(19)
(11)EP 3 444 254 B1

(12)EUROPEAN PATENT SPECIFICATION

(45)Mention of the grant of the patent:
13.05.2020 Bulletin 2020/20

(21)Application number: 17781813.5

(22)Date of filing:  31.03.2017
(51)International Patent Classification (IPC): 
C07D 498/04(2006.01)
C07D 513/04(2006.01)
A61P 35/02(2006.01)
C07D 498/10(2006.01)
A61P 35/00(2006.01)
(86)International application number:
PCT/CN2017/078935
(87)International publication number:
WO 2017/177837 (19.10.2017 Gazette  2017/42)

(54)

HETEROCYCLIC-SUBSTITUTED PYRIDINOPYRIMIDINONE DERIVATIVE AS CDK INHIBITOR AND USE THEREOF

HETEROCYCLISCH SUBSTITUIERTES PYRIDINOPYRIMIDINONDERIVAT ALS CDK-INHIBITOR UND VERWENDUNG DAVON

DÉRIVÉ DE PYRIDINOPYRIMIDINONE SUBSTITUÉ HÉTÉROCYCLIQUE EN TANT QU'INHIBITEUR DE CDK ET SON UTILISATION


(84)Designated Contracting States:
AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

(30)Priority: 11.04.2016 CN 201610220275

(43)Date of publication of application:
20.02.2019 Bulletin 2019/08

(73)Proprietor: Shanghai Xunhe Pharmaceutical Technology Co., Ltd.
Shanghai 201100 (CN)

(72)Inventors:
  • ZHENG, Yongyong
    Shanghai 200240 (CN)
  • JIN, Hua
    Shanghai 200072 (CN)
  • ZHOU, Feng
    Shanghai 200434 (CN)
  • HUANG, Meihua
    Shanghai 200135 (CN)
  • MENG, Xin
    Beijing 100045 (CN)

(74)Representative: Sun, Yiming 
HUASUN Patent- und Rechtsanwälte Friedrichstraße 33
80801 München
80801 München (DE)


(56)References cited: : 
WO-A1-01/55147
WO-A2-2010/039997
WO-A1-2015/066696
CN-A- 105 218 561
  
      
    Note: Within nine months from the publication of the mention of the grant of the European patent, any person may give notice to the European Patent Office of opposition to the European patent granted. Notice of opposition shall be filed in a written reasoned statement. It shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention).


    Description

    TECHNICAL FIELD



    [0001] The invention relates to the technical field of pharmaceutical preparation, in particular to a heterocyclic-substituted pyridinopyrimidinone as CDK inhibitor and use thereof.

    BACKGROUND TECHNOLOGY



    [0002] Cyclin-dependent kinase (CDK) and cyclin are important factors in the regulation of cell cycle. CDK can form a heterodimer with cyclin, wherein CDK is a catalytic subunit, cyclin is a regulatory subunit, and various cyclin-CDK complexes are formed, which phosphorylate different substrates, thereby promoting and transforming the different phases of a cell cycle.

    [0003] There are at least 9 CDKs in mammals.The transition from G1 phase to S phase in cells is mainly controlled by G1 phase CDK kinase. CDK kinases that bind to G1 cyclins mainly comprise CDK2, CDK4, and CKD6. Cyclin D mainly binds to CDK4 and CKD6 and regulates the activity of the latter; cyclin E binds to CDK2 at G1/S phase, exhibiting CDK2 kinase activity and promoting cell's entry into S phase. G2/M phase is mainly regulated by CDK1 kinase, Cyclin A andCyclinB binds to CDK1, and CDK1 phosphorylates the substrate protein, such as histone H1 for chromosome condensation, or laminin for disintegration of nuclear membrane. During M phase, APC, an anaphase-promoting complex that is activated by M-promoting factor (MPF), is ubiquitously linked to Cyclin A and Cyclin B. Through polyubiquitylation, they are degraded by a proteasome, which completes a cell cycle (Malumbres M. et al. Nat Cell Biol 11:1275, 2009; Malumbres M. et al. Nat Rev Cancer 9:153, 2009).

    [0004] In the past decade, CDK inhibitors have been regarded as a hot spot for developing new anti-tumor drug in the global pharmaceutical industry, and more than 20 CDK inhibitors have entered clinical development. Although CDK inhibitors had significant preclinical anti-tumor pharmacodynamics, the results of most previous clinical trials were unsatisfactory.The main problems include lack of efficacy and toxicity in solid tumors (Guha M. Nat Rev Drug Dis 11:892, 2012). During the analysis of serious toxic side effects, it was found that some CDK inhibitor drugs lack selectivity for CDK subtypes, resulting in greater side effects.

    [0005] CDK4 and CDK6 are two closely related kinases that bind to Cyclin D during the tumor cell cycle and cause transition of G1 phase to S phase, which is essential for the cell cycle progression of DNA replication for cell division. Changes in the G1-S phase transition control mechanism through various genetic and biochemical adaptations have been found in more than 90% of human tumors. P16 and human retinoblastoma (Rb) are important tumorsuppressor proteins that regulate cell cycle. P16 gene protein inhibits the feedback loop of CDK4, Cyclin D1 and Rb, and prevents the cell from hyperproliferation by regulating the protein activity of Rb for tumor suppression. It has been shown that activation of CDK4 and CDK6 causes changes in cell cycle in human tumors (such as breast tumor and myeloma). Inhibition of CDK4 and CDK6 can prevent inactivation of tumor suppressor protein Rb and interfere with tumor cell cycle progression (Choi YJ and Anders L, Oncogene 33:1890-903, 2014).

    [0006] CDK4/6 plays a key role in the dysregulation of cell cycle control in various solid tumors and hematological tumors. There are several selective CDK4/6 inhibitors in clinical stages at present (e.g., Palbociclib, LY2835219, and LEE011). The clinical evaluation of these drugs also includes metastatic breast cancer, ovarian cancer, liposarcoma, non-small cell lung cancer, liver cancer, glioblastoma, melanoma, multiple myeloma and lymphoma.

    [0007] Although many CDK inhibitor compounds have been disclosed, a variety of drugs, particularly CDK4/6 inhibitors for treating CDK-related disorders are still needed due to CDK-mediated pathology.

    SUMMARY OF THE INVENTION



    [0008] One of the objects of the present invention is to provide a novel heterocyclic-substituted pyridinopyrimidinone or a pharmaceutically acceptable salt thereof.

    [0009] The second object of the present invention is to provide use of the compound as a novel CDK4/6 inhibitor in the preparation of a medicament for the prevention or treatment of CDK4/6-related diseases. The CDK4/6-related diseases caused by the imbalance of the cycle control involved with CDK4/6, especially malignant tumors to be treated include but not limited to breast cancer, ovarian cancer, prostate cancer, colorectal cancer, pancreatic cancer, liver cancer, melanoma, gastric cancer, and solid tumors.

    [0010] For above object, the present invention provides a heterocyclic-substituted pyridinopyrimidinone represented by the following Formula I or a pharmaceutically acceptable salt thereof:



    [0011] Wherein,
    R1 represents hydrogen, C1-C3 alkyl, or C3-C7 cycloalkyl;
    R2 represents C1-C5 alkyl, C3-C7 cycloalkyl, 5-6 membered heteroaryl, phenyl, or substituted phenyl;
    R3 and R4 independently represents hydrogen, C1-C3 alkyl, C3-C7 cycloalkyl, acetyl, halogen, trifluoromethyl, cyano or CONR5R6;
    or R3, R4 together with the carbon atom to which they are attached form a C3-C7 aliphatic ring;
    R5 and R6 independently represents hydrogen or methyl;
    X represents O, or S;
    n is 0 or 1.

    [0012] The present invention also provides a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, and at least one compound of Formula (I) described herein and a pharmaceutically acceptable salt thereof as a CDK4/6 inhibitor.

    [0013] As used herein, "C1-C3 alkyl" refers to methyl, ethyl, n-propyl, or iso-propyl; "C1-C5 alkyl" refers to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-3-butyl, 1,1-dimethyl-1-propyl, 2,2-dimethyl-1-propyl; "C1-C3alkoxy" refers to methoxy, ethoxy, n-propoxy, isopropoxy; "halogen" refers to F, Cl, Br, I; "C3-C7 cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl; and "5-6 membered heteroaryl" refers to a 5-6 membered aromatic monocyclic ring containing 1-3 heteroatoms selected from N, O, S, and the remaining ring atoms are carbon.

    [0014] Typical compounds of the present invention include but not limited to those in following Table 1:
    CompoundStructureCompoundStructure
    I-1

    I-2

    I-3

    I-4

    I-5

    I-6

    I-7

    I-8

    I-9

    I-10

    I-11

    I-12

    I-13

    I-14

    I-15

    I-16

    I-17

    I-18

    I-19

    I-20

    I-21

    I-22

    I-23

    I-24

    I-25

    I-26

    I-27

    I-28

    I-29

    I-30

    I-31

    I-32

    I-33

    I-34

    I-35

    I-36

    I-37

    I-38

    or a pharmaceutically acceptable salt thereof.

    [0015] Examples of a pharmaceutically acceptable salt include inorganic and organic salts such as hydrochloride, hydrobromide, sulfate, phosphate, citrate, tartrate, succinate, maleate, fumarate, mandelate and oxalate.

