# US 2020/0399266 A1 · Serine threonine kinase (akt) degradation / disruption compounds and methods of use

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- Number: US 2020/0399266 A1
- Document ID: US20200399266A1
- Status: Published application
- Kind: A1
- Application number: 16/977,654
- Filed: 2019-03-06
- Published: 2020-12-24
- Earliest claimed: 2018-03-06
- Assignees: Icahn School of Medicine at Mount Sinai
- Applicants: Icahn School of Medicine at Mount Sinai
- Inventors: Jian Jin; Jing Liu; Ramon E. Parsons; Jia Xu; Xufen Yu
- Web page: https://patentgrep.com/patent/US20200399266A1

## CPC

- C07D 417/14: containing three or more hetero rings
- A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/517: ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
- A61K 31/519: ortho- or peri-condensed with heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/545: {Heterocyclic compounds (A61K47/558 takes precedence)}
- A61K 47/55: the modifying agent being also a pharmacologically or therapeutically active agent, i.e. the entire conjugate being a codrug
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 13/00: Drugs for disorders of the urinary system
- A61P 13/08: of the prostate
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 19/00: Drugs for skeletal disorders
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 27/00: Drugs for disorders of the senses
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 33/00: Antiparasitic agents
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 35/04: specific for metastasis
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 401/14: containing three or more hetero rings
- C07D 471/04: Ortho-condensed systems
- C07D 487/04: Ortho-condensed systems
- G01N 33/5011: {for testing antineoplastic activity}
- G01N 2333/90: Enzymes; Proenzymes
- G01N 2333/912: transferring phosphorus containing groups, e.g. kinases (2.7)
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)

## Abstract

Disclosed herein are serine threonine kinase (AKT) degradation/disruption compounds including an AKT ligand, a degradation/disruption tag, and a linker, and methods of using such compounds in the treatment of AKT-mediated diseases.

## Claims

### Claim 1

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.

### Claim 2 (depends on 1)

The bivalent compound of claim 1, wherein the linker comprises:
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.

### Claim 3 (depends on 1, 2)

The bivalent compound of claim 1 or 2, wherein the linker comprises:
wherein
A is R′C(O)NR″R1, wherein R′ and R″ are each optionally substituted C1-C8 alkylene;
W is R′OR″, wherein R′ and R″ are each null;
B is optionally substituted C1-C8 alkylene;
R1 is hydrogen; and
m is 2 to 5.

### Claim 4 (depends on 3)

The bivalent compound of claim 3, wherein
A is R′C(O)NR″R1, wherein R′ and R″ are each —CH2CH2—;
W is —O—;
B is —CH2CH2—;
R1 is hydrogen; and
m is 2 to 5.

### Claim 5 (depends on 3)

The bivalent compound of claim 3, wherein
A is R′C(O)NR″R1, wherein R′ and R″ are each —CH2CH2—;
W is —O—;
B is —CH2CH2—;
R1 is hydrogen; and
m is 4 or 5.

### Claim 6 (depends on 1, 2)

The bivalent compound of claim 1 or 2, wherein the linker comprises:
wherein
A is R′C(O)R″, wherein R′ is optionally substituted 4-10 membered heterocyclyl and R″ is optionally substituted C1-C8 alkylene;
W is R′OR″, wherein R′ and R″ are each null;
B is optionally substituted C1-C8 alkylene; and
m is 2 to 9.

### Claim 7 (depends on 6)

The bivalent compound of claim 6, wherein
A is R′C(O)R″, wherein R′ is piperazine and R″ is —CH2CH2—;
W is —O—;
B is —CH2CH2—;
R1 is hydrogen; and
m is 2 to 7 or 9.

### Claim 8 (depends on 6)

The bivalent compound of claim 6, wherein
A is R′C(O)R″, wherein R′ is piperazine and R″ is —CH2CH2—;
W is —O—;
B is —CH2CH2—;
R1 is hydrogen; and
m is 4-6, 8 or 9.

### Claim 9 (depends on 1, 2)

The bivalent compound of claim 1 or 2, wherein the linker comprises:
wherein
A is R′C(O)R″, wherein R′ is optionally substituted 4-10 membered heterocyclyl and R″ is optionally substituted C1-C8 alkylene;
W is R′OR″, wherein R′ is null and R″ is optionally substituted C1-C8 alkylene;
B is R′C(O)R″, wherein R′ is null or optionally substituted C1-C8 alkylene; and
m is 1.

### Claim 10 (depends on 9)

The bivalent compound of claim 9, wherein
A is R′C(O)NR″R1, wherein R′ is piperazine and R″ is —CH2—;
W is —OCH2—;
B is —C(O)—; and
m is 1.

### Claim 11 (depends on 9)

The bivalent compound of claim 9, wherein
A is R′C(O)NR″R1, wherein R′ is piperazine and R″ is —CH2—;
W is —OCH2CH2O—;
B is —CH2C(O)—; and
m is 1.

### Claim 12 (depends on 1)

The bivalent compound of claim 1, wherein the linker comprises:
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.

### Claim 13 (depends on 1)

The bivalent compound of claim 1, wherein the linker comprises
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.

### Claim 14 (depends on 1)

The bivalent compound of claim 1, wherein the linker comprises:
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.

### Claim 15 (depends on 14)

The bivalent compound of claim 14, wherein the linker comprises:
wherein
R5 and R6 are at each occurrence, hydrogen;
A is R′C(O)NR″R1 or R′NR1C(O)R″, wherein R′ is optionally substituted C1-C8 alkylene and R″ is null;
B is R′C(O)R″, wherein both R′ and R″ are null, or B is null;
R1 is hydrogen; and
o is 6 to 10; and
p is 0.

### Claim 16 (depends on 15)

The bivalent compound of claim 15, wherein
R5 and R6 are at each occurrence, hydrogen;
A is R′C(O)NR″R1 or R′NR1C(O)R″, wherein R′ is —CH2CH2CH2— and R″ is null;
B is —C(O)—;
R1 is hydrogen; and
o is 7 to 10; and
p is 0.

### Claim 17 (depends on 15)

The bivalent compound of claim 15, wherein
R5 and R6 are at each occurrence, hydrogen;
A is R′C(O)NR″R1 or R′NR1C(O)R″, wherein R′ is —CH2CH2— and R″ is null;
B is —C(O)—;
R1 is hydrogen; and
o is 6 to 10; and
p is 0.

### Claim 18 (depends on 15)

The bivalent compound of claim 15, wherein
R5 and R6 are at each occurrence, hydrogen;
A is R′C(O)NR″R1, wherein R′ is —CH2CH2— and R″ is null;
B is —C(O)—;
R1 is hydrogen; and
o is 6, 9 or 10; and
p is 0.

