Pyrimidopyrimidone compounds and their applications

Abstract

The present invention discloses a class of pyrimidopyrimidone compounds and applications thereof. The compounds have excellent inhibitory activity on cyclin-dependent kinases 2 / 4 / 6 (CDK2 / 4 / 6), can be used as CDK2 / 4 / 6 inhibitors, and are used to prepare drugs for preventing and / or treating diseases related to CDK2 / 4 / 6 overexpression in organisms and drugs for diseases related to angiogenesis or cancer metastasis.

Description

Technical Field

[0001] The present invention belongs to the field of medical technology, and specifically relates to a class of pyrimidopyrimidone compounds and their use in preparing drugs for preventing and / or treating diseases related to overexpression of cyclin-dependent kinases or diseases related to cancer metastasis in organisms. Background Art

[0002] Breast cancer is one of the most common malignant tumors in women worldwide. According to statistics from the World Health Organization's International Center for Cancer Research (IARC), in 2008, there were 1.38 million new cases of breast cancer in women worldwide, accounting for 22.9% of all new cases of female malignant tumors that year. About 458,000 people die of breast cancer each year worldwide. According to statistics, about 169,000 women in my country are diagnosed with breast cancer each year, and 45,000 women die of breast cancer each year. The global breast cancer drug market is currently about US$20 billion, and it is predicted that by 2025, the compound growth rate will be about 11%, expanding to US$38.4 billion. Cyclin-Dependent Kinase (CDK) belongs to the serine / threonine protein kinase family. It is a heterodimeric complex composed of a cell cycle catalytic kinase subunit and a regulatory subunit. It is a key kinase involved in cell cycle regulation and also participates in transcriptional regulation. Among them, CDK1, CDK2, CDK4 and CDK6 are the main subtypes involved in the regulation of the cell growth cycle in the human body. CDK1 mainly regulates the M phase of the cell life cycle, CDK2 mainly regulates the G1, S, and M phases, and CDK4 / 6 mainly participates in the regulation of G1 phase activity. CDK inhibitors play a vital role in cell cycle control, blocking the cell cycle and controlling cell proliferation, thereby achieving the purpose of anti-tumor.

[0003] At present, all the CDK inhibitors marketed at home and abroad are CDK4 / 6 inhibitors, such as palbociclib, ribociclib, abemaciclib, etc. CDK4 / 6 is highly expressed in many malignant tumors, especially hormone receptor (HR)-positive breast cancer. CDK4 / 6 inhibitors mainly block the transition of tumor cells from the growth phase to the DNA replication phase. Its combination with endocrine therapy can significantly improve the progression-free survival and overall survival of patients with metastatic breast cancer. It has become the first choice for patients with HR-positive / HER2-negative advanced breast cancer. The latest studies have shown that CDK4 / 6 inhibitors have a certain effect in cancer treatment, but cancer cells can still escape the effects of CDK4 / 6 inhibitors by enhancing CDK2 signal transduction. At the same time, targeting cyclin-dependent kinases CDK2, CDK4 and CDK6 can overcome resistance to CDK4 / 6 inhibition. Therefore, the development of new CDK2 / 4 / 6 inhibitors with high inhibitory activity and excellent pharmacokinetic properties has become the key to the development of new anti-tumor drugs. Summary of the invention

[0004] In view of the above-mentioned deficiencies of the prior art, the object of the present invention is to provide a class of pyrimidopyrimidone compounds, which have good inhibitory activity against CDK2 / 4 / 6 kinases and can be used as CDK2 / 4 / 6 inhibitors, thereby providing the possibility of treating diseases mediated by CDK2 / 4 / 6.

