Synthesis and Evaluation of Novel 2H-Benzo[e]-[1,2,4]thiadiazine 1,1-Dioxide Derivatives as PI3Kδ Inhibitors.

In previous work, we applied the rotation-limiting strategy and introduced a substituent at the 3-position of the pyrazolo [3,4-]pyrimidin-4-amine as the affinity element to interact with the deeper hydrophobic pocket, discovered a series of novel quinazolinones as potent PI3Kδ inhibitors. Among them, the indole derivative 3 is one of the most selective PI3Kδ inhibitors and the 3,4-dimethoxyphenyl derivative 4 is a potent and selective dual PI3Kδ/γ inhibitor. In this study, we replaced the carbonyl group in the quinazolinone core with a sulfonyl group, designed a series of novel 2-benzo[][1,2,4]thiadiazine 1,1-dioxide derivatives as PI3Kδ inhibitors. After the reduction of nitro group in -(2,6-dimethylphenyl)-2-nitrobenzenesulfonamide and -(2,6-dimethylphenyl)-2-nitro-5-fluorobenzenesulfonamide , the resulting 2-aminobenzenesulfonamides were reacted with trimethyl orthoacetate to give the 3-methyl-2-benzo[][1,2,4]thiadiazine 1,1-dioxide derivatives. After bromination of the 3-methyl group, the nucleophilic substitution with the 3-iodo-1-pyrazolo[3,4-]pyrimidin-4-amine provided the respective iodide derivatives, which were further reacted with a series of arylboronic acids via Suzuki coupling to furnish the 2-benzo[][1,2,4]thiadiazine 1,1-dioxide derivatives 5a-J and 16a-d. In agreement with the quinazolinone derivatives, the introduction of a 5-indolyl or 3,4-dimethoxyphenyl at the affinity pocket generated the most potent analogues and with the IC values of 217 to 266 nM, respectively. In comparison with the quinazolinone lead compounds and , these 2-benzo[][1,2,4]thiadiazine 1,1-dioxide derivatives exhibited much decreased PI3Kδ inhibitory potency, but maintained the high selectivity over other PI3K isoforms. Unlike the quinazolinone lead compound that was a dual PI3Kδ/γ inhibitor, the benzthiadiazine 1,1-dioxide with the same 3,4-dimethoxyphenyl moiety was more than 21-fold selective over PI3Kγ. Moreover, the introducing of a fluorine atom at the 7-position of the 2-benzo[][1,2,4]thiadiazine 1,1-dioxide core, in general, was not favored for the PI3Kδ inhibitory activity. In agreement with their high PI3Kδ selectivity, and significantly inhibited the SU-DHL-6 cell proliferation.