### Claim 19 (depends on 15)

The bivalent compound of claim 15, wherein
R5 and R6 are at each occurrence, hydrogen;
A is R′NR1C(O)R″, wherein R′ is —CH2CH2— and R″ is null;
B is —C(O)—;
R1 is hydrogen; and
o is 6 to 10; and
p is 0.

### Claim 20 (depends on 15)

The bivalent compound of claim 15, wherein
R5 and R6 are at each occurrence, hydrogen;
A is R′C(O)NR″R1, wherein R′ is —CH2CH2CH2— and R″ is null;
B is null;
R1 is hydrogen; and
o is 7 or 8; and
p is 0.

### Claim 21 (depends on 15)

The bivalent compound of claim 15, wherein
R5 and R6 are at each occurrence, hydrogen;
A is R′C(O)NR″R1, wherein R′ is —CH2CH2— and R″ is null;
B is null;
R1 is hydrogen; and
o is 6 to 8; and
p is 0.

### Claim 22 (depends on 15)

The bivalent compound of claim 15, wherein
R5 and R6 are at each occurrence, hydrogen;
A is R′C(O)NR″R1, wherein R′ is —CH2CH2— and R″ is null;
B is null;
R1 is hydrogen; and
o is 8; and
p is 0.

### Claim 23 (depends on 14)

The bivalent compound of claim 14, wherein the linker comprises:
wherein
R5 and R6 are at each occurrence, hydrogen;
A is R′C(O)R″, wherein R′ is optionally substituted 4-10 membered heterocyclyl and R″ is optionally substituted C1-C8 alkylene;
B is R′C(O)R″, wherein R′ and R″ are each null;
o is 4 to 12; and
p is 0.

### Claim 24 (depends on 23)

The bivalent compound of claim 23, wherein
A is R′C(O)R″, wherein R′ is piperazine and R″ is —CH2CH2—;
W is —O—;
B is —C(O)—;
o is 4 to 11; and
p is 0.

### Claim 25 (depends on 23)

The bivalent compound of claim 23, wherein
A is R′C(O)R″, wherein R′ is piperazine and R″ is —CH2CH2—;
W is —O—;
B is —C(O)—;
o is 9 to 12; and
p is 0.

### Claim 26 (depends on 1, 2, 12, 13, 14)

The bivalent compound of any one of claims 1, 2, 12, 13 or 14, wherein A and B, at each occurrence, are independently selected from null, CO, NH, NH—CO, CO—NH, CH2—NH—CO, CH2—CO—NH, NH—CO—CH2, CO—NH—CH2, CH2—NH—CH2—CO—NH, CH2—NH—CH2—NH—CO, —CO—NH, CO—NH—CH2—NH—CH2 and CH2—NH—CH2.

### Claim 27 (depends on 1, 2, 12, 13, 14)

The bivalent compound of any one of claims 1, 2, 12, 13 or 14, wherein o is 0 to 5.

### Claim 28 (depends on 1, 2, 12, 13, 14)

The bivalent compound of any one of claims 1, 2, 12, 13 or 14, wherein 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.

### Claim 29 (depends on 1, 2, 12, 13, 14)

The bivalent compound of any one of claims 1, 2, 12, 13 or 14, wherein the linker comprises one or more rings selected from the group consisting of.

### Claim 30 (depends on 1)

The bivalent compound of claim 1, wherein the linker comprises:
wherein
X is C═O or CH2,
Y is C═O or CH2, and
n is 0-15.

### Claim 31 (depends on 1)

The bivalent compound of claim 1, wherein the linker comprises:
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.

### Claim 32 (depends on 1)

The bivalent compound of claim 1, wherein the linker comprises:
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.

### Claim 33 (depends on 1, 32)

The bivalent compound of claim 1, subpart (h), or claim 32, wherein
R is 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, one or more of which can contain one or more heteroatoms.

### Claim 34 (depends on 1, 32)

The bivalent compound of claim 1, subpart (h), or claim 32, wherein R has a structure of

### Claim 35 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34)

The bivalent compound of any one of claims 1 to 34, wherein the linker is covalently bonded to the AKT ligand.

### Claim 36 (depends on 35)

The bivalent compound of claim 35, wherein the covalent bond is an amide bond or an amino bond.

