-7- [ (1-methanesulfonyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-22)

Preparation method referring to example 1, starting with 2, 4-dichloro-5-pyrimidinecarboxaldehyde, 21mg of a white solid was obtained in 38% yield, MS m/z:419.2[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(ppm):8.83-8.60(m,2H),8.09(s,1H),7.27-7.18(m,2H),5.59-5.05(m,1H),4.86-4.67(m,1H),4.41(s,2H),2.88(s,6H),2.08-1.64(m,4H),1.51-1.38(m,1H),1.27-1.23(m,4H)。

Example 23

1- (pyridin-3-yl) -3-methyl-7- [ (1-methanesulfonyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-23)

Preparation method referring to example 1, starting with 2, 4-dichloro-5-pyrimidinecarboxaldehyde, 20mg of a white solid was obtained in 37% yield, MS m/z:419.2[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(ppm):8.85-8.59(m,2H),8.11(s,1H),7.27-7.16(m,2H),5.61-5.05(m,1H),4.87-4.66(m,1H),4.41(s,2H),2.87(s,6H),2.08-1.67(m,4H),1.50-1.37(m,1H),1.27-1.25(m,4H)。

Example 24

1- (pyridin-2-yl) -3-methyl-7- [ (1-methanesulfonyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-24)

Preparation method referring to example 1, 2, 4-dichloro-5-pyrimidine-carbaldehyde was used as a starting material to give 22mg of a white solid, which was collectedRate 38%, MS m/z 419.2[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(ppm):8.88-8.59(m,2H),8.11(s,1H),7.25-7.18(m,2H),5.61-5.06(m,1H),4.88-4.65(m,1H),4.41(s,2H),2.85(s,6H),2.08-1.70(m,4H),1.52-1.39(m,1H),1.27-1.24(m,4H)。

Example 25

1- (2-chlorophenyl) -3-methyl-7- [ (1-methanesulfonyl-piperidine) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-25)

Preparation method referring to example 1, starting with 2, 4-dichloro-5-pyrimidinecarboxaldehyde, 32mg of a white solid was obtained in a yield of 70%, MS m/z 451.3[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(ppm):8.48-8.45(m,2H),8.10(s,1H),7.20-7.18(m,2H),5.60-5.16(m,1H),4.87-4.66(m,1H),4.40(s,2H),2.83(s,6H),2.08-1.75(m,4H),1.52-1.38(m,1H),1.26-1.21(m,4H)。

Example 26

1- (2, 4-dichlorophenyl) -3-methyl-7- [ (1-methanesulfonyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-26)

Preparation method referring to example 1, using 2, 4-dichloro-5-pyrimidine-carbaldehyde as a starting material gave 35mg of a white solid with a yield of 36%, MS m/z 486.3[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(ppm):8.10(s,1H),8.01-7.78(m,3H),5.61-5.17(m,1H),4.83-4.67(m,1H),4.40(s,2H),2.81(s,6H),2.08-1.77(m,4H),1.52-1.37(m,1H),1.26-1.20(m,4H)。

Example 27

1- (quinolin-4-yl) -3-methyl-7- [ (1-methanesulfonyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-27)

Preparation method referring to example 1, starting with 2, 4-dichloro-5-pyrimidinecarboxaldehyde, 11mg of a white solid was obtained in 8% yield, MS m/z 468.2[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(ppm):8.23-8.01(m,2H),8.09(s,1H),7.97-7.68(m,4H),5.59-5.09(m,1H),4.81-4.68(m,1H),4.40(s,2H),2.86(s,6H),2.08-1.65(m,4H),1.50-1.39(m,1H),1.27-1.20(m,4H)。

Example 28

1- (furan-3-yl) -3-methyl-7- [ (1-methanesulfonyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-28)

