Pyrimidine or pyridopyridone compound and application thereof
The present invention discloses a pyrimidine or pyridopyridone compound as shown in formula (I) and an application thereof relating to the technical field of medicament preparation. The compound can selectively suppress cyclin-dependent kinases (Cdks) CDK4 and CDK6 with almost no suppression of the activity of the kinase CDK2. Thus, the compound can be used for various diseases caused by cell cycle control disorders involving CDK4 and CDK6, and particularly in the treatment of malignant tumors.
1. A pyrimidine or pyridopyridone compound or pharmaceutical acceptable salt or stereoisomer thereof as shown in formula (I):
wherein Y is selected from the group consisting of C and N, and no substitution by R 6 when Y is N;
R 1 is selected from the group consisting of C1-C6 alkyl, C3-C6 cycloalkyl and C3-C6 cycloalkyl-substituted methyl;
R 2 is selected from the group consisting of halogen, COR 5 and COOR 5 ;
R 3 is selected from the group consisting of H and C1-C6 alkyl;
R 4 is selected from the group consisting of C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, alkoxy-substituted C1-C6 alkyl, phenyl and halogen-substituted phenyl;
R 5 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 fluoroalkyl and C3-C6 cycloalkyl;
R 6 is selected from the group consisting of H, F, CN and CH 3 ;
m is selected from the group consisting of 0, 1 and 2;
n is selected from the group consisting of 1, 2 and 3; and
p is selected from the group consisting of 1, 2 and 3.
2. The pyrimidine or pyridopyridone compound or pharmaceutical acceptable salt or stereoisomer thereof according to claim 1 , wherein
R 4 is selected from the group consisting of C1-C6 alkyl, hydroxy-substituted C1-C6 alkyl, and alkoxy-substituted C1-C6 alkyl.
3. The pyrimidine or pyridopyridone compound or pharmaceutical acceptable salt or stereoisomer thereof according to claim 2 , wherein
R 4 is selected from the group consisting of methyl, ethyl, propyl, and isopropyl.
4. The pyrimidine or pyridopyridone compound or pharmaceutical acceptable salt or stereoisomer thereof according to claim 1 , wherein
m is 1;
n is 2; and
p is 1 or 2.
5. The pyrimidine or pyridopyridone compound or pharmaceutical acceptable salt or stereoisomer thereof according to claim 1 , wherein
Y is N.
6. The pyrimidine or pyridopyridone compound or pharmaceutical acceptable salt or stereoisomer thereof according to claim 1 , wherein
R 1 is C3-C6 cycloalkyl;
R 2 is COR 5 ;
R 3 is C1-C6 alkyl;
R 5 is C1-C6 alkyl; and
R 6 is H.
7. The pyrimidine or pyridopyridone compound or pharmaceutical acceptable salt or stereoisomer thereof according to claim 6 , wherein
R 1 is cyclopentyl;
R 2 is COR 5 ;
R 3 is methyl;
R 5 is methyl or ethyl; and
R 6 is H.
8. The pyrimidine or pyridopyridone compound or pharmaceutical acceptable salt or stereoisomer thereof according to claim 1 , wherein the pyrimidine or pyridopyridone compound or pharmaceutical acceptable salt or stereoisomer thereof is a compound selected from the group consisting of:
9. A method of treating a cancer, comprising: administrating to a patient in need thereof an antitumor composition comprising the pyrimidine or pyridopyridone compound or pharmaceutical acceptable salt thereof according to claim 1 , wherein the cancer is a solid tumor or a haematological tumor.
10. The method of claim 9 , wherein the cancer is breast cancer, liposarcoma, non-small cell lung cancer, liver cancer, ovarian cancer, glioblastoma, melanoma, multiple myeloma or mantle cell lymphoma.
11. The method of claim 10 , wherein the breast cancer is a locally advanced or metastatic breast cancer with estrogen receptor positive (ER + ) and human epidermal growth factor receptor 2 negative(HER 2 − ) in postmenopausal women.
12. An antitumor drug composition, comprising the pyrimidine or pyridopyridone compound or pharmaceutical acceptable salt or stereoisomer thereof according to claim 1 as an active ingredient, and a pharmaceutical acceptable carrier.