### Claim 37 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36)

The bivalent compound of any one of claims 1 to 36, wherein the AKT ligand is selected from the group consisting of:
wherein
A, B, and X are independently N, CH, or CR6,
Y is CH2, CO, SO, SO2, CR7R′, CONR7, or SO2NR7,
E is NH, NR9, O, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C3-C8 cycloalkyl, C3-C7 heterocyclyl, C2-C8 alkenyl, C2-C8 alkynyl, OR9, SR9, NR9R10, CN, NO2, (CR9R10)mNR11R12, (CR9R10)mC(O)R11, (NR9R10)mNR11R12, (NR9R10)mC(O)R11, COR9, CO2R9, CONR9R10, NR9COR10, NR9SOR10, NR9SO2R10, SOR9, SO2R9, SO2NR9R10, (CR9R10)m-aryl, or (CR9R10)m-heteroaryl,
R1 is H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, aryl, C1-C8 alkylaryl, haloaryl, arylalkyl, heteroaryl, or heteroarylalkyl,
R2, R3, R4, and R6 are independently hydrogen, halogen, amino, C1-C8 alkylamino, arylamino, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, or C1-C8 alkoxyalkyl,
R5, R7, and R8 are independently H, C1-C8 alkyl, C3-C8 cycloalkyl, or C1-C8 alkoxyalkyl,
R9, R10, R11, and R12 are independently H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl,
R9 and R10, R11 and R12 can independently form 4-8 membered alkyl or heterocyclyl rings,
m=0-8,
and
n=0-8;
wherein
A, B and X are independently selected from N and CR6, wherein
R6 is independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, 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 amino, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;
Y is selected from CR7R8, CO, SO, SO2, CONR7, and SO2NR7, wherein
R7 and R8 is independently selected from hydrogen, halogen, 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 alkylamino, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3 to 10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl, or R7 and R8 together with the atom to which they are connected form an optionally substituted 3-10 membered carbocyclyl or an optionally substituted 4-10 membered heterocyclyl ring;
E is connected to the “linker” moiety of the bivalent compound, and is selected from null, R′—R″ R′OR″, R′SR″, R′NR9R″, R′OC(O)R″, R′OC(O)OR″, R′OCONR9R″, R′C(O)R″, R′C(O)OR″, R′CONR9R″, R′S(O)R″, R′S(O)2R″, R′SO2NR9R″, R′NR10C(O)OR″, R′NR10C(O)R″, R′NR10C(O)NR9R″, R′NR10S(O)R″, R′NR10S(O)2R″, and R′NR10S(O)2NR9R″, wherein
R′ and R″ are independently selected from null, 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 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8alkoxyC1-C8alkylene, optionally substituted C1-C8alkylaminoC1-C8alkylene, optionally substituted (C1-C8 alkylene)O(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)N(C1-C8 alkylene), optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused carbocyclyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged carbocyclyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro carbocyclyl, optionally substituted C3-C13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R9 and R10 are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8alkoxyC1-C8alkyl, 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″, R9 and R10, R′ and R9, R′ and R10, R″ and R9, R″ and R10 together with the atom to which they are connected form a 4-20 membered heterocyclyl ring;
R1 is selected from hydrogen, halogen, and 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 alkylamino, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R2, R3 and R4 are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted aryloxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted amino, optionally substituted C1-C8 alkylamino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted arylamino, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;
R5 is selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;
wherein
A, B, and X are independently N or CR3,
Y is CH2, CO, SO, SO2, CR4R5, CONR4, or SO2NR4,
E is NH, NR6, O, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C3-C8 cycloalkyl, C3-C8 heterocyclyl, C2-C8 alkenyl, C2-C8 alkynyl, OR6, SR6, NR6R7, CN, NO2, (CR6R7)mNR8R9, (CR6R7)mC(O)R8, (NR6R7)mNR8R9, (NR6R7)mC(O)R8, COR6, CO2R6, CONR6R7, NR6COR7, NR6SOR7, NR6SO2R7, SOR6, SO2R6, SO2NR6R7, (CR6R7)m-aryl, or (CR6R7)m-heteroaryl,
Z1—Z2 is CR10═CH, N+CH, or CR10═N,
R1 is hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, aryl, C1-C8 alkylaryl, haloaryl, arylalkyl, heteroaryl, or heteroarylalkyl,
R2, R3, and R4 are independently hydrogen, halogen, amino, C1-C8 alkylamino, arylamino, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, or C1-C8 alkoxyalkyl,
R6, R7, R8, and R9 are independently H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl,
R6 and R7, R8 and R9 can independently form 4-8 membered alkyl or heterocyclyl rings,
R10 is hydrogen, halogen, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, and
n=0-8;
wherein
A, B and X are independently selected from N and CR3, wherein
R3 is independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted amino, optionally substituted C1-C8 alkylamino C1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;
Z1 is selected from CR8 and N, wherein
R8 is selected from hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted amino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;
Z2 is selected from CH and N;
Y is selected from CO, SO, SO2, CR4R5, CONR4, and SO2NR4, wherein
R4 and R5 is independently selected from hydrogen and optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted amino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3 to 10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;
E is connected to the “linker” moiety of the bivalent compound, and is selected from null, R′—R″, R′OR″, RSR, R′NR6R″, R′OC(O)R″, R′OC(O)OR″, R′OCONR6R″, R′C(O)R″, R′C(O)OR″, R′CONR6R″, R′S(O)R″, R′S(O)2R″, R′SO2NR6R″, R′NR7C(O)OR″, R′NR7C(O)R″, R′NR7C(O)NR6R″, R′NR7S(O)R″, R′NR7S(O)2R″, and R′NR7S(O)2NR6R″, wherein
R′ and R″ are independently selected from null, 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 haloalkylene, optionally substituted C1-C8 hydroxyalkylene, optionally substituted C1-C8alkoxyC1-C8alkylene, optionally substituted (C1-C8 alkylene)O(C1-C8 alkylene), optionally substituted (C1-C8 alkylene)N(C1-C8 alkylene), optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C3-C13 fused carbocyclyl, optionally substituted C3-C13 fused heterocyclyl, optionally substituted C3-C13 bridged carbocyclyl, optionally substituted C3-C13 bridged heterocyclyl, optionally substituted C3-C13 spiro carbocyclyl, optionally substituted C3-C13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;
R6 and R7 are independently selected from hydrogen, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or
R′ and R″, R6 and R7, R′ and R6, R′ and R7, R″ and R6, R″ and R7 together with the atom to which they are connected form a 4-20 membered heterocyclyl ring;
R1 is selected from selected from hydrogen, halogen, and optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, optionally substituted C1-C8 alkoxyC1-C8 alkyl, optionally substituted amino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and
R2 is selected from hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C1-C8 alkoxy, or optionally substituted C1-C8 alkoxy C1-C8 alkyl, optionally substituted amino, optionally substituted C1-C8 alkylaminoC1-C8 alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl; and
e. a compound selected from the group consisting of:

### Claim 38 (depends on 37)

The bivalent ligand of claim 37, subpart (b), wherein the AKT ligand comprises:
wherein
A, B and X are each N;
Y is CO;
E is connected to the “linker” moiety of the bivalent compound, and is R′NR9R″, wherein
R′ is optionally substituted C1-C8 alkyl;
R9 is hydrogen;
R″ is null;
R1 is optionally substituted aryl;
R2 is hydrogen;
R3 is optionally substituted C1-C8 alkyl;
R4 is hydrogen; and
R5 is hydrogen.

### Claim 39 (depends on 37)

The bivalent compound of claim 37, subpart (e), wherein the AKT ligand comprises:

### Claim 40 (depends on 37)

The bivalent ligand of claim 37, subpart (d), wherein the AKT ligand comprises:
wherein
A is CR3, wherein
B and X are each N, wherein
R3 is optionally substituted amino;
Z1 is CR8, wherein
R8 is hydrogen;
Z2 is CH;
Y is CONR4, wherein
R4 is hydrogen;
E is connected to the “linker” moiety of the bivalent compound, and is R′—R″, wherein
R′ is optionally substituted C1-C8 alkyl;
R″ is null;
R1 is optionally substituted aryl; and
R2 is hydrogen.

