Design, synthesis and pharmacological characterization of aminopyrimidine derivatives as BTK/FLT3 dual-target inhibitors against acute myeloid leukemia

Recent Advances in Pyrimidine-Based Drugs

“…Hydrochloride 141 was cyclized with diethyl malonate using sodium ethoxide in ethanol to provide dihydroxypyrimidine 142, which was transformed to the corresponding dichloro derivative 143 using POCl 3 . Subsequent S N Ar reaction of 143 with amine 144 , promoted by DIPEA at reflux, provided 145 [ 68 ]. Finally, 145 was reacted with various aliphatic amino alcohols to generate the desired model compounds 146 , which were evaluated for biological activity .…”

“…Ling et al have developed an inhibitor for acute myeloid leukemia (AML), which is a life-threatening malignancy with a 5-year survival rate. This cancer is characterized by its disruption of hematopoietic progenitor cell differentiation and proliferation [ 68 ]. AML treatment, which includes chemotherapy, does not exhibit long-term efficacy, and 70% of people do not survive beyond 1 year [ 69 ].…”

“…Initial S N Ar reaction of 2,4,5-trichloropyrimidine (17) with 2-amino-N-methylbenzamide (66) using sodium bicarbonate (NaHCO 3 ) in ethanol afforded the monosubstituted pyrimidine 67. A second S N Ar reaction on 67 by methyl 2-(4-aminophenyl)acetate (68) promoted by 12 N hydrochloric acid (HCl) in isopropanol yielded the 2,4-diamino-5-chloropyrimidine 69. This compound was then condensed with 1,2,5-oxadiazole-2-oxide derivatives 70 [36] in the presence of N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDAC) and 4-(dimethylamino)pyridine (DMAP) to provide targets 71.…”