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Cyclin‐dependent kinase 4 and 6 (CDK 4/6) overactivation in breast cancer cells has given birth to the successful development of CDK 4/6 inhibitors. Based on the intrinsic relationship of CDK 4/6 and cyclin D, we designed and synthesized a series of endoperoxide‐type pyrido/pyrrolo[2,3‐d]pyrimidine derivatives via extracting active fragments from canonical CDK 4/6 inhibitors and endoperoxide‐type natural products such as artemisinin and plakortin. Eleven novel endoperoxide‐type hybrids were synthesized and characterized by mass spectrometry (MS), high resolution mass spectrometry (HRMS), infrared spectroscopy (IR), hydrogen‐1 nuclear magnetic resonance (1H NMR), and carbon‐13 nuclear magnetic resonance (13C NMR) data. Antiproliferative activities and CDK 4/6 inhibitory effects of target compounds were evaluated via T47D, MDA‐MB‐436 breast cancer cell lines, and CDK6/cyclin D3 kinase respectively. The results showed that S1 and Y7 were the most potent compounds against CDK6/cyclin D3 kinase, with Half maximal inhibitory concentration (IC50) values of 0.126 ± 0.022 and 0.109 ± 0.007 μM respectively, they were about a half or third as potent as positive control palbociclib (0.045 μM). The antiproliferative effects of S2 were close to positive controls palbociclib and ribociclib, with Growth inhibitory dose 50% (GI50) values of 8.42 ± 0.93 and 18.74 ± 1.78 μM towards T47D cells and MDA‐MB‐436 cells respectively. Finally, antiproliferative activities against MCF‐10A cells indicated that our newly synthesized compounds were harmless to normal human mammary epithelial cells.