Certain protein kinase inhibitors
Certain CDK4/6 inhibitors and pharmaceutically acceptable salts thereof are described. In particular, these compounds can inhibit kinase activity of CDK4/6 and may be useful for the treatment of hyper-proliferative diseases like cancer and inflammation. In addition, the pharmaceutical compositions thereof and methods of use thereof are also described.
1. A compound of formula (II)
or a pharmaceutically acceptable salt thereof, wherein
Q is heteroaryl;
R 1 is heterocycle which is substituted with at least one substituent independently selected from R X ;
R 2 is C 3-10 cycloalkyl;
R 3 is selected from hydrogen, C 1-6 alkyl and C 3-10 cycloalkyl;
R 4 is selected from hydrogen, C 1-6 alkyl and C 3-10 cycloalkyl;
R 5 is independently selected from hydrogen and halogen;
each R X is independently selected from heterocyclyl, which is unsubstituted or substituted with at least one substituent independently selected from R Y ;
each R Y is independently selected from halogen, OH, CN, amino, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-10 cycloalkyl, C 1-6 alkoxy, C 1-6 alkoxyalkyl, C 3-10 cycloalkoxy, C 1-6 alkylthio, C 3-10 cycloalkylthio, C 1-6 alkylamino, C 3-10 cycloalkylamino, di(C 1-6 alkyl)amino;
m is selected from 0, 1, 2 and 3.
2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is pyridinyl.
3. The compound of claim 2 or a pharmaceutically acceptable salt thereof, wherein Q is
4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from piperazinyl and piperidinyl, which are independently substituted with at least one substituent independently selected from R X .
5. The compound of claim 4 or a pharmaceutically acceptable salt thereof, wherein each R X is independently selected from piperazinyl, piperidinyl and morpholinyl, which is unsubstituted or substituted with at least one substituent independently selected from R Y .
6. The compound of claim 5 or a pharmaceutically acceptable salt thereof, wherein each R Y is independently selected from C 1-6 alkyl.
7. The compound of claim 6 or a pharmaceutically acceptable salt thereof, wherein R Y is selected from methyl and ethyl.
8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 is selected from cyclopentyl and cyclohexyl.
9. The compound of claim 8 or a pharmaceutically acceptable salt thereof, wherein R 2 is cyclopentyl.
10. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are independently hydrogen or C 1-6 alkyl.
11. The compound of claim 10 or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 are independently methyl.
12. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 is hydrogen.
13. The compound of claim 1 , selected from
7-cyclopentyl-N,N-dimethyl-2-((5-(4-(piperidin-4-yl)piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((5-(4-(1-ethylpiperidin-4-yl)piperazin-1-yl)pyridin-2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(4-(1-methylpiperidin-4-yl)piperazin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(4-(piperazin-1-yl)piperidin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(4-(4-methylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-2-((5-(4-(4-ethylpiperazin-1-yl)piperidin-1-yl)pyridin-2-yl)amino)-N,N-dimethylthieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(4-morpholinopiperidin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
7-cyclopentyl-N,N-dimethyl-2-((5-(4-(4-(methyl-d 3 )piperazin-1-yl)piperidin-1-yl)pyridin-2-yl)amino)thieno[3,2-d]pyrimidine-6-carboxamide,
and pharmaceutically acceptable salts thereof.
14. A pharmaceutical composition, comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
15. A method of treating a cancerous hyperproliferative disorder, comprising administering to a subject in need of such treatment an effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, or of at least one pharmaceutical composition thereof, wherein treatment refers to alleviating, abating or ameliorating a disease or condition, ameliorating the underlying metabolic causes of symptoms, relieving the disease or condition, causing regression of the disease or condition or relieving a condition caused by the disease or condition.
16. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is heterocycle which is substituted with one, two, three, or four substituents, independently selected from R X .
17. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein each R X is independently selected from heterocyclyl, which is substituted with one, two, three, or four substituents, independently selected from R Y .