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US 2014/0213578 A1Published application
Tricyclic compounds as anticancer agents
AssigneeMt. Sinai School of Medicine
InventorsMichael Ohlmeyer, Goutham Narla, Neil Dhawan, David Kastrinsky
Life of this patent
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Abstract
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:
Claims31
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 is
- u 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.
26 more elements
4-6. (canceled)
A compound according to claim 12 wherein t is zero.
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Dependencies are inferred from the claim text.