### Claim 41 (depends on 37)

The bivalent compound of claim 37, subpart (e), wherein the AKT ligand comprises:

### Claim 42 (depends on 37)

The bivalent compound of claim 37, subpart (e), wherein the AKT ligand comprises:

### Claim 43 (depends on 37)

The bivalent compound of claim 37, subpart (e), wherein the AKT ligand comprises:

### Claim 44 (depends on 37)

The bivalent compound of claim 37, subpart (e), wherein the AKT ligand comprises:

### Claim 45 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44)

The bivalent compound of any one of claims 1-44, wherein the degradation/disruption tag is selected from the group consisting of:
wherein
V, W, and X are independently selected from CR2 and N;
Y is selected from CO, CH2, and N═N;
Z is selected from CH2, NH and O; and
R1 and R2 are independently selected from hydrogen, halogen, cyano, nitro, and C1-C5 alkyl;
wherein
R1 and R2 are independently hydrogen, C1-C8 alkyl, C1-C8alkoxyalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, C2-C8 alkenyl, or C2-C8 alkynyl;
wherein
R1 and R2 are independently selected from hydrogen, hydroxyl, amino, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl, optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8 aminoalkyl, optionally substituted C1-C8alkylaminoC1-C8alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl.
R3 is selected from hydrogen, optionally substituted C(O)C1-C8 alkyl, optionally substituted C(O)C1-C8alkoxyC1-C8alkyl, optionally substituted C(O)C1-C8 haloalkyl, optionally substituted C(O)C1-C8 hydroxyalkyl, optionally substituted C(O)C1-C8 aminoalkyl, optionally substituted C(O)C1-C8alkylaminoC1-C8alkyl, optionally substituted C(O)(3-10 membered carbocyclyl), optionally substituted C(O)(4-10 membered heterocyclyl), optionally substituted C(O)C2-C8 alkenyl, optionally substituted C(O)C2-C8 alkynyl, optionally substituted C(O)OC1-C8alkoxyC1-C8alkyl, optionally substituted C(O)OC1-C8 haloalkyl, optionally substituted C(O)OC1-C8 hydroxyalkyl, optionally substituted C(O)OC1-C8 aminoalkyl, optionally substituted C(O)OC1-C8alkylaminoC1-C8alkyl, optionally substituted C(O)O(3-10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(O)OC2-C8 alkenyl, optionally substituted C(O)OC2-C8 alkynyl, optionally substituted C(O)NC1-C8alkoxyC1-C8alkyl, optionally substituted C(O)NC1-C8 haloalkyl, optionally substituted C(O)NC1-C8 hydroxyalkyl, optionally substituted C(O)NC1-C8 aminoalkyl, optionally substituted C(O)NC1-C8alkylaminoC1-C8alkyl, optionally substituted C(O)N(3-10 membered carbocyclyl), optionally substituted C(O)N(4-10 membered heterocyclyl), optionally substituted C(O)NC2-C8 alkenyl, optionally substituted C(O)NC2-C8 alkynyl, optionally substituted P(O)(OH)2, optionally substituted P(O)(OC1-C8 alkyl)2, and optionally substituted P(O)(OC1-C8 aryl)2;
wherein
V, W, X, and Z are independently selected from CR4 and N; and
R1, R2, R3, and R4 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C1-C8 alkyl, optionally substituted C2-C8 alkenyl, and optionally substituted C2-C8 alkynyl; optionally substituted C1-C8alkoxyC1-C8alkyl, optionally substituted C1-C8 haloalkyl, optionally substituted C1-C8 hydroxyalkyl, optionally substituted C1-C8alkoxy, optionally substituted C1-C8alkylamino, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;
e. a compound selected from the group consisting of
and
f. a compound selected from the group consisting of
or a pharmaceutically acceptable salt thereof.

### Claim 46 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45)

The bivalent compound of any one of claims 1 to 45, wherein the degradation/disruption tag binds to a ubiquitin ligase and/or serves as a hydrophobic group that leads to AKT protein misfolding.

### Claim 47 (depends on 46)

The bivalent compound of claim 46, wherein the ubiquitin ligase is an E3 ligase.

### Claim 48 (depends on 47)

The bivalent compound of claim 47, wherein the E3 ligase is a cereblon E3 ligase, a VHL E3 ligase, a MDM2 ligase, a TRIM21 ligase, a TRIM24 ligase, and/or an IAP ligase.

### Claim 49 (depends on 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48)

The bivalent compound of any one of claims 1 to 48, wherein the bivalent compound is selected from the group consisting of: XF038-157A, XF038-158A, XF038-159A, XF038-160A, XF038-161A, XF038-162A, XF038-164A, XF038-165A, XF038-166A, XF038-176A, XF038-177A, XF042-162, XF042-164, XF042-165, XF042-166, XF042-167, XF042-168, XF042-170, XF042-171, XF048-1, XF048-2, XF048-3, XF048-4, XF048-5, XF048-7, XF048-8, XF050-5, XF050-6, XF050-7, XF050-8, XF050-9, XF050-10, XF050-11, XF050-12, XF050-13, XF050-14, XF050-15, XF050-16, XF050-17, XF050-18, XF050-19, XF050-20, XF050-21, XF050-22, XF050-23, XF050-24, XF050-25, XF050-26, XF050-27, XF050-28, XF050-29, XF050-30, XF050-31, XF050-32, XF050-33, XF050-98, XF050-132, XF050-133, XF050-134, XF056-93, XF050-143, XF050-144, XF050-145, XF050-167, XF056-33, XF056-34, XF056-35, XF056-36, XF056-37, XF056-73, XF061-10, XF067-1, XF067-2, XF067-3, XF067-4, XF067-5, XF067-6, XF067-7, XF067-8, XF067-9, XF067-10, XF067-11, XF067-12, XF067-13, XF067-14, XF067-15, XF067-16, XF067-17, XF067-18, XF067-19, XF067-20, XF067-21, XF067-22, XF067-23, XF067-24, XF067-25, XF067-26, XF067-27, XF067-28, XF067-29, XF067-30, XF067-31, XF067-32, XF067-33, XF067-34, XF067-35, XF067-36, XF067-37, XF067-38, XF067-39, XF067-40, XF067-41, XF067-42, XF067-43, XF067-44, XF067-45, XF067-46, XF067-47, XF067-48, XF067-49, XF067-50, XF067-51, XF067-52, XF067-53, XF067-54, XF067-55, XF067-56, XF067-57, XF067-58, XF067-59, XF067-84, XF067-85, XF067-86, XF067-87, XF067-88, XF067-89, XF067-90, XF067-91, XF067-92, XF067-93, XF067-94, XF067-95, XF067-96, XF067-97, XF067-98, XF067-99, XF067-100, XF067-101, XF067-102, XF067-103, XF067-104, XF067-105, XF067-106, XF067-107, XF067-108, XF067-109, XF067-110, XF067-111, XF067-112, XF067-113, and analogs thereof.