    [0016] A part of the compounds of the present invention can be prepared by the following synthetic scheme:



    [0017] I6 is prepared according to the procedure reported in the literature (ISOO ITO, NORIICHI ODA, et al. Chem. Pharm. Bull., 1976, pp1189; BURNETT DUANE A et al. WO2015066697 A1), i.e., substituted 2,4-dichloropyrimidine (I1) is reacting with amine (I2) under basic condition to obtain intermediate I3, which is demethylated to obtain I4, and I4 and I5 are substituted and cyclized to obtain ester intermediate I6.

    [0018] I6 is catalytically reacted with an amine (I7) to obtain the target product I.

    [0019] The present invention relates to said heterocyclic-substituted pyridinopyrimidinone derivatives as CDK4/6 inhibitors that can be used for various clinical diseases caused by dysregulation of the cell cycle wherein CDK4/6 involves, such as cancer. Such diseases include but not limited to breast cancer, ovarian cancer, prostate cancer, colorectal cancer, liver cancer, melanoma, acute lymphocytic leukemia, chronic lymphocytic leukemia, multiple myeloma, lung cancer, gastric cancer, pancreatic cancer.

    [0020] During the treatment of the disease, the derivative of the present invention can be used in composition to treat related cancers and other diseases by oral, injection or the like.

    [0021] The composition comprises a therapeutically effective amount of a compound as described above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

    [0022] The carrier refers to a conventional carrier in the pharmaceutical field, such as a diluent, an excipient such as water, a binder such as a cellulose derivative, gelatin, polyvinylpyrrolidone, etc.; a filler such as starch, etc.; a disintegrant such as calciumcarbonate, sodium bicarbonate. Additionally, other adjuvants such as flavoring agents and sweeteners may also be added to the composition.

    [0023] When used orally, they can be prepared into conventional solid preparations such as tablets, powders or capsules, etc.; when used for injection, they can be prepared as injections.

    [0024] Various dosage forms of the composition of the present invention can be prepared with a conventional method in the medical field, wherein the content of the active ingredient is from 0.1 % to 99.5% by weight.

    [0025] The administration amount of the present invention can be varied according to the route of administration, the age, body weight of the patient, and the type and severity of the disease to be treated, and the daily dose thereof is 0.005-30 mg/kg body weight (for oral) or 0.005-30 mg/kg body weight (for injection).

    THE ADVANTAGEOUS EFFECT OF THE PRESENT INVENTION


    THE ADVANTAGEOUS EFFECT



    [0026] The present invention provides a new heterocyclic-substituted pyridinopyrimidinone derivative or a pharmaceutically acceptable salt, which is as a CDK4/6 inhibitor in the preparation of a medicament for preventing or treating CDK4/6 related diseases, especially for the treatment of a malignant tumor, including but not limited to breast cancer, ovarian cancer, prostate cancer, colorectal cancer, liver cancer, melanoma, gastric cancer and solid tumor, and the like.

    EXAMPLE OF THE PRESENT INVENTION


    THE EMBODIMENT OF THE PRESENT INVENTION


    Example 1


    Compound (I-1)


    6,6-Dimethyl-8-isopropyl-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5,4 -b][1,4]oxazin-7(8H)-one



    [0027] 

    Step 1: 2,4-Dichloro-5-methoxypyrimidine (1.0 g, 5.59 mmol), isopropylamine (0.33 g, 5.59 mmol), N,N-diisopropylethylamine (7.2 g, 55.9 mmol) were added to isopropanol (IPA, 10 mL) and reacted under N2 protection at 100°C for 6 h. The solvent was concentrated to dry and H2O (50mL)/dichloromethane (DCM, 50mL) was added into the residue and stirred for extraction. The organic layer was dried, filtered and concentrated to give 2-chloro-N-isopropyl-5-methoxypyrimidine-4-amine as a pale yellow solid (0.78 g, crude yield 69.3%).

    Step 2: 2-Chloro-N-isopropyl-5-methoxypyrimidine-4-amine (0.78 g, 3.88 mmol) was added to DCM (15 mL) and BBr3 (14.5 g, 58.2mmol) in DCM (15 mL) was added dropwise under an ice bath, and after the completion, the mixture was warmed to room temperature and stirred for 10 h. Methanol (10 mL) was added dropwise to quench the reaction. DCM (20 mL) was added to the reaction liquid, and the pH was adjusted to about 8 with a saturated NaHCO3 solution. After liquid separation, the organic layer was dried, filtered and concentrated to give 2-chloro-N-isopropyl-5-hydroxypyrimidine-4-amine as a white solid (0.54 g, crude yield 74.5%).

    Step 3: 2-Chloro-N-isopropyl-5-hydroxypyrimidine-4-amine (0.54 g, 2.89 mmol), methyl 2-bromoisobutyrate (0.63 g, 3.46 mmol), K2CO3 (1.2 g , 8.66 mmol) was added to acetonitrile (20 mL) and allowed to react under N2 protection at 80°C for 8 h. The solvent was concentrated to dry and H2O (50mL)/dichloromethane (DCM, 50mL) was added into the residue and stirred for extraction. The organic layer was dried, filtered and concentrated to give a pale yellow solid, followed by the recrystallization with ethyl acetate to give 2-chloro-6,6-dimethyl-8-isopropyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (0.73 g, yield 99.0%), MS(m/z): 257 [M+H]+.

    Step 4: 2-Chloro-6,6-dimethyl-8-isopropyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (0.73 g, 2.85mmol), tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate (0.79 g, 2.85 mmol), Pd2(dba)3 (0.26 g, 0.28 mmol), Xantphos (0.25 g, 0.43 mmol) and cesium carbonate (1.39 g, 4.28 mmol) were added to 1,4-dioxane (15 mL), and reacted under N2 protection at 100°C for 8 h. The solvent was concentrated to dry and H2O (50mL)/dichloromethane (DCM, 50mL) was added into the residue and stirred for extraction. The organic layer was dried, filtered and concentrated to give a pale yellow solid, followed by the anhydrous ethanol (10mL) beating to give a pale yellow solid of 6-dimethyl-8-isopropyl-2-(5-(4-tert-butyl carboxylate-1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8 H)-one (0.50 g, yield 35.2%), MS(m/z): 498 [M+H]+.

    Step 5: 6,6-Dimethyl-8-isopropyl-2-(5-(4-tert-butyl carboxylate-1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8 H)-one (0.50 g, 2.0 mmol) was added to ethyl acetate (5 mL). 3N HCl-ethyl acetate solution was added under stirring and allowed to react for 2h. The solid was precipitated, filtered, and the crude product was beated with anhydrous ethyl acetate (5mL) to give a pale yellow solid, which was dried in vacuo to give the title product of 6,6-dimethyl-8-isopropyl-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5,4 -b][1,4]oxazin-7(8H)-one hydrochloride (I-1, 0.2 g, yield 46.0%),MS(m/z): 398 [M+H]+. 1H NMR (DMSO-d6): δ: 11.83 (br, 1H), 9.74 (br, 2H), 8.33 (s, 1H), 8.25-8.23 (d, J = 8.0Hz, 1H), 8.01 (s, 1H), 7.77-7.75 (d, J = 8.0Hz, 1H), 5.32-5.25 (m, 1H), 3.71-3.52 (m, 8H), 1.59 (s, 12H).


    Example 2


    Compound (I-2)


    6,6-Dimethyl-8-cyclopentyl-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[ 5,4-b][1,4]oxazin-7(8H)-one



    [0028] Compound I-2 was synthesized according to the method in Example 1, and the starting materials were 2-chloro-6,6-dimethyl-8-cyclopentyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (its synthesis was similar to that in Example 1, the starting materials were 2,4-dichloro-5-methoxypyrimidine and cyclopentylamine) and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. The title product of 6,6-dimethyl-8-cyclopentyl-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5 ,4-b][1,4]oxazin-7(8H)-one hydrochloride (I-2) was obtained as a pale yellow solid. MS(m/z): 424 [M+H]+. 1H NMR (DMSO-d6): δ: 11.88 (br, 1H), 9.77 (br, 2H), 8.26(s, 1H), 8.24-8.22 (d, J = 8.0Hz, 1H), 7.93(s, 1H), 7.70-7.68 (d, J = 8.0Hz, 1H), 5.37-5.23 (m, 1H), 4.61 (m, 4H), 3.45 (m, 4H), 2.05-1.55 (m, 8H),1.48 (s, 6H).

    Example 3


    Compound (I-3)


    6,6-Dimethyl-8-cyclopentyl-2-(5-(4-ethyl-1-piperazinyl)methyl-pyridin-2-amino) -6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one



    [0029] The synthesis of Compound I-3 was synthesized according to the method in Example 1, and the starting materials were 2-chloro-6,6-dimethyl-8-cyclopentyl-6H- pyrimidine [5,4-b][1,4]oxazin-7(8H)-one and 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine. The title product of 6,6-dimethyl-8-cyclopentyl-2-(5-(4-ethyl-1-piperazinyl)methyl-pyridin-2-amino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one hydrochloride (I-3) was obtained as a white solid. MS(m/z): 466 [M+H]+. 1H NMR (DMSO-d6): δ: 12.04(br, 1H), 11.83(br, 1H), 8.53(s, 1H), 8.36-8.34 (d, J = 8.0Hz, 1H), 8.19(s, 1H), 7.72-7.70 (d, J = 8.0Hz, 1H), 5.29-5.21 (m, 1H), 4.41 (m, 4H), 3.59-3.51 (m, 6H), 3.08 (m, 2H), 1.99-1.47 (m, 8H),1.39 (s, 6H), 1.19-1.15 (t, J = 8.0Hz, 3H).

