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In previous work, we applied the rotation-limiting strategy and introduced a substituent at the 3-position of the pyrazolo [3,4- d ]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 H -benzo[ e ][1,2,4]thiadiazine 1,1-dioxide derivatives as PI3Kδ inhibitors. After the reduction of nitro group in N -(2,6-dimethylphenyl)-2-nitrobenzenesulfonamide 5 and N -(2,6-dimethylphenyl)-2-nitro-5-fluorobenzenesulfonamide 6 , the resulting 2-aminobenzenesulfonamides were reacted with trimethyl orthoacetate to give the 3-methyl-2 H -benzo[ e ][1,2,4]thiadiazine 1,1-dioxide derivatives. After bromination of the 3-methyl group, the nucleophilic substitution with the 3-iodo-1 H -pyrazolo[3,4- d ]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 H -benzo[ e ][1,2,4]thiadiazine 1,1-dioxide derivatives 1 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 15a and 15b with the IC 50 values of 217 to 266 nM, respectively. In comparison with the quinazolinone lead compounds 3 and 4 , these 2 H -benzo[ e ][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 4 that was a dual PI3Kδ/γ inhibitor, the benzthiadiazine 1,1-dioxide 15b 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 H -benzo[ e ][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, 15a and 15b significantly inhibited the SU-DHL-6 cell proliferation.

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