Preparation method referring to example 1, starting with 2, 4-dichloro-5-pyrimidinecarboxaldehyde, 45mg of a white solid was obtained in 49% yield, MS m/z:407.3[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(ppm):8.10(s,1H),7.21-6.98(m,3H),5.58-5.10(m,1H),4.73-4.61(m,1H),4.38(s,2H),2.80(s,6H),2.08-1.78(m,4H),1.53-1.38(m,1H),1.26-1.21(m,4H)。

Example 29

1- (thiophen-3-yl) -3-methyl-7- [ (1-methanesulfonyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidin-2 (1H) -one (I-29)

Preparation method referring to example 1, starting with 2, 4-dichloro-5-pyrimidinecarboxaldehyde, 40mg of a white solid was obtained in 43% yield, MS m/z 423.3[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(ppm):8.11(s,1H),7.18-6.96(m,3H),5.57-5.11(m,1H),4.73-4.60(m,1H),4.37(s,2H),2.82(s,6H),2.08-1.75(m,4H),1.55-1.38(m,1H),1.27-1.20(m,4H)。

Example 30

1-cyclopentyl-3-methyl-7- [ (1-methanesulfonyl-piperidin) -4-ylamino ] -3, 4-dihydropyrimido [4,5-d ] pyrimidine-2 (1H) -thione (I-30)

Preparation method referring to example 1, starting with 2, 4-dichloro-5-pyrimidinecarboxaldehyde, 23mg of a yellow solid was obtained in 26% yield, MS m/z:425.3[ M+H ]] ⁺ 。

¹ H-NMR(400MHz,DMSO-d ₆ )δ(ppm):7.95(s,1H),7.03(s,1H),5.05(t,J＝8.6Hz,1H),4.16(d,J＝3.8Hz,2H),4.10(s,1H),3.81(s,1H),3.55(t,J＝10.4Hz,2H),2.87(s,6H),2.85-2.77(m,2H),2.37-2.24(m,1H),2.17-1.98(m,2H),1.96-1.80(m,2H),1.76-1.66(m,2H),1.62-1.50(m,2H),1.05(s,3H)。

Example 31: biological Activity

1. FGFR4 inhibition activity assay for target compounds

The synthesized compounds were tested for CDK2/4/6 inhibitory activity by Fluorescence Resonance Energy Transfer (FRET) (specific embodiment references: lebakken CS, kang HC, vogel KW, A fluorescence lifetime-based binding assay to characterize kinase inhibitors. JBiomol Screen.2007.12 (6): 828-841.) and screened for compounds having better activity than the positive control. CDK2/4/6 was obtained by direct purchase of the kit.

2. Determination of MCF-7 cytostatic Activity of Compounds of interest

a. Cell resuscitating, culturing the cells to logarithmic growth phase; b. preparing a compound: the test sample is dissolved in DMSO at a concentration of 30mM, and diluted in a gradient ratio of 1:3 for 10 gradients; c. 4 to 6 x 10 ⁴ Cells at a density of/ml were seeded into 384 well plates, 25. Mu.L of each well was seeded, and the compound was added to the wellsThe final concentration of the compounds was 30, 10,3.33,1.11,0.37,0.123,0.041,0.014,0.005,0.002mM; c. the compounds were incubated with the cells for 72h and cell activity was detected by CTG method.

The following table shows the results of in vitro CDK2/4/6 kinase activity and in vitro cancer cell activity assays for some of the compounds:

(in the table, the compound code corresponds to the former compound code)

From the above table, it can be seen that: the compound and the pharmaceutically acceptable salt thereof have CDK2/4/6 inhibition effect, and can provide basis for preparing medicines for treating/preventing CDK2/4/6 related diseases.

Pharmacological test results show that pyrimidopyrimidinone of the invention has better CDK2/4/6 kinase and MCF-7 cell inhibition activity, and part of compound IC ₅₀ The value is equal to or better than that of PF-06873600, and can be used for preventing or treating clinical diseases related to CDK2/4/6 kinase inhibitor.