    Example 4


    Compound (I-4)


    8'-cyclopentyl-2'-(5-(1-piperazinyl)-pyridin-2-amino)spiro[cycloprop-1,6'-pyrimi do[5,4-b][1,4]oxazin]-7'(8'H)-one



    [0030] Compound I-4 was synthesized according to the method in Example 1, and the starting materials were 2'-chloro-8'-cyclopentyl-spiro[cycloprop-1,6'-pyrimido[5,4-b][1,4]oxazin]-7'(8'H) -one (its synthesis was similar to that in Example 1, the starting materials were 2,4-dichloro-5-methoxypyrimidine and methyl 1-bromocyclopropanecarboxylate)and tert-butyl 1-(2-pyridyl) 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. The title product of 8'-cyclopentyl-2'-(5-(1-piperazinyl)-pyridin-2-amino)spiro[cycloprop-1,6'-pyrimi do[5,4-b][1,4]oxazin]-7'(8'H)-one hydrochloride (I-4) was obtained as a pale yellow solid. MS(m/z): 422 [M+H]+.1H NMR (DMSO-d6): δ: 11.89(br, 1H), 9.80(br, 2H), 8.25(s, 1H),8.23-8.21 (d, J = 8.0Hz, 1H), 7.92(s, 1H), 7.70-7.68 (d, J = 8.0Hz, 1H), 5.36-5.23 (m, 1H), 4.60 (m, 4H), 3.47 (m, 4H), 2.03-1.55 (m, 8H),1.01-0.57 (m, 4H).

    Example 5


    Compound (I-5)


    8'-cyclopentyl-2'-(5-(1-piperazinyl)-pyridin-2-amino)spiro[cyclobut-1,6'-pyrimid o[5,4-b][1,4]oxazin]-7'(8'H)-one



    [0031] Compound I-5 was synthesized according to the method in Example 1, and the starting materials were 2'-chloro-8'-cyclopentyl-spiro[cyclobut-1,6'-pyrimido[5,4-b][1,4]oxazin]-7'(8'H)-one (its synthesis was similar to that in Example 1, the starting materials were 2,4-dichloro-5-methoxypyrimidine and methyl 1-bromocyclobutanecarboxylate) and tert-butyl 1-(2-pyridyl) 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. The title product of 8'-cyclopentyl-2'-(5-(1-piperazinyl)-pyridin-2-amino)spiro[cyclobut-1,6'-pyrimid o[5,4-b][1,4]oxazin]-7'(8'H)-one hydrochloride (I-5) was obtained as a pale yellow solid. MS(m/z): 436 [M+H]+.1H NMR (DMSO-d6): δ: 11.87(br, 1H), 9.79(br, 2H), 8.26(s, 1H), 8.24-8.22 (d, J = 8.0Hz, 1H), 7.91 (s, 1H), 7.70-7.68 (d, J = 8.0Hz, 1H), 5.35-5.23 (m, 1H), 4.55 (m, 4H), 3.45 (m, 4H), 2.71-2.59 (m, 4H), 2.03-1.98 (m, 2H), 1.75-1.57 (m, 8H).

    Example 6


    Compound (I-6)


    8'-cyclopentyl-2'-(5-(1-piperazinyl)-pyridin-2-amino)spiro[cyclopenta-1,6'-pyrim ido[5,4-b][1,4]oxazin]-7'(8'H)-one



    [0032] Compound I-6 was synthesized according to the method in Example 1, and the starting material was 2'-chloro-8'-cyclopentyl-spiro[cyclopenta-1,6'-pyrimido[5,4-b][1,4]oxazin-7'(8'H )-one (its synthesis was similar to that in Example 1, starting materials were 2,4-dichloro-5-methoxypyrimidine and methyl 1-bromocyclopentanecarboxylate) and tert-butyl 1-(2-pyridyl) 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. The title product of 8'-cyclopentyl-2'-(5-(1-piperazinyl)-pyridin-2-amino)spiro[cyclopenta-1,6'-pyrim ido[5,4-b][1,4]oxazin]-7'(8'H)-one hydrochloride (I-6) was obtained as a pale yellow solid. MS(m/z): 450 [M+H]+.1H NMR (DMSO-d6): δ: 11.88 (br, 1H), 9.81 (br, 2H), 8.27 (s, 1H), 8.24-8.22 (d, J = 8.0Hz, 1H), 7.90 (s, 1H), 7.70-7.68 (d, J = 8.0Hz, 1H), 5.34-5.23 (m, 1H), 4.59 (m, 4H), 3.47 (m, 4H), 2.25-2.10 (m, 4H), 2.03-1.58 (m, 12H).

    Example 7


    Compound (I-7)


    8'-cyclopentyl-2'-(5-(1-piperazinyl)-pyridin-2-amino)spiro[cyclohex-1,6'-pyrimid o[5,4-b][1,4]oxazin]-7'(8'H)-one



    [0033] Compound I-7 was synthesized according to the method in Example 1, and the starting material was 2'-chloro-8'-cyclopentyl-spiro[cyclohex-1,6'-pyrimido[5,4-b][1,4]oxazin-7'(8'H)-one (its synthesis was similar to that in Example 1, and starting materials were 2,4-dichloro-5-methoxypyrimidine and methyl 1-bromocyclohexanecarboxylate) and tert-butyl 1-(2-pyridyl) 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. The title product of 8'-cyclopentyl-2'-(5-(1-piperazinyl)-pyridin-2-amino)spiro[cyclohex-1,6'-pyrimid o[5,4-b][1,4]oxazin]-7'(8'H)-one hydrochloride (I-7) was obtained as a pale yellow solid. MS(m/z): 464 [M+H]+.1H NMR (DMSO-d6): δ: 11.87(br, 1H), 9.79(br, 2H), 8.27(s, 1H), 8.25-8.23 (d, J = 8.0Hz, 1H), 7.89(s, 1H), 7.70-7.68 (d, J = 8.0Hz, 1H), 5.35-5.23 (m, 1H), 4.65 (m, 4H), 3.57 (m, 4H), 2.23-1.95 (m, 4H), 1.93-1.54 (m, 14H).

    Example 8


    Compound (I-8)


    8'-cyclopentyl-2'-(5-(1-piperazinyl)-pyridin-2-amino)spiro[cyclohepta-1,6'-pyrim ido[5,4-b][1,4]oxazin]-7'(8'H)-one



    [0034] Compound I-8 was synthesized according to the method in Example 1, and the starting material was 2'-chloro-8'-cyclopentyl-spiro[cyclohept-1,6'-pyrimido[5,4-b][1,4]oxazin-7'(8'H)-one (its synthesis was similar to that in Example 1, and the starting materials were 2,4-dichloro-5-methoxypyrimidine and methyl 1-bromocycloheptanecarboxylate) and tert-butyl 1-(2-pyridyl) 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. The title product of 8'-cyclopentyl-2'-(5-(1-piperazinyl)-pyridin-2-amino)spiro[cyclohept-1,6'-pyrimi do[5,4-b][1,4]oxazin]-7'(8'H)-one hydrochloride (I-8) was obtained as a pale yellow solid. MS(m/z): 478 [M+H]+.1H NMR (DMSO-d6): δ: 11.88 (br, 1H), 9.78 (br, 2H), 8.28 (s, 1H), 8.25-8.23 (d, J = 8.0Hz, 1H), 7.91 (s, 1H), 7.71-7.69 (d, J = 8.0Hz, 1H), 5.37-5.23 (m, 1H), 4.63 (m, 4H), 3.58 (m, 4H), 2.21-1.95 (m, 4H), 1.91-1.46 (m, 16H).

    Example 9


    Compound (I-9)


    6-acetyl-8-cyclopentyl-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5,4-b] [1,4]oxazin-7(8H)-one



    [0035] Compound I-9 was synthesized according to the method in Example 1, and the starting material was 2-chloro-6-acetyl-8-cyclopentyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (its synthesis was similar to that in Example 1, and the starting materials were 2,4-dichloro-5-methoxypyrimidine and methyl 2-bromo-2-carbonylacetate) and tert-butyl 1-(2-pyridyl) 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. The title product of 6-acetyl-8-cyclopentyl-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5,4-b] [1,4]oxazin-7(8H)-one hydrochloride (I-9) was obtained as a pale yellow solid. MS(m/z): 438 [M+H]+.1H NMR (DMSO-d6): δ: 11.87(br, 1H), 9.81 (br, 2H), 8.27(s, 1H), 8.25-8.23 (d, J = 8.0Hz, 1H), 7.90(s, 1H), 7.71-7.69 (d, J = 8.0Hz, 1H), 5.57 (s, 1H), 5.35-5.26 (m, 1H), 4.61 (m, 4H), 3.59 (m, 4H), 3.37 (s, 3H), 2.09-1.57 (m, 8H).

    Example 10


    Compound (I-10)


    6-cyano-8-cyclopentyl-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5,4-b] [1,4]oxazin-7(8H)-one



    [0036] Compound I-10 was synthesized according to the method in Example 1, and the starting material was 2-chloro-6-cyano-8-cyclopentyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (its synthesis was similar to that in Example 1, and the starting materials were 2,4-dichloro-5-methoxypyrimidine and methyl 2-bromo-2-cyanoacetate) and tert-butyl 1-(2-pyridyl) 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. The title product of 6-cyano-8-cyclopentyl-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5,4-b] [1,4]oxazin-7(8H)-one hydrochloride (I-10) was obtained as a pale yellow solid. MS(m/z): 421 [M+H]+.1H NMR (DMSO-d6): δ: 11.89(br, 1H), 9.80(br, 2H), 8.28(s, 1H), 8.26-8.24 (d, J = 8.0Hz, 1H), 7.91 (s, 1H), 7.71-7.69 (d, J = 8.0Hz, 1H), 5.58(s, 1H), 5.36-5.26 (m, 1H), 4.62 (m, 4H), 3.59 (m, 4H), 2.03-1.57 (m, 8H).