[0005] In order to achieve the above-mentioned purpose, the present invention adopts the following technical means:

[0006] A compound of general formula I or a pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate or solvate thereof:

[0007]

[0008] In Formula I,

[0009] X is selected from -CR 5 R 6 -、-NR 5 -, O or S, where R 5 , R 6 each independently represents hydrogen, deuterium, halogen, alkyl, aryl or Het;

[0010] Y is selected from O or S;

[0011] Q is selected from -NR 7 CONR 8 -、-CONR 7 -、-NR 7 CO-, -CO-, -NR 7 SO2NR 8 -、-SO2NR 7 -、-NR 7 SO2-, -SO2-, -NR 7 -、-NR 7 (CH2) n N-、-NR 7 (CH2) n O-or-CR 7 R 8 , where n = 1, 2, 3, 4 or 5, R 7 , R 8 each independently represents hydrogen, deuterium, alkyl, aryl or Het;

[0012] Ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl, 5-10 membered heteroaryl;

[0013] R 1is selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl or Het;

[0014] R 2 is selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl or Het;

[0015] R 3 is selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl or Het;

[0016] R 4 is selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl or Het;

[0017] The dashed line indicates that either a single bond or a double bond may be present, wherein when the dashed line indicates a double bond, R 3 does not exist;

[0018] The alkyl group is a straight-chain 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 connected to a straight-chain or branched saturated hydrocarbon group of 1 to 6 carbon atoms;

[0019] In the above groups, aryl is a carbocyclic ring selected from phenyl, naphthyl, acenaphthyl or tetrahydronaphthyl, each of which is optionally substituted by 1, 2 or 3 substituents, each of which is independently selected from hydrogen, alkyl, cyano, halogen, nitro, haloalkyl, hydroxyl, mercapto, alkoxy, alkylthio, alkoxyalkyl, aralkyl, diarylalkyl, aryl or Het;

[0020] 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 quinolyl, quinoxalinyl, indolyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, benzofuranyl, benzothienyl, 2,3-dihydrobenzo[1,4]dioxinyl 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;

[0021] Halogen is selected from fluorine, chlorine, bromine or iodine.

[0022] Further, in Formula I,

[0023] X is -NR 5 - or O, where R 5 is selected from hydrogen, deuterium, halogen, alkyl, aryl or Het;

[0024] Y is selected from O or S;

[0025] Q is selected from -NR 7CONR 8 -、-CONR 7 -、-NR 7 CO-, -CO-, -NR 7 SO2NR 8 -、-SO2NR 7 -、-NR 7 SO2-, -SO2- or -CR 7 R 8 , where R 7 , R 8 each independently represents hydrogen, deuterium, alkyl, aryl or Het;

[0026] Ring A is selected from 3-10 membered cycloalkyl, 3-10 membered heterocyclyl, 6-10 membered aryl;

[0027] R 1 is selected from hydrogen, alkoxy, alkyl, aryl or Het;

[0028] R 2 is selected from hydrogen, halogen, hydroxy, alkoxy, alkyl, aryl or Het;

[0029] R 3 is selected from hydrogen, halogen, alkoxy, alkyl, aryl or Het;

[0030] R 4 is selected from hydrogen, hydroxy, alkoxy, alkyl, aryl or Het.

[0031] Further, in Formula I,

[0032] X is -NR 5 -, where R 5 is selected from hydrogen, deuterium or alkyl;

[0033] Y is selected from O;

[0034] Q is selected from -CO- or -SO2-;

[0035] Ring A is selected from 3-10 membered cycloalkyl, 6-10 membered aryl;

[0036] R 1 is selected from hydrogen, alkoxy, alkyl or aryl;

[0037] R 2 is selected from hydrogen, halogen, hydroxy, alkoxy or alkyl;

[0038] R 3 is selected from hydrogen, alkoxy or alkyl;

[0039] R 4 is selected from hydrogen, alkoxy, alkyl, aryl or Het.

[0040] Further, in Formula I,

[0041] X is -NH-;

[0042] Y is selected from O;

[0043] Q is selected from -CO- or -SO2-;

[0044] Ring A is selected from 3-10 membered cycloalkyl;

[0045] R 1 is hydrogen or alkyl;

[0046] R 2 is selected from hydrogen, halogen or alkyl;

[0047] R 3 is selected from hydrogen, alkoxy or alkyl;

[0048] R 4 is selected from hydrogen, alkoxy, alkyl, aryl or Het.

[0049] Furthermore, the pharmaceutically acceptable salts include acid addition salts formed between the compound of general formula I and the following acids: 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; and also include acid salts formed between the compound of general formula I and inorganic bases.

[0050] Furthermore, the pharmaceutically acceptable salts include alkaline metal cation salts, alkaline earth metal cation salts and ammonium cation salts.

