2,4-disubstituted pyrimidines as CDK inhibitors
The present disclosure relates to a 2,4-disubstituted pyrimidine derivative and the use thereof as a therapeutically effective cyclin-dependent kinase (CDK) inhibitor. In particular, the present disclosure relates to the use of a new 2,4-disubstituted pyrimidine derivatives shown in formula (I) and a pharmaceutical composition thereof as a selective CDK4/6 inhibitor in preventing or treating diseases related to CDK4/6.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof,
wherein:
n is 0 or 1;
Ring A is selected from the group consisting of:
X is CR 6 or N;
Y is CH or N;
Z is CH or N;
R 1 is hydrogen, C 1 -C 3 alkyl, or C 3 -C 7 cycloalkyl;
R 2 is hydrogen, halogen, methyl, trifluoromethyl, or methoxy;
R 3 is C 1 -C 5 alkyl or C 3 -C 7 cycloalkyl;
R 4 is hydrogen, halogen, cyano, C 1 -C 3 alkyl, trifluoromethyl, C 3 -C 5 cycloalkyl, C(O)CH 3 , or C(O)NR 7 R 8 ;
R 5 is hydrogen, halogen, cyano, C 1 -C 3 alkyl, trifluoromethyl, C 3 -C 5 cycloalkyl, C(O)CH 3 , or C(O)NR 7 R 8 ;
R 6 is hydrogen or halogen;
R 7 is hydrogen or methyl; and
R 8 is hydrogen or methyl.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is methyl, ethyl, n-propyl, or isopropyl;
R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-pentyl, 3-pentyl, 3-methyl-2-butyl, 1,1-dimethyl-1-propyl, or neopentyl;
R 4 is methyl, ethyl, n-propyl, or isopropyl; and
R 5 is methyl, ethyl, n-propyl or isopropyl.
3. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl;
R 2 is fluoro, chloro, bromo, or iodo;
R 3 is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl;
R 4 is fluoro, chloro, bromo, iodo, cyclopropyl, cyclobutyl, or cyclopentyl;
R 5 is fluoro, chloro, bromo, iodo, cyclopropyl, cyclobutyl, or cyclopentyl; and
R 6 is fluoro, chloro, bromo, or iodo.
4. The compound according to claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
5. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
6. A method for inhibiting cyclin-dependent kinase 4 activity or cyclin-dependent kinase 6 activity in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of the compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
7. The method according to claim 6 , wherein the subject has a cancer selected from the group consisting of melanoma, breast cancer, colorectal cancer, gastric cancer, liver cancer, ovarian cancer, pancreatic cancer, and prostate cancer.