IP Library › Granted Patent US 11,472,799

Granted Patent B2

US 11,472,799 · App. 16/977,654 · Granted Oct 18, 2022

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

Inventors: Jian Jin (New York, NY); Jing Liu (New York, NY); Ramon E. Parsons (Manhasset, NY); Jia Xu (New York, NY); Xufen Yu (New York, NY)

Assignee: Icahn School of Medicine at Mount Sinai

C07D417/14 A61K31/436 A61K31/496 A61K31/517 A61K31/519 A61K45/06 A61P35/00 C07D401/14 C07D487/04 G01N33/5011 G01N2333/90 G01N2333/912

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Quick Facts

Patent No.: US 11,472,799
App. No.: 16/977,654
Granted: Oct 18, 2022
Kind: B2

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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 (278)

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′CO 2 R″, R′C(O)NR″R 1 , R′C(S)NR″R 1 , R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCONR 1 R″, R′SR″, R′SOR″, R′SO 2 R″, R′SO 2 NR″R 1 , R′NR″R 1 , R′NR 1 COR″, R′NR 1 C(O)OR″, R′NR 1 CONR″R 2 , R′NR 1 C(S)R″, R′NR 1 S(O)R″, R′NR 1 S(O) 2 R″, and R′NR 1 S(O) 2 NR 2 R″, wherein

R′ and R″ are independently selected from null, or a moiety comprising of optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -C 13 fused cycloalkyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged cycloalkyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro cycloalkyl, optionally substituted C 3 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R 1 and R 2 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R′ and R″, R 1 and R 2 , R′ and R 1 , R′ and R 2 , R″ and R 1 , R″ and R 2 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

R 1 , R 2 , R 3 and R 4 , at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylamino, and optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 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

R 1 and R 2 , R 3 and R 4 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′CO 2 R″, R′C(O)NR″R 1 , R′C(S)NR″R 1 , R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCONR 1 R″, R′SR″, R′SOR″, R′SO 2 R″, R′SO 2 NR″R 1 , R′NR″R 1 , R′NR′COR″, R′NR 1 C(O)OR″, R′NR 1 CONR″R 2 , R′NR 1 C(S)R″, R′NR 1 S(O)R″, R′NR 1 S(O) 2 R″, and R′NR 1 S(O) 2 NR 2 R″, wherein

R 5 and R 6 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R′ and R″, R 5 and R 6 , R′ and R 5 , R′ and R 6 , R″ and R 5 , R″ and R 6 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

R 1 and R 2 , at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, and optionally substituted C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylamino, C 1 -C 8 alkylaminoC 1 -C 8 alkyl, 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

R 1 and R 2 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′CO 2 R″, R′C(O)NR″R 1 , R′C(S)NR″R 1 , R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCONR 1 R″, R′SR″, R′SOR″, R′SO 2 R″, R′SO 2 NR″R 1 , R′NR″R 1 , R′NR′COR″, R′NR 1 C(O)OR″, R′NR 1 CONR″R 2 , R′NR 1 C(S)R″, R′NR 1 S(O)R″, R′NR 1 S(O) 2 R″, and R′NR 1 S(O) 2 NR 2 R″, wherein

R 3 and R 4 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R′ and R″, R 3 and R 4 , R′ and R 3 , R′ and R 4 , R″ and R 3 , R″ and R 4 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 NR 7 ;

R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , and R 7 , at each occurrence, are independently selected from hydrogen, halogen, hydroxyl, amino, cyano, nitro, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylamino, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 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′CO 2 R″, R′C(O)NR″R 1 , R′C(S)NR″R 1 , R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCONR 1 R″, R′SR″, R′SOR″, R′SO 2 R″, R′SO 2 NR″R 1 , R′NR″R 1 , R′NR 1 COR″, R′NR 1 C(O)OR″, R′NR 1 CONR″R 2 , R′NR 1 C(S)R″, R′NR 1 S(O)R″, R′NR 1 S(O) 2 R″, and R′NR 1 S(O) 2 NR 2 R″, wherein

R 8 and R 9 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxyalkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R′ and R″, R 8 and R 9 , R′ and R 8 , R′ and R 9 , R″ and R 8 , R″ and R 9 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 CH 2 ,