[0051] Furthermore, the compound of general formula I is one of the following compounds:

[0052]

[0053]

[0054]

[0055]

[0056] A pharmaceutical composition comprises the above compound or its pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate or solvate and a pharmaceutically acceptable carrier or excipient.

[0057] Use of the above compound in preparing drugs for preventing and / or treating CDK2 / 4 / 6 related diseases.

[0058] Furthermore, the CDK2 / 4 / 6-related diseases are 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, breast ductal carcinoma, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, 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, villous adenoma of the large intestine, melanoma, cell tumor and sarcoma, and myelodysplastic syndrome.

[0059] Beneficial effects: The compounds of the general formula I provided by the present invention and their pharmaceutically acceptable salts, prodrugs, crystal forms, stereoisomers, tautomers, hydrates or solvates are used as receptor tyrosine kinase inhibitors, especially having excellent inhibitory activity against CDK2 / 4 / 6 kinases. Therefore, the above compounds can be used to prepare drugs for treating clinical conditions related to CDK2 / 4 / 6, such as drugs for preventing and / or treating diseases related to abnormal cell proliferation, morphological changes and hypermotility related to CDK2 / 4 / 6 in organisms, and drugs for diseases related to angiogenesis or cancer metastasis. DETAILED DESCRIPTION

[0060] The present invention provides compounds of formula I:

[0061]

[0062] The results of pharmacological tests showed that the compound had good inhibitory activity against CDK2 / 4 / 6 and could be used as a new type of CDK2 / 4 / 6 inhibitor, providing the possibility for the treatment of diseases mediated by CDK2 / 4 / 6.

[0063] In the present invention, the compound of formula I may also exist in the form of its salt, hydrate, solvate, which are converted in vivo into the compound of formula I. For example, within the scope of the present invention, the compound of the present invention is converted into a pharmaceutically acceptable salt form according to processes known in the art, and is used in the form of a salt.

[0064] Meanwhile, the compound of formula I may also exist in multiple crystalline or amorphous forms.

[0065] In addition, the compounds of formula I may also exist in specific geometric or stereoisomeric forms. Additional asymmetric carbon atoms may exist in substituents such as alkyl groups, and all such isomers and their mixtures are included within the scope of the present invention.

[0066] As used herein, "prodrug" refers to any covalently bonded carrier that releases the active parent drug when administered to a mammalian patient. Prodrugs can be prepared by modifying functional groups present in a compound in a manner that decomposes to the parent compound, either by conventional manipulation or in vivo. Prodrugs include compounds in which, for example, hydroxyl, amino, sulfhydryl or carboxyl groups are attached to any group that decomposes to form free hydroxyl, amino, sulfhydryl or carboxyl groups, respectively, when administered to a mammalian patient. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohols in the compounds of the invention, or methylamine, ethylamine derivatives of amine functional groups.

[0067] The pharmaceutical composition involved in the present invention includes 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.

[0068] The pharmaceutical composition of the present invention can be administered in various known ways, such as orally, parenterally, by inhalation spray or via an implanted reservoir. The pharmaceutical composition of the present invention can be administered alone or in combination with other anti-tumor drugs. Oral compositions can be in any oral acceptable dosage form, including but not limited to tablets, capsules, emulsions, suspensions, dispersions and solutions. Commonly used pharmaceutically acceptable carriers or excipients include stabilizers, diluents, surfactants, lubricants, antioxidants, adhesives, colorants, fillers, emulsifiers, etc.

[0069] Sterile injectable compositions can be formulated using suitable dispersing agents or wetting agents and suspending agents according to techniques known in the art. Pharmaceutically acceptable carriers and solvents that can be used include water, mannitol, sodium chloride solution, and the like.

[0070] Topical compositions may be formulated as oils, lotions, creams, etc. Carriers for the compositions include vegetable or mineral oils, animal fats, and high molecular weight alcohols, etc. Pharmaceutically acceptable carriers are carriers in which the active ingredient is soluble.

[0071] The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention can be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient. The dosage level selected depends on a variety of factors, including the activity of the specific compound of the present invention or its salt used, the route of administration, the time of administration, the excretion rate of the specific composition used, the duration of treatment, other drugs, compounds and / or materials used in combination with the specific composition used, the age, sex, weight, general health and previous medical history of the patient being treated, and similar factors well known in the medical field.

