TRICYCLIC COMPOUNDS AS ANTICANCER AGENTS

摘要

Tricyclic chemical modulators of FOXO transcription factor proteins are disclosed. The compounds are useful to treat cancer, age-onset proteotoxicity, stress-induced depression, inflammation, and acne. The compounds are of the following phenothiazine, dibenzoazepine and annulene and similar genera:;

主权项

1. A compound of formula (I): wherein: X is selected from the group consisting of: —(CH2—CH2)—, and —CH═CH—; Y is selected from the group consisting of: A is a three to six membered aliphatic carbocycle or heterocycle attached at Y as a spiro ring, and A may be additionally substituted with one or two substituents chosen from OH, F, cyano, amino, (C1-C3)alkylamino, (C1-C3)dialkylamino, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, and (C1-C3)alkoxy; R1, R2, R3, and R4 are independently selected from the group consisting of: H, halo, —N3, —NR6R7, (C1-C6)alkyl, (C1-C6)haloalkyl, —OR6, —C(O)R6, —OC(O)R6, —C(O)NR6R7, —C(O)OR6, —SR6, —SO2R6, and —SO2NR6R7; R5 is —(CR15R16)p-Qq-(CR15R16)n-p—Z or R5a is ═CR14(CR15R16)p-Qq-(CR15R16)m-p—Z; Q is chosen from —O—, —NR14— and each R6 and R7 is independently selected from the group consisting of: H and (C1-C6)alkyl; R14 is H or (C1-C3)alkyl; R15 and R16, in each occurrence are chosen independently from H, OH, cyano, amino, (C1-C3)alkylamino, (C1-C3)dialkylamino, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, and (C1-C3)alkoxy, or, taken together, two of R14, R15 and R16 may form a three to seven membered non-aromatic carbocycle or heterocycle wherein said three to seven membered carbocycle or heterocycle may be additionally substituted with one or two substituents chosen from OH, F, cyano, amino, (C1-C3)alkylamino, (C1-C3)dialkylamino, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, and (C1-C3)alkoxy; m is an integer from 1 to 3; n is an integer from 2 to 4; p is zero, 1 or 2; q is zero or 1; t is zero, 1 or 2; u is zero, 1 or 2, with the proviso that when Y isu is 2;
v is 1, 2 or 3; with the proviso that when q is zero and R15 and R16, in all of their occurrences are H, n is not 4; Z is selected from the group consisting of: —NHSO2R17, —NHC(O)NR8R9, —NHC(O)OR8, —S(O)2NR8R9, substituted or unsubstituted cyclic carbamate; substituted or unsubstituted cyclic urea, cyclic imide, cyanoguanidine; R8 and R9 are independently selected from H, substituted or unsubstituted (C1-C6)alkyl, and substituted or unsubstituted (C3-C7) cycloalkyl; and R17 is chosen from phenyl and monocyclic heteroaryl, said phenyl and monocyclic heteroaryl optionally substituted with one or two substituents chosen from OH, halogen, cyano, nitro, (C1-C3)alkylamino, (C1-C3)dialkylamino, (C1-C3)acylamino, (C1-C3)alkylsulfonyl, (C1-C3)alkylthio, (C1-C3)alkyl, (C1-C3)haloalkyl, (C1-C3)haloalkoxy, and (C1-C3)alkoxy.