Preparation of triazole derivatives as bromodomain inhibitors for treatment of cancers and disorders

Abstract

The present invention relates to I [A = benzo or fused heteroaryl; B = (un)satd. (hetero)carbocyclic, (hetero)bicyclic, or (hetero)aryl rings; E = C, (un)substituted CH2 or NH; L = a bond or (un)substituted bivalent hydrocarbon chain; R1 = halo, (un)substituted aliph., OH, SH, CN, NH2, C(O)H, C(S)H, CO2H, C(O)NH2, C(O)SH, C(O)C(O)H, C(O)CH2C(O)H, C(S)NH2, C(S)OH, S(O)H, SO2H, SO2NH2, NHC(O)H, NHC(O)NH2, NHC(S)NH2, NHSO2H, NHSO2NH2, NHNH2, NHC(NH)NH2, C=NNH2, C=NOH, C(NH)NH2, OC(O)H, or OC(O)NH2; R2 = halog, CN, (un)substituted SH, aliph., or R1 and R2 together = (un)substituted (un)satd. spiro-fused heteroring; R3 = (un)substituted aliph.; R4 and R5 = independently halo, CN, NO2, (un)substituted OH, SH, NH2, C(O)H, C(S)H, CO2H, C(O)NH2, C(O)SH, C(O)C(O)H, C(O)CH2C(O)H, C(S)NH2, C(S)OH, S(O)H, SO2H, SO2NH2, NHC(O)H, NHC(O)NH2, NHC(S)NH2, NH2SO2H, NHSO2NH2, NHNH2, NHC(NH)NH2, C(NNH2), C(NOH), C(NH)NH2, OC(O)H, or OC(O)NH2; m and n = independently 0-4], their pharmaceutically acceptable salts and compns. useful as inhibitors of bromodomain contg. proteins for treatment of inflammatory and autoimmune diseases, sepsis, viral infection, and cancers. For example, compd. II (R6 = H) was synthesized by reaction of (2-amino-4,5-dimethylthiophen-3-yl)(4-chlorophenyl)methanone and (1S,2R)-ethyl-1-[(diphenylmethylene)amino]-2-(methoxymethyl)cyclopropanecarboxylate, which reacts with acetohydrazide generating compd. II (R6 = Me). The bromodomain inhibition activity of the exemplified compds. are tested with best IC50 value < 0.5 μM using BRD4 Alpha-Lisa binding assay. [on SciFinder(R)]