### Claim 50 (depends on 1)

The bivalent compound of claim 1, wherein the bivalent compound is selected from the group consisting of: XF038-165A, XF038-166A, XF038-176A, XF038-177A, XF042-162, XF042-168, XF042-170, XF048-1, XF048-2, XF048-3, XF048-4, XF048-5, XF048-7, XF048-8, XF050-5, XF050-7, XF050-16, XF050-17, XF050-18, XF050-19, XF050-20, XF050-21, XF050-30, XF050-31, XF050-32, XF050-33, XF050-98, XF050-133, XF056-93, XF050-143, XF050-144, XF050-145, XF050-167, XF056-33, XF056-34, XF056-35, XF056-37, XF067-15, XF067-16, XF067-17, XF067-18, XF067-44, XF067-45, XF067-46, XF067-47, XF067-98, XF067-99, XF067-100, XF067-101, XF067-112 and XF067-113.

### Claim 51 (depends on 1)

The bivalent compound of claim 1, wherein the bivalent compound is selected from the group consisting of: XF050-21, XF050-32, XF050-33, XF050-143, XF050-144, XF050-145, XF050-167, XF056-33, XF056-34, XF056-35, and XF056-73.

### Claim 52 (depends on 51)

The bivalent compound of claim 51, wherein the bivalent compound is selected from the group consisting of: XF050-21, XF050-143, XF050-144, XF050-145, and XF050-167.

### Claim 53 (depends on 51)

The bivalent compound of claim 51, wherein the bivalent compound is selected from the group consisting of: XF050-32, XF050-33, XF056-33, XF056-34, XF056-35, and XF056-73.

### Claim 54 (depends on 1)

The bivalent compound of claim 1, wherein the bivalent compound is selected from the group consisting of: XF038-162A, XF038-165A, XF038-166A, XF038-176A, XF038-177A, XF042-162, XF042-170, XF050-98, XF050-133, and XF056-93.

### Claim 55 (depends on 54)

The bivalent compound of claim 54, wherein the bivalent compound is selected from the group consisting of: XF038-162A, XF038-165A, XF038-166A, XF042-162, and XF050-98.

### Claim 56 (depends on 54)

The bivalent compound of claim 54, wherein the bivalent compound is selected from the group consisting of: XF038-176A and XF038-177A.

### Claim 57 (depends on 54)

The bivalent compound of claim 54, wherein the bivalent compound is selected from the group consisting of: XF042-170, XF050-133, and XF056-93.

### Claim 58 (depends on 1)

The bivalent compound of claim 1, wherein the bivalent compound is selected from the group consisting of: XF067-15, XF067-16, XF067-17, XF067-18, XF067-44, XF067-45, XF067-46, and XF067-47.

### Claim 59 (depends on 1)

The bivalent compound of claim 1, wherein the bivalent compound is selected from the group consisting of: XF067-98, XF067-99, XF067-100, XF067-101, XF067-112, and XF067-113.

### Claim 60 (depends on 59)

The bivalent compound of claim 59, wherein the bivalent compound is selected from the group consisting of: XF067-98, XF067-99, XF067-100, and XF067-101.

### Claim 61 (depends on 59)

The bivalent compound of claim 59, wherein the bivalent compound is selected from the group consisting of: XF067-112, and XF067-113.

### Claim 62

A bivalent compound selected from the group consisting of: XF038-157A, XF038-158A, XF038-159A, XF038-160A, XF038-161A, XF038-162A, XF038-164A, XF038-165A, XF038-166A, XF038-176A, XF038-177A, XF042-162, XF042-164, XF042-165, XF042-166, XF042-167, XF042-168, XF042-170, XF042-171, XF048-1, XF048-2, XF048-3, XF048-4, XF048-5, XF048-7, XF048-8, XF050-5, XF050-6, XF050-7, XF050-8, XF050-9, XF050-10, XF050-11, XF050-12, XF050-13, XF050-14, XF050-15, XF050-16, XF050-17, XF050-18, XF050-19, XF050-20, XF050-21, XF050-22, XF050-23, XF050-24, XF050-25, XF050-26, XF050-27, XF050-28, XF050-29, XF050-30, XF050-31, XF050-32, XF050-33, XF050-98, XF050-132, XF050-133, XF050-134, XF056-93, XF050-143, XF050-144, XF050-145, XF050-167, XF056-33, XF056-34, XF056-35, XF056-36, XF056-37, XF056-73, XF061-10, XF067-1, XF067-2, XF067-3, XF067-4, XF067-5, XF067-6, XF067-7, XF067-8, XF067-9, XF067-10, XF067-11, XF067-12, XF067-13, XF067-14, XF067-15, XF067-16, XF067-17, XF067-18, XF067-19, XF067-20, XF067-21, XF067-22, XF067-23, XF067-24, XF067-25, XF067-26, XF067-27, XF067-28, XF067-29, XF067-30, XF067-31, XF067-32, XF067-33, XF067-34, XF067-35, XF067-36, XF067-37, XF067-38, XF067-39, XF067-40, XF067-41, XF067-42, XF067-43, XF067-44, XF067-45, XF067-46, XF067-47, XF067-48, XF067-49, XF067-50, XF067-51, XF067-52, XF067-53, XF067-54, XF067-55, XF067-56, XF067-57, XF067-58, XF067-59, XF067-84, XF067-85, XF067-86, XF067-87, XF067-88, XF067-89, XF067-90, XF067-91, XF067-92, XF067-93, XF067-94, XF067-95, XF067-96, XF067-97, XF067-98, XF067-99, XF067-100, XF067-101, XF067-102, XF067-103, XF067-104, XF067-105, XF067-106, XF067-107, XF067-108, XF067-109, XF067-110, XF067-111, XF067-112, XF067-113, and analogs thereof.

### Claim 63

A bivalent compound selected from the group consisting of: XF050-21, XF050-32, XF050-33, XF050-143, XF050-144, XF050-145, XF050-167, XF056-33, XF056-34, XF056-35, and XF056-73.

### Claim 64 (depends on 63)

The bivalent compound of claim 63, wherein the bivalent compound is selected from the group consisting of: XF050-21, XF050-143, XF050-144, XF050-145, and XF050-167.

### Claim 65 (depends on 63)

The bivalent compound of claim 63, wherein the bivalent compound is selected from the group consisting of: XF050-32, XF050-33, XF056-33, XF056-34, XF056-35, and XF056-73.

### Claim 66

A bivalent compound selected from the group consisting of: XF038-162A, XF038-165A, XF038-166A, XF038-176A, XF038-177A, XF042-162, XF042-170, XF050-98, XF050-133, and XF056-93.

### Claim 67 (depends on 66)

The bivalent compound of claim 66, wherein the bivalent compound is selected from the group consisting of: XF038-162A, XF038-165A, XF038-166A, XF042-162, and XF050-98.

### Claim 68 (depends on 66)

The bivalent compound of claim 66, wherein the bivalent compound is selected from the group consisting of: XF038-176A and XF038-177A.