    Example 11


    Compound (I-11)


    6-trifluoromethyl-8-cyclopentyl-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimi do[5,4-b][1,4]oxazin-7(8H)-one



    [0037] Compound I-11 was synthesized according to the method in Example 1, and the starting material was 2-chloro-6-trifluoromethyl-8-cyclopentyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-o ne (its synthesis was similar to that in Example 1, and the starting materials were 2,4-dichloro-5-methoxypyrimidine and methyl 2-bromo-2-trifluoromethylacetate) and tert-butyl 1-(2-pyridyl) 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. The title product of 6-trifluoromethyl-8-cyclopentyl-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimi do[5,4-b][1,4]oxazin-7(8H)-one hydrochloride (I-11) was obtained as a pale yellow solid. MS(m/z): 464 [M+H]+.1H NMR (DMSO-d6): δ: 11.87(br, 1H), 9.81 (br, 2H), 8.27(s, 1H), 8.26-8.24 (d, J = 8.0Hz, 1H), 7.90(s, 1H), 7.70-7.68 (d, J = 8.0Hz, 1H), 5.57-5.54(m, 1H), 5.35-5.26 (m, 1H), 4.61 (m, 4H), 3.64 (m, 4H), 2.01-1.54 (m, 8H).

    Example 12


    Compound (I-12)


    6,6-difluoro-8-cyclopentyl-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5, 4-b][1,4]oxazin-7(8H)-one



    [0038] Compound I-12 was synthesized according to the method in Example 1, and the starting material was 2-chloro-6,6-difluoro-8-cyclopentyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (its synthesis was similar to that in Example 1, and the starting materials were 2,4-dichloro-5-methoxypyrimidine and methyl 2-bromo-2,2-difluoroacetate) and tert-butyl 1-(2-pyridyl) 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. The title product of 6,6-difluoro-8-cyclopentyl-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5, 4-b][1,4]oxazin-7(8H)-one hydrochloride (I-12) was obtained as a pale yellow solid. MS(m/z): 432 [M+H]+.1H NMR (DMSO-d6): δ: 11.88 (br, 1H), 9.79 (br, 2H), 8.26 (s, 1H), 8.23-8.21 (d, J = 8.0Hz, 1H), 7.90 (s, 1H), 7.70-7.67 (d, J = 8.0Hz, 1H), 5.37-5.26 (m, 1H), 4.62 (m, 4H), 3.63 (m, 4H), 2.03-1.57 (m, 8H).

    Example 13


    Compound (I-13)


    6-cyclopropyl-8-cyclopentyl-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrinnido[ 5,4-b][1,4]oxazin-7(8H)-one



    [0039] Compound I-13 was synthesized according to the method in Example 1, and the starting materials were 2-chloro-6-cyclopropyl-8-cyclopentyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (its synthesis was similar to that in Example 1, and the starting materials were 2,4-dichloro-5-methoxypyrimidine and methyl 2-bromo-2-cyclopropylacetate) and 1-(2-pyridyl) and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. The title product of 6-cyclopropyl-8-cyclopentyl-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[ 5,4-b][1,4]oxazin-7(8H)-one hydrochloride (I-13) was obtained as a pale yellow solid. MS(m/z): 436 [M+H]+.1H NMR (DMSO-d6): δ: 11.89(br, 1H), 9.81 (br, 2H), 8.27(s, 1H), 8.24-8.22 (d, J = 8.0Hz, 1H), 7.89(s, 1H), 7.70-7.68 (d, J = 8.0Hz, 1H), 5.58-5.57 (d, J = 4.0Hz, 1H), 5.38-5.26 (m, 1H), 4.67 (m, 4H), 3.69 (m, 4H), 2.03-1.58 (m, 8H), 1.05-1.01 (m, 1H), 0.87-0.69 (m, 4H).

    Example 14


    Compound (I-14)


    6-cyclobutyl-8-cyclopentyl-2-(5-(4-ethyl-1-piperazinyl)methyl-pyridin-2-amino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one



    [0040] Compound I-14 was synthesized according to the method in Example 1, and the starting material was 2-chloro-6-cyclobutyl-8-cyclopentyl-6H-pyrimido[5,4-b] [1,4]oxazin-7(8H)-one (its synthesis was similar to that in Example 1, and the starting materials were 2,4-dichloro-5-methoxypyrimidine and methyl 2-bromo-2-butylpropyl acetate) and 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine. The title product of 6-cyclobutyl-8-cyclopentyl-2-(5-(4-ethyl-1-piperazinyl)methyl-pyridin-2-amino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (I-14) was obtained as a white solid. MS(m/z): 492 [M+H]+. 1H NMR (DMSO-d6): δ: 11.81 (br, 1H), 8.53 (s, 1H), 8.35-8.33 (d, J = 8.0Hz, 1H), 8.20(s, 1H), 7.71-7.69 (d, J = 8.0Hz, 1H), 5.58-5.57 (d, J = 4.0Hz, 1H), 5.27-5.21 (m, 1H), 4.87 (s, 2H), 4.45-4.23 (m, 11H), 2.47-2.21 (m, 14H), 1.19-1.15 (t, J = 8.0Hz, 3H).

    Example 15


    Compound (I-15)


    6-isopropyl-8-methyl-2-(5-(4-ethyl-1-piperazinyl)methyl-pyridin-2-amino)-6H-p yrimido[5,4-b][1,4]oxazin-7(8H)-one



    [0041] Compound I-15 was synthesized according to the method in Example 1, and the starting material was 2-chloro-6-isopropyl-8-methyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (its synthesis was similar to that in Example 1, and the starting materials were 2,4-dichloro-5-methoxypyrimidine, methylamine and methyl 2-bromoisovalerate) and 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine. The title product of 6-isopropyl-8-methyl-2-(5-(4-ethyl-1-piperazinyl)methyl-pyridin-2-amino)-6H-p yrimido[5,4-b][1,4]oxazin-7(8H)-one (I-15) was obtained as a white solid. MS(m/z): 426 [M+H]+. 1H NMR (DMSO-d6): δ: 11.81 (br, 1H), 8.55(s, 1H), 8.35-8.33 (d, J = 8.0Hz, 1H), 8.18(s, 1H), 7.70-7.68 (d, J = 8.0Hz, 1H), 5.58-5.57 (d, J = 4.0Hz, 1H), 4.89(s, 2H), 4.59 (s, 3H), 4.41-4.23 (m, 11H), 1.19-1.15 (t, J = 8.0Hz, 3H), 1.05-1.04 (d, J = 4.0Hz, 6H).

    Example 16


    Compound (I-16)


    6-methyl-6,8-diethyl-2-(5-(4-methyl-1-piperazinyl)methyl-pyridin-2-amino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one



    [0042] Compound I-16 was synthesized according to the method in Example 1, and the starting material was 2-chloro-6-methyl-6,8-diethyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (its synthesis was similar to that in Example 1, and the starting materials were 2,4-dichloro-5-methoxypyrimidine, ethylamine and methyl 2-bromo-2-methylbutylate) and 5-[(4-methylpiperazin-1-yl)methyl]pyridin-2-amine. The title product of 6-methyl-6,8-diethyl-2-(5-(4-methyl-1-piperazinyl)methyl-pyridin-2-amino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (I-16) was obtained as a white solid. MS(m/z): 426 [M+H]+. 1H NMR (DMSO-d6): δ: 11.82(br, 1H), 8.56(s, 1H), 8.35-8.33 (d, J = 8.0Hz, 1H), 8.19(s, 1H), 7.70-7.68 (d, J = 8.0Hz, 1H), 4.89 (s, 2H), 4.67-4.63 (q, J =4.0Hz, 2H), 4.59 (s, 3H), 4.40-4.22 (m, 8H), 3.25-3.21 (q, J =4.0Hz, 2H), 2.35 (s, 3H), 2.01-1.99 (t, J = 4.0Hz, 3H), 1.58-1.56 (t, J = 4.0Hz, 3H).

    Example 17


    Compound (I-17)


    6-cyclopentyl-8-sec-butyl-2-(5-(1-piperazinyl)methyl-pyridin-2-amino)-6H-pyri mido[5,4-b][1,4]thiazin-7(8H)-one



    [0043] Compound I-17 was synthesized according to the method in Example 1, and the starting material was 2-chloro-6-cyclopentyl-8-sec-butyl-6H-pyrimidine[5,4-b][1,4]thiazin-7(8H)-one (its synthesis was similar to that in Example 1, and the starting materials were 2,4-dichloro-5-methylthiopyrimidine, sec-butylamine and methyl 2-bromo-2-cyclopentyl acetate) and 5-[(piperazin-1-yl)methyl]pyridin-2-amine. The title product of 6-cyclopentyl-8-sec-butyl-2-(5-(1-piperazinyl)methyl-pyridin-2-amino)-6H-pyri mido[5,4-b][1,4]thiazin-7(8H)-one hydrochloride (I-17) was obtained as a white solid. MS(m/z): 482 [M+H]+. 1H NMR (DMSO-d6): δ: 11.89 (br, 1H), 9.81 (br, 2H), 8.55(s, 1H), 8.35-8.33 (d, J = 8.0Hz, 1H), 8.21 (s, 1H), 7.70-7.68 (d, J = 8.0Hz, 1H), 4.88-4.65(m, 4H), 4.42-4.25 (m, 8H), 2.21-1.95(m,14H), 0.98-0.96 (t, J = 4.0Hz, 3H).