The above-mentioned compounds and pharmaceutically acceptable salts thereof of the present invention have CDK2/4/6 inhibitory action and are useful as active ingredients in pharmaceuticals. Therefore, the medicament containing the compound as an active ingredient can be used for preparing medicaments for treating clinical symptoms related to CDK2/4/6, such as: the application of the composition in preparing medicines for preventing and/or treating diseases related to abnormal proliferation, morphological change, hyperkinesia and the like of CDK2/4/6 in organisms and diseases related to angiogenesis or cancer metastasis.

As described above, although the present invention has been shown and described with reference to certain preferred embodiments, it is not to be construed as limiting the invention itself. Various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims.

Claims

1. A compound of formula I or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof:

in the formula I, the compound (I),

y is selected from O or S;

R ¹ selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl or Het;

R ² selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl or Het;

R ³ selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl or Het;

R ⁴ selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl or Het;

the dotted line indicates that there may be a single bond or a double bond, wherein when the dotted line indicates a double bond, R ³ Absence of;

halogen is selected from fluorine, chlorine, bromine or iodine.

2. A compound according to claim 1, characterized in that: in the formula I, the compound (I),

y is selected from O or S;

R ¹ selected from hydrogen, alkoxy, alkyl, aryl or Het;

R ² selected from hydrogen, halogen, hydroxy, alkoxyAlkyl, aryl or Het;

R ³ selected from hydrogen, halogen, alkoxy, alkyl, aryl or Het;

R ⁴ selected from hydrogen, hydroxy, alkoxy, alkyl, aryl or Het.

3. A compound according to claim 1, characterized in that: in the formula I, the compound (I),

x is-NR ⁵ -, wherein R is ⁵ Selected from hydrogen, deuterium or alkyl;

y is selected from O;

q is selected from-CO-or-SO ₂ -；

Ring A is selected from 3-10 membered cycloalkyl, 6-10 membered aryl;

R ¹ selected from hydrogen, alkoxy, alkyl or aryl;

R ² selected from hydrogen, halogen, hydroxy, alkoxy or alkyl;

R ³ selected from hydrogen, alkoxy or alkyl;

R ⁴ selected from hydrogen, alkoxy, alkyl, aryl or Het.

4. A compound according to claim 1, characterized in that: in the formula I, the compound (I),

x is-NH-;

y is selected from O;

q is selected from-CO-or-SO ₂ -；

Ring a is selected from 3-10 membered cycloalkyl;

R ¹ is hydrogen or alkyl;

R ² selected from hydrogen, halogen or alkyl;

R ³ selected from hydrogen, alkoxy or alkyl;

R ⁴ selected from hydrogen, alkoxy, alkyl, aryl or Het.

5. A compound according to claim 1, characterized in that: the pharmaceutically acceptable salts include acid addition salts of compounds of formula I with: hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, maleic acid or succinic acid, fumaric acid, salicylic acid, phenylacetic acid, mandelic acid; also included are the acid salts of the compounds of formula I with inorganic bases.

6. A compound according to claim 5, characterized in that: the pharmaceutically acceptable salts include basic metal cation salts, alkaline earth metal cation salts, and ammonium cation salts.

7. A compound according to claim 1, characterized in that: the compound of formula I is one of the following compounds:

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8. a pharmaceutical composition characterized by: a compound of claim 1, or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate, or solvate thereof, and a pharmaceutically acceptable carrier or excipient.

9. Use of a compound according to claim 1 in the manufacture of a medicament for the prophylaxis and/or treatment of a kinase CDK2/4/6 associated disorder.

10. The use according to claim 9, characterized in that: the kinase CDK2/4/6 associated disease is selected from, but not limited to, hyperlipidemia or cancer; the cancers include lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, ductal carcinoma of the breast, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, renal pelvis cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, cancer of the female reproductive system, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, pharyngeal cancer, multiple myeloma, leukemia, non-hodgkin's lymphoma, large intestine villous adenoma, melanoma, cytoma and sarcoma, and myelodysplastic syndrome.