Serine threonine kinase (akt) degradation / disruption compounds and methods of use

A bivalent compound comprising a serine threonine kinase AKT ligand conjugated to a degradation/disruption tag through a linker, said linker selected from the group consisting of:

• wherein
• A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R′—R″, R′COR, R′CO2R, R′C(O)NR″R1, R′C(S)NR″R1, R′OR″, R′OC(O)R″, R′OC(O)OR, R′OCONR1R″, R′SR″, R′SOR″, R′SO2R″, R′SO2NR″R1, R′NR″R1, R′NR1COR″, R′NR1C(O)OR″, R′NR1CONR″R2, R′NR1C(S)R″, R′NR1S(O)R″, R′NR1S(O)2R″, and R′NR1S(O)2NR2R″, wherein
• R′ and R″ are independently selected from null, or a moiety comprising of optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8alkoxyC1-C8alkylene, optionally substituted C1-C8alkylaminoC1-C8alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R1 and R2 are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R′ and R″, R1 and R2, R′ and R1, R′ and R2, R″ and R1, R″ and R2 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
• and
• m is 0 to 15;
• wherein
• R1, R2, R3 and R4, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, and optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-8 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
• R1 and R2, R3 and R4 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
• A, W and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R′—R″, R′COR″, R′CO2R″, R′C(O)NR″R1, R′C(S)NR″R1, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCONR1R″, R′SR″, R′SOR″, R′SO2R″, R′SO2NR″R1, R′NR″R1, R′NR1COR″, R′NR1C(O)OR″, R′NR1CONR″R2, R′NR1C(S)R″, R′NR1S(O)R″, R′NR1S(O)2R″, and R′NR1S(O)2NR2R″, wherein
• R′ and R″ are independently selected from null, or a moiety comprising of optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8alkoxyC1-C8alkylene, optionally substituted C1-C8alkylaminoC1-C8alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R5 and R6 are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R′ and R″, R5 and R6, R′ and R5, R′ and R6, R″ and R5, R″ and R6 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
• m is 0 to 15;
• n, at each occurrence, is 0 to 15;
• and
• o is 0 to 15;
• wherein
• R1 and R2, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, and optionally substituted C1-C8 alkyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, C1-C8alkylaminoC1-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered cycloalkoxy, optionally substituted 3-10 membered carbocyclylamino, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
• R1 and R2 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
• A and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R′—R″, R′COR″, R′CO2R″, R′C(O)NR″R1, R′C(S)NR″R1, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCONR1R″, R′SR″, R′SOR″, R′SO2R″, R′SO2NR″R1, R′NR″R1, R′NR1COR″, R′NR1C(O)OR″, R′NR1CONR″R2, R′NR1C(S)R″, R′NR1S(O)R″, R′NR1S(O)2R″, and R′NR1S(O)2NR2R″, wherein
• R′ and R″ are independently selected from null, or a moiety comprising of optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8alkoxyC1-C8alkylene, optionally substituted C1-C8alkylaminoC1-C8alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R3 and R4 are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R′ and R″, R3 and R4, R′ and R3, R′ and R4, R″ and R3, R″ and R4 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
• each m is 0 to 15;
• and
• n is 0 to 15;
• wherein
• X is selected from O, NH, and NR7;
• R1, R2, R3, R4, R5, R6, and R7, at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 3-10 membered cycloalkoxy, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
• A and B are independently selected from null, or bivalent moiety selected from R′—R″, R′COR″, R′CO2R″, R′C(O)NR″R1, R′C(S)NR″R1, R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCONR1R″, R′SR″, R′SOR″, R′SO2R″, R′SO2NR″R1, R′NR″R1, R′NR1COR″, R′NR1C(O)OR″, R′NR1CONR″R2, R′NR1C(S)R″, R′NR1S(O)R″, R′NR1S(O)2R″, and R′NR1S(O)2NR2R″, wherein
• R′ and R″ are independently selected from null, or a moiety comprising of optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 alkylene, optionally substituted C2-C8 alkenylene, optionally substituted C2-C8 alkynylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8alkoxyC1-C8alkylene, optionally substituted C1-C8alkylaminoC1-C8alkylene, optionally substituted C1-C8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused cycloalkyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged cycloalkyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro cycloalkyl, optionally substituted C3-C13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R8 and R9 are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyalkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
• R′ and R″, R8 and R9, R′ and R8, R′ and R9, R″ and R8, R″ and R9 together with the atom to which they are connected form a 3-20 membered cycloalkyl or 4-20 membered heterocyclyl ring;
• m, at each occurrence, is 0 to 15;
• n, at each occurrence, is 0 to 15;
• o is 0 to 15;
• and
• p is 0 to 15;
• e. the linker comprises one or more rings selected from the group consisting of a 3 to 13 membered ring, a 3 to 13 membered fused ring, a 3 to 13 membered bridged ring, and a 3 to 13 membered spiro ring;
• wherein
• X is C═O or CH2,
• Y is C═O or CH2, and
• n is 0-15;
• wherein
• X is C═O or CH2,
• Y is C═O or CH2,
• m is 0-15,
• n is 0-6, and
• o is 0-15;
• and
• wherein
• X is C═O or CH2,
• Y is C═O or CH2,
• R is —CH2—, —CF2—, —CH(C1-3 alkyl)-, —C(C1-3 alkyl)(C1-3 alkyl)-, —CH═CH—, —C(C1-3 alkyl)═C(C1-3 alkyl)-, —C═C—, —O—, —NH—, —N(C1-3 alkyl)-, —C(O)NH—, —C(O)N(C1-3 alkyl)-, a 3-13 membered ring, a 3-13 membered fused ring, a 3-13 membered bridged ring, and/or a 3-13 membered spiro ring,
• m is 0-15, and
• n is 0-15.