    Example 18


    Compound (I-18)


    6-cyclohexyl-8-tert-amyl-2-(5-(4-cyclopropyl-1-piperazinyl)methyl-pyridin-2-am ino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one



    [0044] Compound I-18 was synthesized according to the method in Example 1, and the starting material was 2-chloro-6-cyclohexyl-8-tert-amyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (its synthesis was similar to that in Example 1, and the starting materials were2,4-dichloro-5-methoxypyrimidine, tert-amylamine and methyl 2-bromo-2-cyclohexylacetate) and 5-[(4-cyclopropylpiperazin-1-yl)methyl]pyridin-2-amine. The title product of 6-cyclohexyl-8-tert-amyl-2-(5-(4-cyclopropyl-1-piperazinyl)methyl-pyridin-2-am ino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (I-18) was obtained as a white solid. MS(m/z): 534 [M+H]+. 1H NMR (DMSO-d6): δ: 11.81 (br, 1H), 8.57(s, 1H), 8.34-8.32 (d, J = 8.0Hz, 1H), 8.19(s, 1H), 7.70-7.68 (d, J = 8.0Hz, 1H), 5.58-5.57 (d, J = 4.0Hz, 1H), 4.88(s, 2H), 4.42-4.21 (m, 9H), 2.21-2.01 (m, 19H), 1.19-1.15 (t, J = 8.0Hz, 1H), 0.75-0.69 (m, 4H).

    Example 19


    Compound (I-19)


    6-cycloheptyl-8-(3-methyl-2-butyl)-2-(5-(4-n-propyl-1-piperazinyl)methyl-pyridi ne-2-amino)-6H-pyrimido[5,4-b][1,4]thiazin-7(8H)-one



    [0045] Compound I-19 was synthesized according to the method in Example 1, and the starting material was 2-chloro-6-cycloheptyl-8-(3-methyl-2-butyl)-6H-pyrimido[5,4-b][1,4]thiazin-7(8 H)-one (its synthesis was similar to that in Example 1, and the starting materials were 2,4-dichloro-5-methylthiopyrimidine, 3-methyl-2-butylamine and methyl 2-bromo-2-cycloheptylacetate) and 5-[(4-propylpiperazin-1-yl)methyl]pyridin-2-amine. The title product of 6-cycloheptyl-8-(3-methyl-2-butyl)-2-(5-(4-n-propyl-1-piperazinyl)methyl-pyridi n-2-amino)-6H-pyrimido[5,4-b][1,4]thiazin-7(8H)-one (I-19) was obtained as a white solid. MS(m/z): 567 [M+H]+. 1H NMR (DMSO-d6): δ: 11.82 (br, 1H), 8.55 (s, 1H), 8.34-8.32 (d, J = 8.0Hz, 1H), 8.21 (s, 1H), 7.70-7.68 (d, J = 8.0Hz, 1H), 5.58-5.57 (d, J = 4.0Hz, 1H), 4.87-4.65 (m, 4H), 4.43-4.21 (m, 11H), 2.19-2.01 (m, 17H), 1.21-1.18 (m, 9H).

    Example 20


    Compound (I-20)


    6,6-dimethyl-8-cyclopentyl-2-(5-(4-cyclobutyl-1-piperazinyl)-pyridin-2-amino)-6 H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one



    [0046] Compound I-20 was synthesized according to the method in Example 1, and the starting materials were 2-chloro-6,6-dimethyl-8-cyclopentyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one and 1-cyclobutyl-4-(6-aminopyridin-3-yl)piperazine. The title product of 6,6-dimethyl-8-cyclopentyl-2-(5-(4-cyclobutyl-1-piperazinyl)-pyridin-2-amino)-6 H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (I-20) was obtained as a pale yellow solid. MS(m/z): 478 [M+H]+. 1H NMR (DMSO-d6): δ: 11.83(br, 1H), 8.26 (s, 1H), 8.22-8.20 (d, J = 8.0Hz, 1H), 7.91 (s, 1H), 7.70-7.68 (d, J = 8.0Hz, 1H), 5.37-5.23 (m, 1H), 4.61-4.56 (m, 5H), 3.45-3.40 (m, 4H), 2.05-1.47 (m, 20H).

    Example 21


    Compound (I-21)


    6,6-dimethyl-8-cyclopentyl-2-(5-(4-cyclopentyl-1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one



    [0047] Compound I-21 was synthesized according to the method in Example 1, and the starting materials were 2-chloro-6,6-dimethyl-8-cyclopentyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one and 1-cyclopentyl-4-(6-aminopyridin-3-yl)piperazine. The title product of 6,6-dimethyl-8-cyclopentyl-2-(5-(4-cyclopentyl-1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (I-21) was obtained as a pale yellow solid. MS(m/z): 492 [M+H]+. 1H NMR (DMSO-d6): δ: 11.81 (br, 1H), 8.25 (s, 1H), 8.23-8.21 (d, J = 8.0Hz, 1H), 7.92 (s, 1H), 7.70-7.68 (d, J = 8.0Hz, 1H), 5.36-5.23 (m, 1H), 4.60 (m, 4H), 3.45-3.39 (m, 5H), 2.03-1.43 (m, 22H).

    Example 22


    Compound (I-22)


    6,6-dimethyl-8-cyclopentyl-2-(5-(4-cyclohexyl-1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one



    [0048] Compound I-22 was synthesized according to the method in Example 1, and the starting materials were 2-chloro-6,6-dimethyl-8-cyclopentyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one and 1-cyclohexyl-4-(6-aminopyridin-3-yl)piperazine. The title product of 6,6-dimethyl-8-cyclopentyl-2-(5-(4-cyclohexyl-1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (I-22) was obtained as a pale yellow solid. MS(m/z): 506 [M+H]+. 1H NMR (DMSO-d6): δ: 11.83(br, 1H), 8.26(s, 1H), 8.23-8.21 (d, J = 8.0Hz, 1H), 7.93(s, 1H), 7.70-7.68 (d, J = 8.0Hz, 1H), 5.35-5.25 (m, 1H), 4.61 (m, 4H), 3.47-3.39 (m, 5H), 2.05-1.43 (m, 24H).

    Example 23


    Compound (I-23)


    6,6-dimethyl-8-cyclopentyl-2-(5-(4-cycloheptyl-1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5,4-b][1,4]thiazin-7(8H)-one



    [0049] Compound I-23 was synthesized according to the method in Example 1, and the starting materials were 2-chloro-6,6-dimethyl-8-cyclopentyl-6H-pyrimido[5,4-b][1,4]thiazin-7(8H)-one and 1-cycloheptyl-4-(6-aminopyridin-3-yl)piperazine. The title product of 6,6-dimethyl-8-cyclopentyl-2-(5-(4-cycloheptyl-1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5,4-b][1,4]thiazin-7(8H)-one (I-23) was obtained as a pale yellow solid. MS(m/z): 536 [M+H]+. 1H NMR (DMSO-d6): δ: 11.81 (br, 1H), 8.27 (s, 1H), 8.22-8.20 (d, J = 8.0Hz, 1H), 7.91 (s, 1H), 7.71-7.69 (d, J = 8.0Hz, 1H), 5.35-5.25 (m, 1H), 4.61 (m, 4H), 3.46-3.37 (m, 5H), 2.07-1.42 (m, 26H).

    Example 24


    Compound (I-24)


    6,6-dimethyl-8-cyclopentyl-2-(5-(4-isopropyl-1-piperazinyl)-pyridin-2-amino)-6 H-pyrimido[5,4-b][1,4]thiazin-7(8H)-one



    [0050] Compound I-24 was synthesized according to the method in Example 1, and the starting materials were 2-chloro-6,6-dimethyl-8-cyclopentyl-6H-pyrimido[5,4-b][1,4]thiazin-7(8H)-one and 1-isopropyl-4-(6-aminopyridin-3-yl)piperazine. The title product of 6,6-dimethyl-8-cyclopentyl-2-(5-(4-isopropyl-1-piperazinyl)-pyridin-2-amino)-6 H-pyrimido[5,4-b][1,4]thiazin-7(8H)-one (I-24) was obtained as a pale yellow solid. MS(m/z): 482 [M+H]+. 1H NMR (DMSO-d6): δ: 11.82 (br, 1H), 8.26 (s, 1H), 8.23-8.21 (d, J = 8.0Hz, 1H), 7.91 (s, 1H), 7.71-7.69 (d, J = 8.0Hz, 1H), 5.38-5.27 (m, 1H), 4.63 (m, 4H), 3.47-3.37 (m, 5H), 2.01-1.45 (m, 14H), 1.58-1.57 (d, J = 4.0Hz, 6H).