[0072] The present invention also provides the use of the compound of formula I or its pharmaceutically acceptable salt, prodrug, crystal form, stereoisomer, tautomer, hydrate or solvate in the preparation of a drug for preventing and / or treating CDK2 / 4 / 6 related diseases, such as: the use of the drug for preventing and / or treating diseases related to abnormal cell proliferation, morphological changes and hypermotility related to CDK2 / 4 / 6 in the body and the drug for diseases related to angiogenesis or cancer metastasis.

[0073] The CDK2 / 4 / 6-related diseases are 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, breast ductal carcinoma, head and neck cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, kidney cancer, renal pelvis cancer, esophageal cancer, esophageal adenocarcinoma, glioma, prostate cancer, thyroid cancer, female reproductive system cancer, 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, villous adenoma of the large intestine, melanoma, cell tumor and sarcoma, myelodysplastic syndrome.

[0074] The preparation method of the compound of general formula I of the present invention is described below in conjunction with specific examples, but these specific methods do not constitute any limitation to the present invention. The compound of the present invention can also be conveniently prepared by optionally combining various synthetic methods described in this specification or known in the art, and such a combination can be easily carried out by a technician in the field to which the present invention belongs.

[0075] The starting materials, reaction reagents, etc. used in the specific examples of the present invention are all commercially available. The present invention can be prepared in the form of salts by using salt-forming methods commonly used in the art.

[0076] Example 1

[0077] 1-Cyclopentyl-3-methyl-7-[(1-methylsulfonyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-1)

[0078]

[0079] The synthetic route is as follows:

[0080]

[0081] Synthesis of compound I-1-1:

[0082] Add 2,4-dichloro-5-pyrimidinecarboxaldehyde (2.00 g, 11 mmol) and 10 mL of THF to a 100 mL single-mouth bottle, cool to 0°C, add sodium borohydride (1.25 g, 14 mmol) in batches, react at 0°C for 3 h, and monitor the completion of the reaction by TLC. Pour the reaction solution into 15 mL of ice water and extract with EA (5 mL*3) until there is no product in the water layer, stop extraction, concentrate to obtain a crude product, and purify by column chromatography (CH2Cl2:MeOH=100:1) to obtain 0.45 g of a yellow solid with a yield of 22%, MS m / z: 179.1 [M+H] + .

[0083] Synthesis of compound I-1-2:

[0084] 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 10 mL were added to a 100 mL single-necked bottle, and the temperature was raised to 60 ° C for 5 h. The reaction was monitored by TLC (PE: EA = 2: 1). The reaction solution was poured into 10 mL of ice water, extracted with EA (20 mL * 3), dried with sodium sulfate, and column chromatography (PE: EA = 2: 1) to obtain 0.37 g, with a yield of 65%, MS m / z: 228.2 [M + H] + .

[0085] Synthesis of compound I-1-3:

[0086] Compound I-1-2 (0.37 g, 1.63 mmol) and CH2Cl2 10 mL were added to a 100 mL single-mouth bottle, cooled to 0 ° C, and Dess-Martin oxidant (1.04 g, 2.45 mmol) was added. The reaction was reacted at room temperature for 4 h. TLC (PE: EA = 2: 1) monitored the completion of the reaction. The reaction solution was poured into 10 mL of ice water, and 5 mL of sodium bicarbonate aqueous solution was added. Stir at room temperature for 0.5 h, extracted with CH2Cl2 (10 mL * 3), washed once with sodium chloride solution, dried with sodium sulfate, concentrated to dryness, and column chromatography (PE: EA = 2: 1) to obtain 0.40 g, with a yield of 100%, MS m / z: 226.4 [M + H] + . Synthesis of compound I-1-4:

[0087] 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), and methanol 10 mL were added to a 50 mL single-mouth bottle, and the temperature was raised to 70 ° C for 3 h. After the reaction was completed by TLC monitoring, it was cooled to room temperature, sodium borohydride (0.13 g, 3.28 mmol) was added, and the reaction was continued at room temperature for 2 h. After post-treatment, 10 mL of water was added, and EA (15 mL * 3) was extracted, dried with sodium sulfate, and concentrated by column chromatography (DCM: MEOH = 20: 1) to obtain 0.055 g, with a yield of 14%, MS m / z: 241.2 [M + H] + .