Y is C═O or CH 2 , and

n is 0-15;

wherein

X is C═O or CH 2 ,

Y is C═O or CH 2 ,

m is 0-15,

n is 0-6, and

o is 0-15; and

wherein

X is C═O or CH 2 ,

Y is C═O or CH 2 ,

R is —CH 2 —, —CF 2 —, —CH(C 1-3 alkyl)-, —C(C 1-3 alkyl)(C 1-3 alkyl)-, —CH═CH—, —C(C 1-3 alkyl)═C(C 1-3 alkyl)-, —C═C—, —O—, —NH—, —N(C 1-3 alkyl)-, —C(O)NH—, —C(O)N(C 1-3 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 and pharmaceutically acceptable salts and enantiomers thereof.

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

wherein

m is 0 to 15.

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

wherein

R 1 and R 2 , R 3 and R 4 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′CO 2 R″, R′C(O)NR″R 1 , R′C(S)NR″R 1 , R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCONR′R″, R′SR″, R′SOR″, R′SO 2 R″, R′SO 2 NR″R 1 , R′NR″R 1 , R′NR′COR″, R′NR′C(O)OR″, R′NR′CONR″R 2 , R′NR′C(S)R″, R′NR′S(O)R″, R′NR 1 S(O) 2 R″, and R′NR 1 S(O)NR 2 R″, wherein

m is 0 to 15;

n, at each occurrence, is 0 to 15; and

o is 0 to 15.

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

wherein

A and B, at each occurrence, are independently selected from null, or bivalent moiety selected from R′—R″, R′COR″, R′CO 2 R″, R′C(O)NR″R 1 , R′C(S)NR″R 1 , R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCONR′R″, R′SR″, R′SOR″, R′SO 2 R″, R′SO 2 NR″R 1 , R′NR″R 1 , R′NR′COR″, R′NR′C(O)OR″, R′NR′CONR″R 2 , R′NR′C(S)R″, R′NR′S(O)R″, R′NR′S(O) 2 R″, and R′NR′S(O) 2 NR 2 R″, wherein

each m is 0 to 15; and

n is 0 to 15.

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

wherein

X is selected from O, NH, and NR 7 ;

A and B are independently selected from null, or bivalent moiety selected from R′—R″, R′COR″, R′CO 2 R″, R′C(O)NR″R 1 , R′C(S)NR″R 1 , R′OR″, R′OC(O)R″, R′OC(O)OR″, R′OCONR′R″, R′SR″, R′SOR″, R′SO 2 R″, R′SO 2 NR″R 1 , R′NR″R 1 , R′NR′COR″, R′NR′C(O)OR″, R′NR′CONR″R 2 , R′NR′C(S)R″, R′NR′S(O)R″, R′NR′S(O) 2 R″, and R′NR′S(O) 2 NR 2 R″, wherein

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.

6. The bivalent compound according to claim 1 , wherein the linker comprises one or more rings selected from the group consisting of:

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

wherein

X is C═O or CH 2 ,

Y is C═O or CH 2 , and

n is 0-15.

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

wherein

X is C═O or CH 2 ,

Y is C═O or CH 2 ,

m is 0-15,

n is 0-6, and

o is 0-15.

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

wherein

X is C═O or CH 2 ,

Y is C═O or CH 2 ,

m is 0-15, and

n is 0-15.

10. The bivalent compound of claim 1 , wherein the AKT ligand is selected from the group consisting of:

wherein

A, B, and X are independently N, CH, or CR 6 ,

Y is CH 2 , CO, SO, SO 2 , CR 7 R 8 , CONR 7 , or SO 2 NR 7 ,

E is NH, NR 9 , O, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkoxyalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 hydroxyalkyl, C 3 -C 8 cycloalkyl, C 3 -C 7 heterocyclyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, OR 9 , SR 9 , NR 9 R 10 , CN, NO 2 , (CR 9 R 10 ) m NR 11 R 12 , (CR 9 R 10 ) m C(O)R 11 , (NR 9 R 10 ) m NR 11 R 12 , (NR 9 R 10 ) m C(O)R″, COR 9 , CO 2 R 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 SOR 10 , NR 9 SO 2 R 10 , SOR 9 , SO 2 R 9 , SO 2 NR 9 R 10 , (CR 9 R 10 ) m -aryl, or (CR 9 R 10 ) m -heteroaryl,