    Example 25


    Compound (I-25)


    8'-cyclopentyl-2'-(5-(4-ethyl-1-piperazinyl)-pyridin-2-amino)spiro[cycloprop-1,6' -pyrimido[5,4-b][1,4]oxazin]-7'(8'H)-one



    [0051] Compound I-25 was synthesized according to the method in Example 1, and the starting materials were 2'-chloro-8'-cyclopentyl-spiro[cycloprop-1,6'-pyrimido[5,4-b][1,4]oxazin]-7'(8'H) -one and 1-(2-pyridyl) and 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine. The title product of 8'-cyclopentyl-2'-(5-(4-ethyl-1-piperazinyl)-pyridin-2-amino)spiro[cycloprop-1,6' -pyrimido[5,4-b][1,4]oxazin]-7'(8'H)-one (I-25) was obtained as a pale yellow solid. MS(m/z): 464 [M+H]+.1H NMR (DMSO-d6): δ: 11.83 (br, 1H), 8.53 (s, 1H), 8.36-8.34 (d, J = 8.0Hz, 1H), 8.21 (s, 1H), 7.71-7.69 (d, J = 8.0Hz, 1H), 5.01-4.95 (m, 3H), 4.25-3.56 (m, 10H), 2.05-1.57 (m, 8H), 1.21-0.97 (m, 7H).

    Example 26


    Compound (I-26)


    6-acetyl-8-cyclopentyl-2-(5-(4-ethyl-1-piperazinyl)methyl-pyridin-2-amino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one



    [0052] Compound I-26 was synthesized according to the method in Example 1, and the starting materials were 2-chloro-6-acetyl-8-cyclopentyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one and 1-(2-pyridyl) and 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine. The title product of 6-acetyl-8-cyclopentyl-2-(5-(4-ethyl-1-piperazinyl)methyl-pyridin-2-amino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (I-26) was obtained as a pale yellow solid. MS(m/z): 480 [M+H]+.1H NMR (DMSO-d6): δ: 11.81 (br, 1H), 8.52 (s, 1H), 8.36-8.34 (d, J = 8.0Hz, 1H), 8.20 (s, 1H), 7.71-7.69 (d, J = 8.0Hz, 1H), 6.15 (s, 1H), 5.01-4.85 (m, 3H), 4.23-3.58 (m, 10H), 3.39 (s, 3H), 2.01-1.57 (m, 8H), 1.23-1.21 (t, J = 4.0Hz, 3H).

    Example 27


    Compound (I-27)


    6-cyano-8-cyclopentyl-2-(5-(4-ethyl-1-piperazinyl)methyl-pyridin-2-amino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one



    [0053] Compound I-27 was synthesized according to the method in Example 1, and the starting materials were 2-chloro-6-cyano-8-cyclopentyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one and 1-(2-pyridyl) and 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine. The title product of 6-cyano-8-cyclopentyl-2-(5-(4-ethyl-1-piperazinyl)methyl-pyridin-2-amino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (I-27) was obtained as a pale yellow solid. MS(m/z): 463 [M+H]+.1H NMR (DMSO-d6): δ: 11.80 (br, 1H), 8.51 (s, 1H), 8.37-8.35 (d, J = 8.0Hz, 1H), 8.21 (s, 1H), 7.71-7.69 (d, J = 8.0Hz, 1H), 6.17 (s, 1H), 5.00-4.87 (m, 3H), 4.21-3.58 (m, 10H), 2.01-1.58 (m, 8H), 1.24-1.22 (t, J= 4.0Hz, 3H).

    Example 28


    Compound (I-28)


    8'-cyclopentyl-2'-(5-(4-ethyl-1-piperazinyl)-pyridin-2-amino)spiro[cyclobut-1,6'-pyrimido[5,4-b][1,4]oxazin]-7'(8'H)-one



    [0054] Compound I-28 was synthesized according to the method in Example 1, and the starting materials were 2'-chloro-8'-cyclopentyl-spiro[cyclobut-1,6'-pyrimido[5,4-b][1,4]oxazin]-7'(8'H)-one and 1-(2-pyridyl) and 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine. The title product of 8'-cyclopentyl-2'-(5-(4-ethyl-1-piperazinyl)-pyridin-2-amino)spiro[cyclobut-1,6'-pyrimido[5,4-b][1,4]oxazin]-7'(8'H)-one (I-28) was obtained as a pale yellow solid. MS(m/z): 478 [M+H]+.1H NMR (DMSO-d6): δ: 11.82 (br, 1H), 8.52 (s, 1H), 8.37-8.35 (d, J = 8.0Hz, 1H), 8.23 (s, 1H), 7.71-7.69 (d, J = 8.0Hz, 1H), 4.98-4.94 (m, 3H), 4.23-3.56 (m, 14H), 2.03-1.55 (m, 10H), 1.23-1.21 (t, J = 4.0Hz, 3H).

    Example 29


    Compound (I-29)


    6,6-dimethyl-8-(2-thienyl)-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5, 4-b][1,4]oxazin-7(8H)-one



    [0055] Compound I-29 was synthesized according to the method in Example 1, and the starting material was 2-chloro-6,6-dimethyl-8-(2-thienyl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (its synthesis was similar to that in Example 1, and the starting materials were 2,4-dichloro-5-methoxypyrimidine and 2-aminothiophene) and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. The title product of 6,6-dimethyl-8-(2-thienyl)-2-(5-(1-piperazinyl)-pyridin-2-yl)-6H-pyrimido[5,4-b][ 1,4]oxazin-7(8H)-one hydrochloride (I-29) was obtained as a pale yellow solid. MS(m/z): 438 [M+H]+. 1H NMR (DMSO-d6): δ: 11.89 (br, 1H), 9.78 (br, 2H), 8.26 (s, 1H), 8.24-8.22 (d, J = 8.0Hz, 1H), 7.91-7.78 (m, 4H), 6.58-6.52 (m, 1H), 4.61 (m, 4H), 3.47 (m, 4H), 1.48 (s, 6H).

    Example 30


    Compound (I-30)


    6,6-dimethyl-8-(2-pyridyl)-2-(5-(4-ethyl-1-piperazinyl)methyl-pyridine-2-amino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one



    [0056] Compound I-30 was synthesized according to the method in Example 1, and the starting materials were 2-chloro-6,6-dimethyl-8-(2-pyridyl)-6H-pyrimidio[5,4-b][1,4]oxazin-7(8H)-one and 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine. The title product of 6,6-dimethyl-8-(2-pyridyl)-2-(5-(4-ethyl-1-piperazinyl)methyl-pyridin-2-amino)-6 H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (I-30) was obtained as a white solid. MS(m/z): 475 [M+H]+. 1H NMR (DMSO-d6): δ: 11.83 (br, 1H), 8.67-8.64 (m, 1H), 8.61-8.58 (m, 1H), 8.51-8.47 (m, 2H), 8.36-8.34 (d, J = 8.0Hz, 1H), 8.21 (s, 1H), 8.05-8.01 (m, 1H), 7.72-7.70 (d, J = 8.0Hz, 1H), 4.87 (s, 2H), 4.23-3.56 (m, 10H), 1.58 (s, 6H), 1.19-1.17 (t, J = 4.0Hz, 3H).

    Example 31


    Compound (I-31)


    6,6-dimethyl-8-(2-pyrimidinyl)-2-(5-(4-ethyl-1-piperazinyl)methyl-pyridine-2-am ino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one



    [0057] Compound I-31 was synthesized according to the method in Example 1, and the starting materials were 2-chloro-6,6-dimethyl-8-(2-pyrimidinyl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-on e and 5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-amine. The title product of 6,6-dimethyl-8-(2-pyrimidinyl)-2-(5-(4-ethyl-1-piperazinyl)methyl-pyridin-2-ami no)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (I-31) was obtained as a white solid. MS(m/z): 476 [M+H]+. 1H NMR (DMSO-d6): δ: 11.81 (br, 1H), 8.92-8.89 (m, 2H), 8.53 (s, 1H), 8.37-8.34 (m, 2H), 8.20 (s, 1H), 7.72-7.70 (d, J = 8.0Hz, 1H), 4.87 (s, 2H), 4.21-3.64 (m, 10H), 1.57 (s, 6H), 1.19-1.17 (t, J = 4.0Hz, 3H).

    Example 32


    Compound (I-32)


    6,6-dimethyl-8-(2-furyl)-2-(5-(1-piperazinyl)-pyridin-2-yl)-6H-pyrimido[5,4-b][1, 4]oxazin-7(8H)-one



    [0058] Compound I-32 was synthesized according to the method in Example 1, and the starting materials were 2-chloro-6,6-dimethyl-8-(2-furyl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. The title product of 6,6-dimethyl-8-(2-furyl)-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one hydrochloride (I-32) was obtained as a pale yellow solid. MS(m/z): 422 [M+H]+. 1H NMR (DMSO-d6): δ: 11.87 (br, 1H), 9.81 (br, 2H), 8.25 (s, 1H), 8.24-8.22 (d, J = 8.0Hz, 1H), 7.98-7.82 (m, 3H), 6.57-6.52 (m, 2H), 4.62 (m, 4H), 3.48 (m, 4H), 1.51 (s, 6H).

    Example 33


    Compound (I-33)


    N,N-dimethyl-6-carboxamide-8-cyclopentyl-2-(5-(1-piperazinyl)-pyridin-2-amin o)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one



    [0059] Compound I-33 was synthesized according to the method in Example 1, and the starting materials were 2-chloro-N,N-dimethyl-6-carboxamide-8-cyclopentyl-6H-pyrimido[5,4-b][1,4]ox azin-7(8H)-one and 1-(2-pyridyl) and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. The title product of N,N-dimethyl-6-carboxamide-8-cyclopentyl-2-(5-(1-piperazinyl)-pyridin-2-amin o)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one hydrochloride (I-33) was obtained as a pale yellow solid. MS(m/z): 467 [M+H]+.1H NMR (DMSO-d6): δ: 11.88(br, 1H), 9.80(br, 2H), 8.27 (s, 1H), 8.23-8.21 (d, J = 8.0Hz, 1H), 7.91 (s, 1H), 7.71-7.69 (d, J = 8.0Hz, 1H), 5.58(s, 1H), 5.33-5.26 (m, 1H), 5.01 (s, 6H), 4.62 (m, 4H), 3.61 (m, 4H), 2.05-1.57 (m, 8H).

