Inhibitors of Akt activity
Inventors
Fan, Weiming • Haxell, Thomas F. N. • Jenks, Matthew G. • Kawanishi, Nobuhiko • Lee, Shuliang • Liu, Hao • Malaska, Michael J. • Moore, III, Joseph A. • Ogino, Yoshio • Onozaki, Yu • Pandi, Bharathi • Peel, Michael R. • Sakamoto, Toshihiro • Siu, Tony
Assignees
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Publication Number
US-8614221-B2
Publication Date
2013-12-24
Expiration Date
Abstract
The instant invention provides for substituted fused naphthyridine derivatives that inhibit Akt activity. In particular, the compounds disclosed selectively inhibit one or two of the Akt isoforms. The invention also provides for compositions comprising such inhibitory compounds and methods of inhibiting Akt activity by administering the compound to a patient in need of treatment of cancer.
Core Innovation
The invention relates to compounds according to Formula A, defined by Ring Z selected from (C3-C8)cycloalkyl, aryl, and heterocyclyl, and by variable substituent groups R1, R1′, R1″, R1‴ and R1⁗, R2, R6, R6a, R7 and R8. The substituent options include H, oxo, alkyl, aryl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, halo, OH, CO2H, CN, perfluoroalkyl, SH, S(O)mNR7R8, CHO, and related sulfur- or nitrogen-containing groups, with optional substitution patterns and parameter constraints on a, b, m, and p.
Formula A further includes a single or double bond with an oxo-adjacent constraint requiring a single bond when each of R1, R1′, R1″ and R1‴ is oxo, and requiring H on the carbonyl-bearing attachment. The disclosure also allows R7 and R8 to be taken together with the nitrogen to form a monocyclic, bicyclic or tricyclic heterocycle with 3-7 members in each ring, optionally containing additional heteroatoms selected from N, O and S. The compounds are expressly described in pharmaceutically acceptable salt, stereoisomer, and N-oxide derivative forms.
The document further refines the scaffold through Formula C and Formula D variants, with additional restricted ring and substituent selections including Ring X and Ring Y. It also includes explicit substituted heterocyclic embodiments and a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of the compound or a pharmaceutically acceptable salt, stereoisomer or N-oxide derivative thereof.
Claims Coverage
The claim coverage centers on a broad Formula A compound family with extensive substituent options and structural constraints, and includes 7 principal inventive feature groupings across the independent compound claims, dependent refinements, and the pharmaceutical composition claim.
Formula A compound with Ring Z and defined substituent variables
A compound according to Formula A wherein Ring Z is selected from (C3-C8)cycloalkyl, aryl, and heterocyclyl, and R1, R1′, R1″, R1‴, R1⁗, R2, R6, R6a, R7 and R8 are independently selected from the defined structural groups with optional substitution patterns.
Single or double bond with oxo-adjacent constraint
The bond is a single or double bond, provided that when each R1, R1′, R1″ and R1‴ is oxo, the bond adjacent to the oxo is a single bond and C or N attached to the resulting carbonyl bears H.
Optional heterocycle formation by R7 and R8
R7 and R8 may be taken together with the nitrogen to form a monocyclic, bicyclic or tricyclic heterocycle with 3-7 members in each ring, optionally containing additional heteroatoms selected from N, O and S.
Formula C variant
A compound according to Formula C, with specified substituent options and structural variables, optionally as a pharmaceutically acceptable salt, stereoisomer, or N-oxide derivative.
Formula D variant
A compound according to Formula D, with specified substituent variables and bond conditions, optionally as a pharmaceutically acceptable salt, stereoisomer, or N-oxide derivative.
Specific substituted heterocyclic compounds
A compound selected from a list of specific substituted heterocyclic compounds, together with pharmaceutically acceptable salt, stereoisomer, or N-oxide derivative forms.
Pharmaceutical composition with therapeutically effective amount
A pharmaceutical composition comprising a pharmaceutical carrier and dispersed therein a therapeutically effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt, stereoisomer or N-oxide derivative thereof.
Overall, the claims cover a broad Formula A compound class with defined ring selection, substituent selection, and bond/oxo-adjacent constraints, while also covering Formula C and Formula D refinements, explicit substituted heterocyclic embodiments, and a pharmaceutical composition containing a therapeutically effective amount.
Stated Advantages
Akt inhibition, including Akt1, Akt2 and Akt3.
PH domain selectivity.
Selective inhibition of one or two Akt isoforms rather than nonspecific PI3K or PDK1 inhibition.
Treatment of cancer.
Documented Applications
Cancer treatment via Akt inhibition with PH domain selectivity.
Pharmaceutical composition coverage for the claimed compounds.
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