CDK2/4/6 Inhibitors
This invention relates to compounds of general Formula (I) and pharmaceutically acceptable salts thereof, in which R 1 , R 2 , R 2A , R 2B , R 3 , R 4 , R 5A , R 5B , R 6 , R 7 , R 8 , R 9 , p, q and r are as defined herein, to pharmaceutical compositions comprising such compounds and salts, and to methods of using such compounds, salts and compositions for the treatment of abnormal cell growth, including cancer.
1 . A process of preparing 6-(difluoromethyl)-8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methyl-sulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one (Example 10) having the following structure:
comprising contacting 8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one (Example 2) having the following structure:
with zinc difluoromethanesulfinate.
2 . The process of claim 1 , wherein the process is conducted in a solvent comprising an acid.
3 . The process of claim 1 , further comprising preparing 8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one (Example 2) from a multi-step synthesis starting from 4-{[(1R,2R)-2-hydroxy-2-methylcyclopentyl]amino}-2-(methylsulfanyl)pyrimidine-5-carbaldehyde (Intermediate 2).
4 . The process of claim 3 , wherein the multi-step synthesis comprising contacting Intermediate 2 with ethyl acetate to produce 8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one (2A) in the presence of a strong base.
5 . The process of claim 4 , wherein the strong base is LHMDS.
6 . The process of claim 4 , wherein the multi-step synthesis further comprising converting 8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-(methylsulfanyl)pyrido[2,3-d]pyrimidin-7(8H)-one (2A) to 8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-(methylsulfonyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (2B) in the presence of an oxidizing agent.
7 . The process of claim 6 , wherein the oxidizing agent is potassium peroxymonosulfate.
8 . The process of claim 6 , wherein the multi-step synthesis further comprising contacting 8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-(methylsulfonyl)-pyrido[2,3-d]pyrimidin-7(8H)-one (2B) with 4-amino-1-methanesulfonylpiperidine to produce 8-[(1R,2R)-2-hydroxy-2-methylcyclopentyl]-2-{[1-(methylsulfonyl)piperidin-4-yl]amino}pyrido[2,3-d]pyrimidin-7(8H)-one (Example 2).
9 . The process of claim 4 , wherein the Intermediate 2 is prepared from a multi-step synthesis comprising the step of preparing (1R,2R)-2-(benzylamino)-1-methylcyclopentanol (2b-00) from the chiral salt (1R,2R)—N-benzyl-2-hydroxy-2-methylcyclopentanaminium (2S)-[(3,5-dinitrobenzoyl)amino](phenyl)acetate (2b-RR).