    Example 34


    Compound (I-34)


    6-carboxamide-8-cyclopentyl-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimid o[5,4-b][1,4]oxazin-7(8H)-one



    [0060] Compound I-34 was synthesized according to the method in Example 1, and the starting materials were 2-chloro-6-carboxamide-8-cyclopentyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-on e and 1-(2-pyridyl) and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. The title product of 6-carboxamide-8-cyclopentyl-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimid o[5,4-b][1,4]oxazin-7(8H)-one hydrochloride (I-34) was obtained as a pale yellow solid. MS(m/z): 439 [M+H]+.1H NMR (DMSO-d6): δ: 11.86 (br, 1H), 9.83 (br, 2H), 9.57 (br, 2H), 8.26 (s, 1H), 8.22-8.20 (d, J = 8.0Hz, 1H), 7.91 (s, 1H), 7.71-7.69 (d, J = 8.0Hz, 1H), 5.59 (s, 1H), 5.34-5.26 (m, 1H), 4.63 (m, 4H), 3.63 (m, 4H), 2.01-1.62 (m, 8H).

    Example 35


    Compound (I-35)


    6,6-dimethyl-8-phenyl-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5,4-b] [1,4]oxazin-7(8H)-one



    [0061] Compound I-35 was synthesized according to the method in Example 1, and the starting material was 2-chloro-6,6-dimethyl-8-phenyl-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (its synthesis was similar to that in Example 1, and the starting materials were 2,4-dichloro-5-methoxypyrimidine and aniline) and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. The title product of 6,6-dimethyl-8-phenyl-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5,4-b] [1,4]oxazin-7(8H)-one (I-35) was obtained as a pale yellow solid. MS(m/z): 432 [M+H]+. 1H NMR (DMSO-d6): δ: 11.86 (br, 1H), 9.82 (br, 2H), 8.56-8.52 (m, 4H), 8.26 (s, 1H), 8.24-8.22 (d, J = 8.0Hz, 1H), 7.99-7.92 (m, 3H), 4.61 (m, 4H), 3.49 (m, 4H), 1.52 (s, 6H).

    Example 36


    Compound (I-36)


    6,6-dimethyl-8-(4-chlorophenyl)-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrim ido[5,4-b][1,4]oxazin-7(8H)-one



    [0062] Compound I-36 was synthesized according to the method in Example 1, and the starting material was 2-chloro-6,6-dimethyl-8-(4-chlorophenyl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (its synthesis was similar to that in Example 1, and the starting materials were 2,4-dichloro-5-methoxypyrimidine and 4-chlorophenylamine) and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. The title product of 6,6-dimethyl-8-(4-chlorophenyl)-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrim ido[5,4-b][1,4]oxazin-7(8H)-one (I-36) was obtained as a pale yellow solid. MS(m/z): 466 [M+H]+. 1H NMR (DMSO-d6): δ: 11.87 (br, 1H), 9.85 (br, 2H), 8.56-8.54 (d, J = 8.0Hz, 2H), 8.45-8.43 (d, J = 8.0Hz, 2H), 8.26 (s, 1H), 8.23-8.21 (d, J = 8.0Hz, 1H), 7.90 (s, 1H), 7.71-7.69 (d, J = 8.0Hz, 1H), 4.63 (m, 4H), 3.51 (m, 4H), 1.54 (s, 6H).

    Example 37


    Compound (I-37)


    6,6-dimethyl-8-(3-pentyl)-2-(5-(1-piperazinyl)-pyridin-2-amino)-6H-pyrimido[5,4 -b][1,4]oxazin-7(8H)-one



    [0063] Compound I-37 was synthesized according to the method in Example 1, and the starting materials were 2-chloro-6,6-dimethyl-8-(3-pentyl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate. The title product of 6,6-dimethyl-8-(3-pentyl)-2-(5-(1-piperazinyl)-pyriin-2-amino)-6H-pyrimido[5,4 -b][1,4]oxazin-7(8H)-one hydrochloride (I-37) was obtained as a pale yellow solid. MS(m/z): 426 [M+H]+. 1H NMR (DMSO-d6): δ: 11.87 (br, 1H), 9.78 (br, 2H), 8.27 (s, 1H), 8.24-8.22 (d, J = 8.0Hz, 1H), 7.91 (s, 1H), 7.70-7.68 (d, J = 8.0Hz, 1H), 5.35-5.22 (m, 1H), 4.61 (m, 4H), 3.48 (m, 4H), 1.58 (s, 6H), 1.45-1.42 (m, 4H), 0.92-0.88 (m, 6H).

    Example 38


    Compound (I-38)


    6,6-dimethyl-8-(3-pentyl)-2-(5-(4-ethyl-1-piperazinyl)methyl-pyridine-2-amino)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one



    [0064] Compound I-37 was synthesized according to the method in Example 1, and the starting materials were 2-chloro-6,6-dimethyl-8-(3-pentyl)-6H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one and tert-butyl 4-(6-aminopyridin-3-yl)piperazine-1-carboxylate 5-[(4-ethylpiperazin-1-yl)methyl]pyridyl-2-amine. The title product of 6,6-dimethyl-8-(3-pentyl)-2-(5-(4-ethyl-1-piperazinyl)methyl-pyridin-2-amino)-6 H-pyrimido[5,4-b][1,4]oxazin-7(8H)-one (I-38) was obtained as a pale yellow solid. MS(m/z): 468 [M+H]+. 1H NMR (DMSO-d6): δ: 11.82(br, 1H), 8.51 (s, 1H), 8.36-8.34 (d, J = 8.0Hz, 1H), 8.18 (s, 1H), 7.72-7.70 (d, J = 8.0Hz, 1H), 5.21-5.08 (m, 3H), 4.61-4.02 (m, 10H), 1.59 (s, 6H), 1.46-1.42 (m, 4H), 0.93-0.88 (m, 9H).

    Example 39


    Biological assays



    [0065] Activity assay: The CDK4 protein kinase activity was measured using the Caliper mobility shift assay (see J. Biomol. Screen, 2009, PP31).The test compound was dissolved in DMSO and diluted with a kinase buffer solution (20 mM HEPES-pH 7.5, 0.01% Triton X-100, 10 mM MgCl2, 2 mM DTT) and 5 µL of the compound at 5-fold final concentration of reaction dissolved in 10% DMSO was added in a 384-well plate. The compound-free control well was 5 µL of 10% DMSO, and the no-activity control well was 5 µL of kinase buffer.10 µL of a 2.5-fold diluted CDK4 enzyme solution (GST-CDK4(1-303 end)) was added and incubated at room temperature for 10 min, and then 10 µL of the 2.5-fold diluted substrate solution Peptide FAM-P8 was added.The reaction was stopped by adding 25 µL of stop solution after incubation at 28°C for 3 h, and the conversion rate data was read on a Caliper EZ Reader II (Caliper Life Sciences) and the conversion rate was converted to inhibition rate data according to above method. Among them, the inhibition rate % = (max - conversion)/(max - min) x 100%.

    [0066] Activity Assay: The CDK6 protein kinase activity was measured using the Caliper mobility shift assay (see J. Biomol. Screen, 2009, PP31). The test compound was dissolved in DMSO and diluted with a kinase buffer solution (20 mM HEPES-pH 7.5, 0.01% Triton X-100, 10 mM MgCl2, 2 mM DTT) and 5 µL of the compound at 5-fold final concentration of reaction dissolved in 10% DMSO was added in a 384-well plate. The compound-free control well was 5 µL of 10% DMSO, and the no-activity control well was 5 µL of kinase buffer.10 µL of a 2.5-fold diluted CDK6 enzyme solution (GST-CDK6(1-326 end)) was added and incubated at room temperature for 10 min, and then 10 µL of the 2.5-fold diluted substrate solution Peptide FAM-P8 was added.The reaction was stopped by adding 25 µL of stop solution after incubation at 28°C for 3 h, and the conversion rate data was read on a Caliper EZ Reader II (Caliper Life Sciences) and the conversion rate was converted to inhibition rate data according to above method. Among them, the inhibition rate % = (max - conversion)/(max - min) x 100%.

    [0067] Results of above experiments are summaried in Table 2.
    Table 2. Results of the assay
    CompoundCDK4CDK6CompoundCDK4CDK6
    Palbociclib D D I-1 D D
    I-2 D D I-3 D D
    I-4 D C I-5 D C
    I-6 D C I-7 D D
    I-8 D C I-9 D C
    I-10 D B I-11 D C
    I-12 D C I-13 D D
    I-14 D D I-15 D C
    I-16 D D I-17 D A
    I-18 D D I-19 D C
    I-20 D D I-21 D C
    I-22 D D I-23 D D
    I-24 D D I-25 D D
    I-26 D B I-27 D D
    I-28 D C I-29 D D
    I-30 D C I-31 D D
    I-32 D A I-33 D D
    I-34 D D I-35 C C
    I-36 D D I-37 D C
    I-38 D C      
    Note: A represents IC50> 500nM, B represents 500nM ≥ IC50> 100nM, C represents 100nM ≥ IC50> 20nM, D represents IC50≤ 20nM.