[0088] Synthesis of compound I-1-5:

[0089] 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 5 mL were added to a 100 mL single-mouth bottle, and the reaction was carried out at room temperature for 4 h. After the reaction was completed, the reaction solution was poured into ice water, 5 mL of sodium bicarbonate aqueous solution was added and stirred, extracted with EA (10 mL * 3), washed once with sodium chloride solution, dried with sodium sulfate, concentrated and purified by column chromatography (DCM: MEOH = 20: 1) to obtain 0.15 g, with a yield of 79%, MS m / z: 267.2 [M + H] + .

[0090] Synthesis of compound I-1:

[0091] I-8-5 (0.09 g, 0.34 mmol), 1-methylsulfonyl-4-aminopiperidine (0.072 g, 0.41 mmol), Cs2CO3 (0.33 g, 1.02 mmol) and 1,4-dioxane 5 mL were added to a 50 mL single-mouth bottle. Pd2(dba)3 (0.02 g, 0.034 mmol) and BINAP (0.043 g, 0.068 mmol) were added under nitrogen atmosphere. The nitrogen was replaced 3 times, and the temperature was raised to 120 ° C for 5 h. The reaction was completed by TLC (DCM: MEOH = 20: 1). The reaction solution was cooled to room temperature, 5 mL of ice water was added to the reaction solution, and EA (5 mL * 3) was extracted. The organic phase was dried and concentrated, and 0.04 g of a white solid was obtained by column chromatography (DCM: MeOH = 50: 1). The yield was 29%, MS m / z: 409.1 [M + H] + .

[0092] 1H-NMR (400MHz, DMSO-d6) 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).

[0093] Example 2

[0094] (R)-1-(2-Hydroxy-2-methylcyclopentyl)-3-methyl-7-[(1-methylsulfonyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-2)

[0095]

[0096] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 40 mg of white solid, with a yield of 17%, MS m / z: 439.2 [M+H] + .

[0097] 1 H-NMR (400MHz, DMSO-d6) 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 = 10.4H z,2H),2.87(s,6H),2.85-2.78(m,2H),2.36-2.24(m,1H),2.17-1.99(m,2 H),1.96-1.82(m,2H),1.76-1.65(m,2H),1.62-1.50(m,2H),1.05(s,3H).

[0098] Example 3

[0099] 1-Cycloheptyl-3-methyl-7-[(1-methylsulfonyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-3)

[0100]

[0101] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 140 mg of white solid, with a yield of 49%, MS m / z: 437.5 [M+H] + .

[0102] 1 H-NMR (400MHz, DMSO-d6) 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).

[0103] Example 4

[0104] 1-Phenyl-3-isopropyl-7-[(1-acetyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-4)

[0105]

[0106] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 150 mg of white solid with a yield of 74%. MS m / z: 409.1 [M+H] + .

[0107] 1 H-NMR (400MHz, CDCl3) 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),4.49-4.3 7(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).

[0108] Example 5

[0109] 1-Phenyl-3-isopropyl-7-[(1-methyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-5)

[0110]

[0111] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 36 mg of white solid, with a yield of 19%, MS m / z: 381.3 [M+H] + .

[0112] 1 H-NMR (400MHz, CDCl3) 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(d t,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).

[0113] Example 6

[0114] 1-Phenyl-3-isopropyl-7-[(1-isopropyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-6)

[0115]

[0116] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 130 mg of white solid, with a yield of 64%, MS m / z: 409.1 [M+H] + .

[0117] 1H-NMR (400MHz, CDCl3) 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).

[0118] Example 7

[0119] 1-phenyl-3-isopropyl-7-[(1-methanesulfonyl-piperidin)-3-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-7)

[0120]

[0121] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 140 mg of white solid, with a yield of 63%, MS m / z: 445.3 [M+H] + .

[0122] 1 H-NMR (400MHz, CDCl3) 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),2.7 5(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).

[0123] Example 8

[0124] 1-Phenyl-3-isopropyl-7-[(1-propionyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-8)

[0125]

[0126] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 70 mg of white solid with a yield of 52%. MS m / z: 423.2 [M+H] + .