### Claim 69 (depends on 66)

The bivalent compound of claim 66, wherein the bivalent compound is selected from the group consisting of: XF042-170, XF050-133, and XF056-93.

### Claim 70

A bivalent compound selected from the group consisting of: XF067-15, XF067-16, XF067-17, XF067-18, XF067-44, XF067-45, XF067-46, and XF067-47.

### Claim 71

A bivalent compound selected from the group consisting of: XF067-98, XF067-99, XF067-100, XF067-101, XF067-112, and XF067-113.

### Claim 72 (depends on 71)

The bivalent compound of claim 71, wherein the bivalent compound is selected from the group consisting of: XF067-98, XF067-99, XF067-100, and XF067-101.

### Claim 73 (depends on 71)

The bivalent compound of claim 71, wherein the bivalent compound is selected from the group consisting of: XF067-112, and XF067-113.

### Claim 74

A method of treating a serine threonine kinase (AKT)-mediated disease, comprising administering, to a subject with an AKT-mediated disease, a bivalent compound comprising an AKT ligand conjugated to a degradation/disruption tag through a linker.

### Claim 75 (depends on 74)

The method of claim 74, wherein the AKT-mediated disease results from ALK activation or mutation.

### Claim 76 (depends on 74, 75)

The method of claim 74 or 75, wherein a tissue from the subject has elevated AKT enzymatic activity relative to a wild-type tissue of the same species and tissue type.

### Claim 77 (depends on 74, 75, 76)

The method of any one of claims 74-76, wherein the bivalent compound is selected from the group consisting of XF038-157A, XF038-158A, XF038-159A, XF038-160A, XF038-161A, XF038-162A, XF038-164A, XF038-165A, XF038-166A, XF038-176A, XF038-177A, XF042-162, XF042-164, XF042-165, XF042-166, XF042-167, XF042-168, XF042-170, XF042-171, XF048-1, XF048-2, XF048-3, XF048-4, XF048-5, XF048-7, XF048-8, XF050-5, XF050-6, XF050-7, XF050-8, XF050-9, XF050-10, XF050-11, XF050-12, XF050-13, XF050-14, XF050-15, XF050-16, XF050-17, XF050-18, XF050-19, XF050-20, XF050-21, XF050-22, XF050-23, XF050-24, XF050-25, XF050-26, XF050-27, XF050-28, XF050-29, XF050-30, XF050-31, XF050-32, XF050-33, XF050-98, XF050-132, XF050-133, XF050-134, XF056-93, XF050-143, XF050-144, XF050-145, XF050-167, XF056-33, XF056-34, XF056-35, XF056-36, XF056-37, XF056-73, XF061-10, XF067-1, XF067-2, XF067-3, XF067-4, XF067-5, XF067-6, XF067-7, XF067-8, XF067-9, XF067-10, XF067-11, XF067-12, XF067-13, XF067-14, XF067-15, XF067-16, XF067-17, XF067-18, XF067-19, XF067-20, XF067-21, XF067-22, XF067-23, XF067-24, XF067-25, XF067-26, XF067-27, XF067-28, XF067-29, XF067-30, XF067-31, XF067-32, XF067-33, XF067-34, XF067-35, XF067-36, XF067-37, XF067-38, XF067-39, XF067-40, XF067-41, XF067-42, XF067-43, XF067-44, XF067-45, XF067-46, XF067-47, XF067-48, XF067-49, XF067-50, XF067-51, XF067-52, XF067-53, XF067-54, XF067-55, XF067-56, XF067-57, XF067-58, XF067-59, XF067-84, XF067-85, XF067-86, XF067-87, XF067-88, XF067-89, XF067-90, XF067-91, XF067-92, XF067-93, XF067-94, XF067-95, XF067-96, XF067-97, XF067-98, XF067-99, XF067-100, XF067-101, XF067-102, XF067-103, XF067-104, XF067-105, XF067-106, XF067-107, XF067-108, XF067-109, XF067-110, XF067-111, XF067-112, XF067-113, and analogs thereof.

### Claim 78 (depends on 74, 75, 76, 77)

The method of any one of claims 74-77, wherein the bivalent compound is administered to the subject orally, parenterally, intradermally, subcutaneously, topically, or rectally.

### Claim 79 (depends on 74, 75, 76, 77, 78)

The method of any one of claims 74-78, further comprising treating the subject with an additional therapeutic regimen for treating cancer.

### Claim 80 (depends on 79)

The method of claim 79, wherein the additional therapeutic regimen is selected from the group consisting of surgery, chemotherapy, radiation therapy, hormone therapy, and immunotherapy.

### Claim 81 (depends on 74, 75, 76, 77, 78, 79, 80)

The method of any one of claims 74-80, wherein the AKT-mediated disease is selected from the group consisting of inflammatory, hyperproliferative, cardiovascular, neurodegenerative, gynecological, and dermatological diseases and disorders.

### Claim 82 (depends on 81)

The method of claim 81, wherein the hyperproliferative disease or disorder is selected from the group consisting of cancers angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma, myxoma, rhabdomyoma, fibroma, lipoma, teratoma, squamous cell carcinoma, undifferentiated small cell carcinoma, undifferentiated large cell carcinoma, adenocarcinoma, alveolar carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma, non-small cell lung cancer, small cell lung cancer, leiomyosarcoma, stomach carcinoma, ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, neurofibroma, tubular adenoma, villous adenoma, hamartoma, kidney cancer, Wilm's tumor, nephroblastoma, leukemia, bladder cancer, urethra cancer, transitional cell carcinoma, prostate cancer, seminoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, interstitial cell carcinoma, fibroadenoma, adenomatoid tumors, hepatoma, hepatocellular carcinoma, cholangiocarcinoma, hepatoblastoma, hepatocellular adenoma, osteogenic sarcoma, osteosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma, reticulum cell sarcoma, multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma, osteocartilaginous exostoses, benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma, giant cell tumors, osteoma, granuloma, xanthoma, osteitis deformans, meningioma, meningiosarcoma, gliomatosis, astrocytoma, medulloblastoma, glioma, ependymoma, germinoma, pinealoma, glioblastoma multiforme, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors, spinal cord neurofibroma, endometrial carcinoma, cervical carcinoma, pre-tumor cervical dysplasia, ovarian carcinoma, serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma, granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, intraepithelial carcinoma, melanoma, clear cell carcinoma, botryoid sarcoma, embryonal fallopian tubes carcinoma, acute myeloid leukemia, chronic myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, myeloproliferative diseases, myelodysplastic syndrome, Hodgkin's disease, non-Hodgkin's lymphoma, advanced melanoma, malignant melanoma, basal cell carcinoma, moles dysplastic nevi, angioma, dermatofibroma, keloids, psoriasis, neuroblastoma, metastatic breast cancer, colon cancer, oral cancer, hairy cell leukemia, head and neck cancer, refractory metastatic disease; Kaposi's sarcoma, Bannayan-Zonana syndrome, Cowden disease, and Lhermitte-Duclos disease.