    Claims

    1. A heterocyclic-substituted pyridinopyrimidinone derivative, that has the following Formula I or a pharmaceutically acceptable salt thereof:

    Wherein,

    R1 represents hydrogen, C1-C3 alkyl, or C3-C7 cycloalkyl;

    R2 represents C1-C5 alkyl,or C3-C7 cycloalkyl;

    R3 and R4 independently represent- hydrogen, C1-C3 alkyl, C3-C7 cycloalkyl, acetyl, halogen, trifluoromethyl, cyano or CONR5R6;

    or R3, R4 together with the carbon atom to which they are attached form a C3-C7 aliphatic ring;

    R5 and R6 independently represents hydrogen or methyl;

    X represents O, or S;

    n is 0 or 1.


     
    2. The heterocyclic-substituted pyridinopyrimidinone derivative according to claim 1, wherein the C1-C3 alkyl is methyl, ethyl, n-propyl, or iso-propyl, the C1-C5 alkyl is methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-3-butyl, 1,1 -dimethyl-1 -propyl, or 2,2-dimethyl-1-propyl
     
    3. The heterocyclic-substituted pyridinopyrimidinone derivative according to claim 1, wherein the C3-C7 cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl, and the halogen is F, Cl, Br, or I.
     
    4. The heterocyclic-substituted pyridinopyrimidinone derivative according to claim 1, wherein the derivative is a compound selected from the group consisting of:
    CompoundStructureCompoundStructure
    I-1

    I-2

    I-3

    I-4

    I-5

    I-6

    I-7

    I-8

    I-9

    I-10

    I-11

    I-12

    I-13

    I-14

    I-15

    I-16

    I-17

    I-18

    I-19

    I-20

    I-21

    I-22

    I-23

    I-24

    I-25

    I-26

    I-27

    I-28

           
           
    I-33

    I-34

           
    I-37

    I-38

    or a pharmaceutically acceptable salt thereof.
     
    5. The heterocyclic-substituted pyridinopyrimidinone derivative and a pharmaceutically acceptable salt thereof according to any of claims 1-4 for use as a CDK4/6 inhibitor in preventing or treating diseases related to CDK4/6.
     
    6. The compound for use in treating diseases according to claim 5, wherein the diseases are cancers related to CDK4/6.
     
    7. A pharmaceutical composition comprising a therapeutically effective amount of the heterocyclic-substituted pyridinopyrimidinone derivative according to any of claims 1-4 and a pharmaceutically acceptable carrier or excipient.
     


    Ansprüche

    1. Heterocyclisch substituiertes Pyridinopyrimidinonderivat mit der folgenden Formel I oder ein pharmazeutisch akzeptables Salz davon:

    wobei

    R1 für Wasserstoff, C1-C3-Alkyl oder C3-C7-Cycloalkyl steht;

    R2 für C1-C5-Alkyl oder C3-C7-Cycloalkyl steht;

    R3 und R4 unabhängig für Wasserstoff, C1-C3-Alkyl, C3-C7-Cycloalkyl, Acetyl, Halogen, Trifluormethyl, Cyano oder CONR5R6 stehen;

    oder R3, R4 zusammen mit dem Kohlenstoffatom, an das sie gebunden sind, einen aliphatischen C3-C7-Ring bilden;

    R5 und R6 unabhängig für Wasserstoff oder Methyl stehen;

    X für O oder S steht;

    n 0 oder 1 ist.


     
    2. Heterocyclisch substituiertes Pyridinopyrimidinonderivat nach Anspruch 1, wobei das C1-C3-Alkyl Methyl, Ethyl, n-Propyl oder Isopropyl ist, das C1-C5-Alkyl Methyl, Ethyl, n-Propyl, Isopropyl, n-Butyl, Isobutyl, sec-Butyl, tert-Butyl, 1-Pentyl, 2-Pentyl, 3-Pentyl, 2-Methyl-3-butyl, 1, 1 -Dimethyl-1 -propyl oder 2,2-Dimethyl-1-propyl ist.
     
    3. Heterocyclisch substituiertes Pyridinopyrimidinonderivat nach Anspruch 1, wobei das C3-C7-Cycloalkyl Cyclopropyl, Cyclobutyl, Cyclopentyl, Cyclohexyl oder Cycloheptyl ist und das Halogen F, CI, Br oder I ist.
     
    4. Heterocyclisch substituiertes Pyridinopyrimidinonderivat nach Anspruch 1, wobei das Derivat eine Verbindung ist, die aus der Gruppe ausgewählt ist, welche aus Folgenden besteht:
    VerbindungStrukturVerbindungStruktur
    I-1

    I-2

    I-3

    I-4

    I-5

    I-6

    I-7

    I-8

    I-9

    I-10

    I-11

    I-12

    I-13

    I-14

    I-15

    I-16

    I-17

    I-18

    I-19

    I-20

    I-21

    I-22

    I-23

    I-24

    I-25

    I-26

    I-27

    I-28

           
           
    I-33

    I-34

           
    I-37

    I-38

    oder ein pharmazeutisch akzeptables Salz davon.
     
    5. Heterocyclisch substituiertes Pyridinopyrimidinonderivat und ein pharmazeutisch akzeptables Salz davon nach einem der Ansprüche 1 bis 4 zur Verwendung als CDK4/6-Inhibitor beim Verhindern oder Behandeln von Krankheiten im Zusammenhang mit CDK4/6.
     
    6. Verbindung zur Verwendung beim Behandeln von Krankheiten nach Anspruch 5, wobei es sich bei den Krankheiten um Krebskrankheiten im Zusammenhang mit CDK4/6 handelt.
     
    7. Pharmazeutische Zusammensetzung, umfassend eine therapeutisch wirksame Menge des heterocyclisch substituierten Pyridinopyrimidinonderivats nach einem der Ansprüche 1 bis 4 und einen pharmazeutisch akzeptablen Träger oder Hilfsstoff.
     


    Revendications

    1. Dérivé de pyridinopyrimidinone à substitution hétérocyclique qui répond à la formule I suivante ou un sel pharmaceutiquement acceptable de celui-ci :

    dans laquelle

    R1 représente un atome d'hydrogène, un groupe alkyle en C1 à C3 ou un groupe cycloalkyle en C3 à C7 ;

    R2 représente un groupe alkyle en C1 à C5 ou un groupe cycloalkyle en C3 à C7 ;

    R3 et R4 représentent indépendamment un atome d'hydrogène, un groupe alkyle en C1 à C3, un groupe cycloalkyle en C3 à C7, un groupe acétyle, un atome d'halogène, un groupe trifluorométhyle, un groupe cyano ou CONR5R6;

    ou R3, R4 ensemble avec l'atome de carbone auquel ils sont attachés forment un cycle aliphatique en C3 à C7;

    R5 et R6 représentent indépendamment un atome d'hydrogène ou un groupe méthyle ;

    X représente O ou S ;

    n est 0 ou 1.


     
    2. Dérivé de pyridinopyrimidinone à substitution hétérocyclique selon la revendication 1, dans lequel le groupe alkyle en C1 à C3 est un groupe méthyle, éthyle, n-propyle ou iso-propyle, le groupe alkyle en C1 à C5 est un groupe méthyle, éthyle, n-propyle, iso-propyle, n-butyle, iso-butyle, sec-butyle, tert-butyle, 1-pentyle, 2-pentyle, 3-pentyle, 2-méthyl-3-butyle, 1,1-diméthyl-1-propyle ou 2,2-diméthyl-1-propyle.
     
    3. Dérivé de pyridinopyrimidinone à substitution hétérocyclique selon la revendication 1, dans lequel le groupe cycloalkyle en C3 à C7 est un groupe cyclopropyle, cyclobutyle, cyclopentyle, cyclohexyle ou cycloheptyle, et l'atome d'halogène est F, Cl, Br ou I.
     
    4. Dérivé de pyridinopyrimidinone à substitution hétérocyclique selon la revendication 1, dans lequel le dérivé est un composé choisi dans le groupe constitué par :
    ComposéStructureComposéStructure
    I-1

    I-2

    I-3

    I-4

    I-5

    I-6

    I-7

    I-8

    I-9

    I-10

    I-11

    I-12

    I-13

    I-14

    I-15

    I-16

    I-17

    I-18

    I-19

    I-20

    I-21

    I-22

    I-23

    I-24

    I-25

    I-26

    I-27

    I-28

           
           
    I-33

    I-34

           
    I-37

    I-38

    ou un sel pharmaceutiquement acceptable de ceux-ci.
     
    5. Dérivé de pyridinopyrimidinone à substitution hétérocyclique et un sel pharmaceutiquement acceptable de celui-ci selon l'une quelconque des revendications 1 à 4 pour une utilisation comme inhibiteur de CDK4/6 dans la prévention ou le traitement de maladies associées à CDK4/6.
     
    6. Composé pour une utilisation dans le traitement de maladies selon la revendication 5, dans lequel les maladies sont des cancers liés à CDK4/6.
     
    7. Composition pharmaceutique comprenant une quantité thérapeutiquement efficace du dérivé de pyridinopyrimidinone à substitution hétérocyclique selon l'une quelconque des revendications 1 à 4 et un véhicule ou un excipient pharmaceutiquement acceptable.
     






    Cited references

    REFERENCES CITED IN THE DESCRIPTION



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    Patent documents cited in the description




    Non-patent literature cited in the description