US 2012/0238541 A1 · PHARMACEUTICAL COMPOUNDS

Abstract

The invention relates to a series of compounds with particular activity as inhibitors of the serine-threonine kinase AKT. Also provided are pharmaceutical compositions comprising same as well as methods for treating cancer.

A compound according to Formula (I):

wherein:
0, 1 or 2 of D, E, F and G are independently selected from N, NH and NR1 and the others are independently selected from CH and CR2, wherein each R1 is independently selected from aryl, C1-C10 alkyl, CONHR3, CONR3aR3b, COR3 and CO2R3 and each R2 is independently selected from aryl, C1-C10 alkyl, CN, CHO, CO2H, CONH2, CONHR3, CONR3aR3b, COR3, CO2R3, NH2, NHR3, NR3aR3b, oxo, OH, OR3, SH, SR3, SOR3, SO2R3, SO2NHR3, SO2NR3aR3b, F, Cl, Br and I, wherein each R3, R3a and R3b is independently selected from optionally substituted C1-C10 alkyl, and optionally substituted C1-C10 aryl, including wherein R3a and R3b are joined to one another to form a heterocycle that includes the nitrogen to which they are attached,
wherein A is N or CH;
wherein at least D or G is NH or NR1 if E or F is CO and at least E or F is NH or NR1 if D or G is CO,
wherein separate R1 and/or R2 groups may be joined to one another to form a heterocycle that includes the C and/or N atoms to which they are attached if the separate R1 and/or R2 groups are contained on D and E and/or F and G, or D and F and the separate R2 groups are selected from OR3, SR3, SOR3, SO2NHR3, SO2NHR3, SO2NR3aR3b, NHR3, NR3aR3b, CO2R3, CONHR3 and CONR3aR3, and/or wherein separate R1 and/or R2 groups on F and G may be joined to form the structure:
where 0 or 1 of K and L are N and the other(s) is/are C, and wherein H, I and J are independently selected from O, S, NH, NR4, N, CH and CR5, wherein each R4 is independently selected from aryl, C1-C10 alkyl, CONHR6, CONR6aR6b, COR6 and CO2R6 and each R5 is independently selected from aryl, C1-C10 alkyl, CN, CHO, CO2H, CONH2, CONHR6, CONR6aR6b, COR6, CO2R6, oxo, NH2, NHR6, NR6aR6b, OH, OR6, SH, SR6, SOR6, SO2R6, SO2NHR6, SO2NR6aR6b, F, Cl, Br and I, wherein each R6, R6a and R6b is independently selected from C1-C10 alkyl, including wherein R6a and R6b are joined to one another to form a heterocycle that includes the nitrogen to which they are attached,
X is selected from O, S, SO, SO2 or a carbon-carbon bond;
R7a and R7b are independently selected from H and alkyl, including wherein R7a and R7b are joined to one another to form a heterocycle that includes the nitrogen to which they are attached;
and
is selected from:
or where the R7a and R7b groups are absent as is the nitrogen to which they are bound and Y is geminal dimethyl so that the moiety bound is
ring Cy is selected from (C3 to C8)cycloalkyl and aryl, wherein m is 0, 1, 2, 3, 4 or 5, and each R8 is independently selected from alkyl, CN, CHO CO2H, CONH2, CONHR9, CONHR9aR9b, COR9, CO2R9, NH2, NHR9, NR9aR9b, OH, OR9, SH, SR9, F, Cl, Br and I, wherein each R9, R9a and R9b is independently selected from alkyl, including wherein R9a and R9b form a heterocycle that includes the nitrogen to which they are attached;
or where the ketone carboxyl oxygen opposite X is replaced with a sulphur atom to give a thioketone or with a group comprising nitrogen to give an imine or optionally lower alkyl substituted oxime;
and pharmaceutically acceptable salts, stereoisomers and tautomers thereof.

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Pharmaceutical compounds

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Pharmaceutical compounds

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Abstract

Claims15