### Claim 83 (depends on 74, 75, 76, 77, 78, 79, 80, 81, 82)

The method of any one of claims 74-82, wherein the AKT-mediated disease is a relapsed cancer.

### Claim 84 (depends on 74, 75, 76, 77, 78, 79, 80, 81)

The method of any one of claims 74-81, wherein the AKT-mediated disease is selected from the group consisting of rheumatoid arthritis, osteoarthritis, Crohn's disease, angiofibroma, retinal vascularization, diabetic retinopathy, age-related macular degeneration, macular degeneration, multiple sclerosis, obesity, Alzheimer's disease, restenosis, autoimmune diseases, allergy, asthma, endometriosis, atherosclerosis, vein graft stenosis, peri-anastomatic prosthetic graft stenosis, prostate hyperplasia, chronic obstructive pulmonary disease, psoriasis, inhibition of neurological damage due to tissue repair, scar tissue formation, multiple sclerosis, inflammatory bowel disease, infections, particularly bacterial, viral, retroviral or parasitic infections, pulmonary disease, neoplasm, Parkinson's disease, transplant rejection, and septic shock.

### Claim 85 (depends on 74, 75, 76, 77, 78, 79, 80, 81, 82, 84)

The method of any one of claims 74-82 or 84, wherein the AKT-mediated disease is a relapsed disease.

### Claim 86 (depends on 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85)

The method of any one of claims 74-85, wherein the AKT-mediated disease is refractory to one or more previous treatments.

### Claim 87 (depends on 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85)

The method of any one of claims 74-85, wherein the AKT-mediated disease is refractory to one or more previous treatments by different therapies.

### Claim 88 (depends on 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87)

The method of any one of claims 74-87, further comprising treatment with an m-TOR inhibitor.

### Claim 89 (depends on 88)

The method of claim 88, wherein the m-Tor inhibitor is Torin 1 or rapamycin.

### Claim 90

A bivalent compound comprising a serine threonine kinase (AKT) ligand conjugated to a degradation/disruption tag through a linker.

### Claim 91 (depends on 88)

The bivalent compound of claim 88, wherein the AKT ligand is an AKT inhibitor.

### Claim 92 (depends on 89)

The bivalent compound of claim 89, wherein the AKT ligand is selected from the group consisting of GSK690693, GSK2110183, GSK2141795, AZD5363, GDC-0068, MK-2206, ARQ-092, and analogs thereof.

### Claim 93 (depends on 88, 89, 90)

The bivalent compound of any one of claims 88-90, wherein the AKT ligand is bound to AKT or AKT mutant proteins.

### Claim 94 (depends on 88, 89, 90, 91)

The bivalent compound of any one of claims 88-91, wherein the degradation/disruption tag is selected from the group consisting of pomalidomide, thalidomide, lenalidomide, VHL-1, adamantane, 1-((4,4,5,5,5-pentafluoropentyl)sulfinyl)nonane, nutlin-3a, RG7112, RG7338, AMG232, AA-115, bestatin, MV-1, LCL161, and analogs thereof.

### Claim 95 (depends on 88, 89, 90, 91, 92)

The bivalent compound of any one of claims 88-92, wherein the degradation/disruption tag binds to a ubiquitin ligase or serves as a hydrophobic group that leads to AKT protein misfolding.

### Claim 96 (depends on 88, 89, 90, 91, 92, 93)

The bivalent compound of any one of claims 88-93, wherein the bivalent compound has the form
wherein PI comprises an AKT ligand and EL comprises a degradation/disruption tag.

### Claim 97 (depends on 94)

The bivalent compound of claim 94, wherein PI comprises:
wherein
A, B, and X are independently N, CH, or CR6,
Y is CH2, CO, SO, SO2, CR7R8, CONR7, or SO2NR7,
E is NH, NR9, O, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C3-C8 cycloalkyl, C3-C7 heterocyclyl, C2-C8 alkenyl, C2-C8 alkynyl, OR9, SR9, NR9R10, CN, NO2, (CR9R10)mNR11R12, (CR9R10)mC(O)R11, (NR9R10)mNR11R12, (NR9R10)mC(O)R11, COR9, CO2R9, CONR9R10, NR9COR10, NR9SOR10, NR9SO2R10, SOR9, SO2R9, SO2NR9R10, (CR9R10)m-aryl, or (CR9R10)m-heteroaryl,
R1 is H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, aryl, C1-C8 alkylaryl, haloaryl, arylalkyl, heteroaryl, or heteroarylalkyl,
R2, R3, R4, and R6 are independently hydrogen, halogen, amino, C1-C8 alkylamino, arylamino, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, or C1-C8 alkoxyalkyl,
R5, R7, and R8 are independently H, C1-C8 alkyl, C3-C8 cycloalkyl, or C1-C8 alkoxyalkyl,
R9, R10, R11, and R12 are independently H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl,
R9 and R10, R11 and R12 can independently form 4-8 membered alkyl or heterocyclyl rings,
m=0-8,
and
n=0-8.

### Claim 98 (depends on 94)

The bivalent compound of claim 94, wherein PI comprises:
wherein
A, B, and X are independently N or CR3,
Y is CH2, CO, SO, SO2, CR4R5, CONR4, or SO2NR4,
E is NH, NR6, O, C1-C8 alkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C3-C8 cycloalkyl, C3-C8 heterocyclyl, C2-C8 alkenyl, C2-C8 alkynyl, OR6, SR6, NR6R7, CN, NO2, (CR6R7)mNR8R9, (CR6R7)mC(O)R8, (NR6R7)mNR8R9, (NR6R7)mC(O)R8, COR6, CO2R6, CONR6R7, NR6COR7, NR6SOR7, NR6SO2R7, SOR6, SO2R6, SO2NR6R7, (CR6R7)m-aryl, or (CR6R7)m-heteroaryl,
Z1—Z2 is CR10═CH, N+CH, or CR10═N,
R1 is hydrogen, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl, aryl, C1-C8 alkylaryl, haloaryl, arylalkyl, heteroaryl, or heteroarylalkyl,
R2, R3, and R4 are independently hydrogen, halogen, amino, C1-C8 alkylamino, arylamino, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, or C1-C8 alkoxyalkyl,
R6, R7, R8, and R9 are independently H, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C2-C8 alkenyl, C2-C8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl,
R6 and R7, R8 and R9 can independently form 4-8 membered alkyl or heterocyclyl rings,
R10 is hydrogen, halogen, C1-C8 alkyl, C3-C8 cycloalkyl, C1-C8 alkoxy, C1-C8 alkoxyalkyl,
m=0-8,
and
n=0-8.

