Preparation of azabicyclic compounds as BET inhibitors and therapeutic uses thereof.

Abstract

The invention relates to substituted azabicyclic compds. of formula I which are useful for the inhibition of bromodomain and extra terminal domain (BET) proteins, pharmaceutical compns. comprising these compds., and use of the compds. and compns. for treatment of BET-assocd. diseases such as cancer, inflammation, autoimmune disease, cardiovascular disease, benign proliferative and fibrotic disorders, and other diseases. Compds. of formulas I [wherein A is selected from 5- or 6-membered monocyclic carbocycle or heterocycles fused to ring B; B is a 6-membered carbocycle or heterocycle; Y is N or C; X is NH, alkyl, C(O)O, etc.; W1 and W2 are independently selected from N or CR; R at each occurrence is independently selected from H, NH2, OH, etc.; W3 and W4 are independently selected from N, CH, and C with the proviso that both W3 and W4 cannot be N; R3 is 4-7 membered carbocycle, 4-7 membered heterocycle, bicyclic carbocycle, etc.; D1 is 5-membered monocyclic carbocycle or heterocycle connected to the B ring via a carbon-carbon bond with proviso] or a stereoisomer, tautomer, pharmaceutically acceptable salt, or hydrate thereof are claimed and exemplified. Reaction of 3,5-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole with 4,6-dibromo-2-methylbenzimidazole afforded II in 60% yield. I were evaluated for inhibition of tetra-acetylated histone H4 binding to BET bromodomains using TR-FRET anal. from which II was detd. to inhibit the first bromodomain of Brd4 with an IC50 value of ≤ 0.3 μM. [on SciFinder(R)]