[0127] 1 H-NMR (400MHz, CDCl3) δ (ppm): 7.99 (s, 1H), 7.49 (t, J = 7.5Hz, 2H), 7.39-7.32 (m, 1 H),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).

[0128] Example 9

[0129] 1-Phenyl-3-isopropyl-7-[(1-cyclopropanecarbonyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-9)

[0130]

[0131] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 82 mg of white solid, with a yield of 59%, MS m / z: 435.1 [M+H] + .

[0132] 1H-NMR (400MHz, CDCl3) 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).

[0133] Example 10

[0134] 1-phenyl-3-isopropyl-7-[(1-cyclopropylmethanesulfonyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-10)

[0135]

[0136] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 130 mg of white solid, with a yield of 86%, MS m / z: 471.2 [M+H] + .

[0137] 1 H-NMR (400MHz, CDCl3) 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),2.9 2(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).

[0138] Embodiment 11

[0139] 1-Phenyl-3-ethyl-7-[(1-acetyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-11)

[0140]

[0141] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 12 mg of white solid, with a yield of 8%, MS m / z: 395.3 [M+H] + .

[0142] 1 H-NMR (400MHz, CDCl3) 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).

[0143] Example 12

[0144] 1-Phenyl-3-ethyl-7-[(1-methyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-12)

[0145]

[0146] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 34 mg of white solid, with a yield of 24%, MS m / z: 337.2 [M+H] + .

[0147] 1 H-NMR (400MHz, CDCl3) 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).

[0148] Example 13

[0149] 1-Phenyl-3-ethyl-7-[(1-isopropyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-13)

[0150]

[0151] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 76 mg of white solid, with a yield of 49%, MS m / z: 395.1 [M+H] + .

[0152] 1 H-NMR (400MHz, CDCl3) 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).

[0153] Embodiment 14

[0154] 1-Phenyl-3-ethyl-7-[(1-propionyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-14)

[0155]

[0156] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 25 mg of white solid, with a yield of 37%, MS m / z: 409.5 [M+H] + .

[0157] 1H-NMR (400MHz, CDCl3) 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=1 1.8Hz,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).

[0158] Embodiment 15

[0159] 1-Phenyl-3-ethyl-7-[(1-cyclopropanecarbonyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-15)

[0160]

[0161] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 36 mg of white solid, with a yield of 20%, MS m / z: 421.2 [M+H] + .

[0162] 1 H-NMR (400MHz, CDCl3) 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).

[0163] Example 16

[0164] 1-Phenyl-3-ethyl-7-[(1-cyclopropylmethanesulfonyl-piperidinyl)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-16)

[0165]

[0166] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 17 mg of white solid, with a yield of 9%, MS m / z: 457.2 [M+H] + .

[0167] 1 H-NMR (400MHz, CDCl3) δ (ppm): 7.93 (s, 1H), 7.46 (t, J = 7.5Hz, 2H), 7.38 (t, J = 7.3Hz, 1 H),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).

[0168] Embodiment 17

[0169] 1-Phenyl-3-ethyl-7-[(1-methanesulfonyl-piperidin)-3-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-17)

[0170]

[0171] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 49 mg of yellow solid, with a yield of 16%, MS m / z: 431.2 [M+H] + .

[0172] 1H-NMR (400MHz, CDCl3) δ (ppm): 7.94 (s, 1H), 7.47 (t, J = 7.6 Hz, 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).

[0173] Embodiment 18

[0174] 1-(Pyridin-4-yl)-3-isopropyl-7-[(1-acetyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-18)

[0175]

[0176] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 79 mg of white solid, with a yield of 45%, MS m / z: 410.2 [M+H] + .

[0177] 1 H-NMR (400MHz, CDCl3) 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,1 H),2.46-2.18(m,1H),2.10(s,3H),1.96-1.71(m,2H),1.28-1.25(m,6H).

[0178] Embodiment 19

[0179] 1-(Pyridin-4-yl)-3-isopropyl-7-[(1-isopropyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-19)

[0180]

[0181] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 100 mg of white solid, with a yield of 56%, MS m / z: 410.1 [M+H] + .

[0182] 1 H-NMR (400MHz, CDCl3) 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).

[0183] Embodiment 20

[0184] 1-(Pyridin-4-yl)-3-isopropyl-7-[(1-methyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-20)

[0185]

[0186] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 80 mg of white solid, with a yield of 48%, MS m / z: 382.2 [M+H] + .