### Claim 99 (depends on 94)

The bivalent compound of claim 94, wherein PI is selected from the group consisting of:

### Claim 100 (depends on 94)

The bivalent compound of claim 94, wherein EL is selected from the group consisting of:
wherein
V, W, and X are independently CR2 or N,
Y is CO or CH2,
Z is CH2, NH, or O,
R1 is hydrogen, methyl, or fluoro, and
R2 is hydrogen, halogen, or C1-C5 alkyl;
wherein R1 and R2 are independently hydrogen, C1-C8 alkyl, C1-C8 alkoxyalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, C2-C8 alkenyl, or C2-C8 alkynyl; and
wherein R1, R2, R3, and R4 are independently hydrogen, C1-C8 alkyl, C1-C8 alkoxyalkyl, C1-C8 haloalkyl, C1-C8 hydroxyalkyl, C3-C7 cycloalkyl, C3-C7 heterocyclyl, C2-C8 alkenyl, or C2-C8 alkynyl, and
V, W, X, and Z are independently CR4 or N.

### Claim 101 (depends on 94)

The bivalent compound of claim 94, wherein EL binds to an ubiquitin ligase selected from the group consisting of a cereblon E3 ligase, a VHL E3 ligase, a MDM2 ligase, a TRIM21 ligase, a TRIM24 ligase, and an IAP ligase, or EL is a hydrophobic group that leads to ALK protein misfolding.

### Claim 102 (depends on 94)

The bivalent compound of claim 94, wherein the linker comprises acyclic or cyclic saturated or unsaturated carbon, ethylene glycol, amide, amino, ether, urea, carbamate, aromatic, heteroaromatic, heterocyclic or carbonyl containing groups with different lengths.

### Claim 103 (depends on 99)

The bivalent compound of claim 99, wherein the linker is selected from the group consisting of:
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, or a 3-13 membered spiro ring,
m is 0-15, and
n is 0-15.

### Claim 104 (depends on 101)

The bivalent compound of claim 101, wherein the linker is Formula C and R is selected from the group consisting of 3-13 membered rings, 3-13 membered fused rings, 3-13 membered bridged rings, and 3-13 membered spiro rings, wherein R contains one or more heteroatoms.

### Claim 105 (depends on 101)

The bivalent compound of claim 101, wherein the linker is Formula C and R is selected from the group consisting of:

### Claim 106 (depends on 88)

The bivalent compound of claim 88, wherein the AKT ligand is selected from the group consisting of:

### Claim 107 (depends on 93)

The bivalent compound of claim 93, wherein the ubiquitin ligase is an E3 ligase.

### Claim 108 (depends on 105)

The bivalent compound of claim 105, wherein the E3 ligase is selected from the group consisting of a cereblon E3 ligase, a VHL E3 ligase, a MDM2 ligase, a TRIM24 ligase, a TRIM21 ligase, and an IAP ligase.

### Claim 109 (depends on 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106)

The bivalent compound of any one of claims 88-106, wherein the bivalent compound is selected from the group consisting of XF038-157A, XF038-158A, XF038-159A, XF038-160A, XF038-161A, XF038-162A, XF038-164A, XF038-165A, XF038-166A, XF038-176A, XF038-177A, XF042-162, XF042-164, XF042-165, XF042-166, XF042-167, XF042-168, XF042-170, XF042-171, XF048-1, XF048-2, XF048-3, XF048-4, XF048-5, XF048-7, XF048-8, XF050-5, XF050-6, XF050-7, XF050-8, XF050-9, XF050-10, XF050-11, XF050-12, XF050-13, XF050-14, XF050-15, XF050-16, XF050-17, XF050-18, XF050-19, XF050-20, XF050-21, XF050-22, XF050-23, XF050-24, XF050-25, XF050-26, XF050-27, XF050-28, XF050-29, XF050-30, XF050-31, XF050-32, XF050-33, XF050-98, XF050-132, XF050-133, XF050-134, XF056-93, XF050-143, XF050-144, XF050-145, XF050-167, XF056-33, XF056-34, XF056-35, XF056-36, XF056-37, XF056-73, XF061-10, XF067-1, XF067-2, XF067-3, XF067-4, XF067-5, XF067-6, XF067-7, XF067-8, XF067-9, XF067-10, XF067-11, XF067-12, XF067-13, XF067-14, XF067-15, XF067-16, XF067-17, XF067-18, XF067-19, XF067-20, XF067-21, XF067-22, XF067-23, XF067-24, XF067-25, XF067-26, XF067-27, XF067-28, XF067-29, XF067-30, XF067-31, XF067-32, XF067-33, XF067-34, XF067-35, XF067-36, XF067-37, XF067-38, XF067-39, XF067-40, XF067-41, XF067-42, XF067-43, XF067-44, XF067-45, XF067-46, XF067-47, XF067-48, XF067-49, XF067-50, XF067-51, XF067-52, XF067-53, XF067-54, XF067-55, XF067-56, XF067-57, XF067-58, XF067-59, XF067-84, XF067-85, XF067-86, XF067-87, XF067-88, XF067-89, XF067-90, XF067-91, XF067-92, XF067-93, XF067-94, XF067-95, XF067-96, XF067-97, XF067-98, XF067-99, XF067-100, XF067-101, XF067-102, XF067-103, XF067-104, XF067-105, XF067-106, XF067-107, XF067-108, XF067-109, XF067-110, XF067-111, XF067-112, XF067-113, and analogs thereof.

### Claim 110

A method for identifying a bivalent compound which mediates degradation/disruption of AKT, the method comprising:
providing a heterobifunctional test compound comprising an AKT ligand conjugated to a degradation/disruption tag through a linker;
contacting the heterobifunctional test compound with a cell comprising a ubiquitin ligase and AKT;
determining whether AKT levels decrease in the cell; and
identifying the heterobifunctional test compound as a bivalent compound which mediates degradation/reduction of AKT levels decrease in the cell.

### Claim 111 (depends on 108)

The method of claim 108, wherein the cell is a cancer cell.

### Claim 112 (depends on 109)

The method of claim 109, wherein the cancer cell is an AKT-mediated cancer cell.