[0187] 1 H-NMR (400MHz, CDCl3) δ (ppm): 8.82-8.62 (m, 2H), 8.09 (s, 1H), 7.27-7.19 (m, 2H), 5.59-5.05 (m, 1H), 4.86-4.6 6(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).

[0188] Embodiment 21

[0189] 1-Cyclopentyl-3-methyl-7-[(1-methylsulfonyl-piperidin)-4-ylamino]-pyrimido[4,5-d]pyrimidin-2(1H)-one (I-21)

[0190]

[0191] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 15 mg of white solid, with a yield of 22%, MS m / z: 393.2 [M+H] + .

[0192] 1 H-NMR (400MHz, DMSO-d6) 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).

[0193] Embodiment 22

[0194] 1-(Pyridin-4-yl)-3-methyl-7-[(1-methylsulfonyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-22)

[0195]

[0196]

[0197] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 21 mg of white solid, with a yield of 38%, MS m / z: 419.2 [M+H] + .

[0198] 1 H-NMR(400MHz,DMSO-d6)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).

[0199] Embodiment 23

[0200] 1-(Pyridin-3-yl)-3-methyl-7-[(1-methanesulfonyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-23)

[0201]

[0202] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 20 mg of white solid, with a yield of 37%, MS m / z: 419.2 [M+H] + .

[0203] 1 H-NMR(400MHz,DMSO-d6)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).

[0204] Embodiment 24

[0205] 1-(Pyridin-2-yl)-3-methyl-7-[(1-methylsulfonyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-24)

[0206]

[0207] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 22 mg of white solid, with a yield of 38%, MS m / z: 419.2 [M+H] + .

[0208] 1 H-NMR(400MHz,DMSO-d6)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).

[0209] Embodiment 25

[0210] 1-(2-Chlorophenyl)-3-methyl-7-[(1-methylsulfonyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-25)

[0211]

[0212] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 32 mg of white solid, with a yield of 70%, MS m / z: 451.3 [M+H] + .

[0213] 1 H-NMR(400MHz,DMSO-d6)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).

[0214] Embodiment 26

[0215] 1-(2,4-dichlorophenyl)-3-methyl-7-[(1-methylsulfonyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-26)

[0216]

[0217] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 35 mg of white solid, with a yield of 36%, MS m / z: 486.3 [M+H] + .

[0218] 1 H-NMR (400MHz, DMSO-d6) 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).

[0219] Embodiment 27

[0220] 1-(Quinolin-4-yl)-3-methyl-7-[(1-methanesulfonyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-27)

[0221]

[0222] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 11 mg of white solid, with a yield of 8%, MS m / z: 468.2 [M+H] + .

[0223] 1 H-NMR(400MHz,DMSO-d6)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).

[0224] Embodiment 28

[0225] 1-(Furan-3-yl)-3-methyl-7-[(1-methanesulfonyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-28)

[0226]

[0227] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 45 mg of white solid, with a yield of 49%, MS m / z: 407.3 [M+H] + .

[0228] 1 H-NMR (400MHz, DMSO-d6) 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).

[0229] Embodiment 29

[0230] 1-(Thien-3-yl)-3-methyl-7-[(1-methylsulfonyl-piperidin)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (I-29)

[0231]

[0232] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 40 mg of white solid, with a yield of 43%, MS m / z: 423.3 [M+H] + .

[0233] 1 H-NMR (400MHz, DMSO-d6) 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).

[0234] Embodiment 30

[0235] 1-Cyclopentyl-3-methyl-7-[(1-methylsulfonyl-piperidinyl)-4-ylamino]-3,4-dihydropyrimido[4,5-d]pyrimidine-2(1H)-thione (I-30)

[0236]

[0237] Preparation method: Refer to Example 1, using 2,4-dichloro-5-pyrimidinecarboxaldehyde as the starting material to obtain 23 mg of yellow solid, with a yield of 26%, MS m / z: 425.3 [M+H] + .

[0238] 1 H-NMR (400MHz, DMSO-d6) 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 = 10.4H) z,2H),2.87(s,6H),2.85-2.77(m,2H),2.37-2.24(m,1H),2.17-1.98(m,2 H),1.96-1.80(m,2H),1.76-1.66(m,2H),1.62-1.50(m,2H),1.05(s,3H).

[0239] Example 31: Biological Activity

[0240] 1. Determination of FGFR4 inhibitory activity of target compounds

[0241] The synthesized compounds were tested for their inhibitory activity against CDK2 / 4 / 6 using the fluorescence resonance energy transfer (FRET) method (reference for specific implementation methods: Lebakken CS, Kang HC, Vogel KW, A fluorescence lifetime-based binding assay to characterize kinase inhibitors. J Biomol Screen. 2007. 12(6): 828–841.), and compared with positive control drugs to screen out compounds with better activity. CDK2 / 4 / 6 was obtained by directly purchasing the kit.

[0242] 2. Determination of the inhibitory activity of target compounds in MCF-7 cells

[0243] a. Cell recovery, culture cells to logarithmic growth phase; b. Compound preparation: dissolve the test sample in DMSO at a concentration of 30mM, dilute in a 1:3 ratio, a total of 10 gradients; c. 4 / ml cells were inoculated into a 384-well plate, 25 μL was inoculated into each well, and compounds were added. The final concentrations of the compounds were 30, 10, 3.33, 1.11, 0.37, 0.123, 0.041, 0.014, 0.005, and 0.002 mM; c. The compounds were incubated with cells for 72 h, and the cell activity was detected by the CTG method.

[0244] The following table shows the in vitro CDK2 / 4 / 6 kinase activity and in vitro cancer cell activity test results of some compounds:

[0245]

[0246] (Compound codes in the table correspond to the previous compound codes)

[0247] It can be seen from the above table that the above compounds of the present invention and their medically acceptable salts have CDK2 / 4 / 6 inhibitory effects, and can provide a basis for the preparation of drugs for treating / preventing diseases related to CDK2 / 4 / 6.

[0248] The pharmacological test results show that the pyrimidopyrimidone of the present invention has good CDK2 / 4 / 6 kinase and MCF-7 cell inhibitory activity, and some compounds IC 50 The value is comparable to or better than that of PF-06873600 and is superior to that of the positive control, and can be used to prevent or treat clinical diseases associated with CDK2 / 4 / 6 kinase inhibitors.

[0249] The above-mentioned compounds and medically acceptable salts thereof of the present invention have CDK2 / 4 / 6 inhibitory effects and can be used as active ingredients in pharmaceuticals. Therefore, drugs containing the above-mentioned compounds as active ingredients can be used to prepare drugs for treating clinical conditions related to CDK2 / 4 / 6, such as: drugs for preventing and / or treating diseases related to abnormal cell proliferation, morphological changes, and hypermotility related to CDK2 / 4 / 6 in vivo, and drugs for diseases related to angiogenesis or cancer metastasis.

[0250] As described above, although the present invention has been shown and described with reference to specific preferred embodiments, it should not be construed as limiting the present invention itself. Various changes in form and details may be made without departing from the spirit and scope of the present invention as defined in the appended claims.

Claims

1. A compound or a pharmaceutically acceptable salt thereof, characterized in that: The compound is selected from any one of the following: 。 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, characterized in that: The pharmaceutically acceptable salt is selected from the acid addition salts formed with the following acids: 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.

3. A pharmaceutical composition, characterized in that: The invention comprises the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

4. Use of the compound according to claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a medicament for preventing and / or treating diseases related to kinase CDK2 / 4 / 6.

5. The use according to claim 4, characterized in that: The kinase CDK2 / 4 / 6 related disease is selected from hyperlipidemia or cancer.

6. The use according to claim 5, characterized in that: The cancer is selected from lung cancer, squamous cell carcinoma, bladder cancer, gastric cancer, ovarian cancer, peritoneal cancer, breast cancer, endometrial cancer, uterine cancer, rectal cancer, liver cancer, kidney cancer, esophageal cancer, glioma, prostate cancer, thyroid cancer, carcinoma in situ, lymphoma, neurofibromatosis, bone cancer, skin cancer, brain cancer, colon cancer, testicular cancer, gastrointestinal stromal tumor, oral cancer, multiple myeloma, leukemia, colorectal villous adenoma, melanoma, sarcoma or myelodysplastic syndrome.

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