R 1 is H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkoxyalkyl, aryl, C 1 -C 8 alkylaryl, haloaryl, arylalkyl, heteroaryl, or heteroarylalkyl,

R 2 , R 3 , R 4 , and R 6 are independently hydrogen, halogen, amino, C 1 -C 8 alkylamino, arylamino, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, or C 1 -C 8 alkoxyalkyl,

R 5 , R 7 , and R 8 are independently H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 alkoxyalkyl,

R 9 , R 10 , R 11 , and R 12 are independently H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl, R 9 and R 10 , R 11 and R 12 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 CR 6 , wherein

R 6 is independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, amino, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted amino, optionally substituted C 1 -C 8 alkylamino, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;

Y is selected from CR 7 R 8 , CO, SO, SO 2 , CONR 7 , and SO 2 NR 7 , wherein

R 7 and R 8 is independently selected from hydrogen, halogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl; optionally substituted C 1 -C 8 alkylamino, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted 3 to 10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl, or

R 7 and R 8 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′NR 9 R″, R′OC(O)R″, R′OC(O)OR″, R′OCONR 9 R″, R′C(O)R″, R′C(O)OR″, R′CONR 9 R″, R'S(O)R″, R'S(O) 2 R″, R′SO 2 NR 9 R″, R′NR 10 C(O)OR″, R′NR 10 C(O)R″, R′NR 10 C(O)NR 9 R″, R′NR 10 S(O)R″, R′NR 10 S(O) 2 R″, and R′NR 10 S(O) 2 NR 9 R″, wherein

R′ and R″ are independently selected from null, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkylene, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkylene, optionally substituted (C 1 -C 8 alkylene)O(C 1 -C 8 alkylene), optionally substituted (C 1 -C 8 alkylene)N(C 1 -C 8 alkylene), optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -C 13 fused carbocyclyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged carbocyclyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro carbocyclyl, optionally substituted C 3 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R 9 and R 10 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R′ and R″, R 9 and R 10 , R′ and R 9 , R′ and R 10 , R″ and R 9 , R″ and R 10 together with the atom to which they are connected form a 4-20 membered heterocyclyl ring;

R 1 is selected from hydrogen, halogen, and optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylamino, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R 2 , R 3 and R 4 are independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted aryloxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted amino, optionally substituted C 1 -C 8 alkylamino, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted arylamino, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;

R 5 is selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;

wherein

A, B, and X are independently N or CR 3 ,

Y is CH 2 , CO, SO, SO 2 , CR 4 R 5 , CONR 4 , or SO 2 NR 4 ,

E is NH, NR 6 , O, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkoxyalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 hydroxyalkyl, C 3 -C 8 cycloalkyl, C 3 -C 8 heterocyclyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, OR 6 , SR 6 , NR 6 R 7 , CN, NO 2 , (CR 6 R 7 ) m NR 8 R 9 , (CR 6 R 7 ) m C(O)R 8 , (NR 6 R 7 ) m NR 8 R 9 , (NR 6 R 7 ) m C(O)R 8 , COR 6 , CO 2 R 6 , CONR 6 R 7 , NR 6 COR 7 , NR 6 SOR 7 , NR 6 SO 2 R 7 , SOR 6 , SO 2 R 6 , SO 2 NR 6 R 7 , (CR 6 R 7 ) m -aryl, or (CR 6 R 7 ) m -heteroaryl,

Z 1 -Z 2 is CR 10 ═CH, N+CH, or CR 10 ═N,

R 1 is hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkoxyalkyl, aryl, C 1 -C 8 alkylaryl, haloaryl, arylalkyl, heteroaryl, or heteroarylalkyl,

R 2 , R 3 , and R 4 are independently hydrogen, halogen, amino, C 1 -C 8 alkylamino, arylamino, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, or C 1 -C 8 alkoxyalkyl,

R 6 , R 7 , R 8 , and R 9 are independently H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, arylalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, or heteroarylalkyl, R 6 and R 7 , R 8 and R 9 can independently form 4-8 membered alkyl or heterocyclyl rings,

R 10 is hydrogen, halogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkoxyalkyl, and

n=0-8;

wherein

A, B and X are independently selected from N and CR 3 , wherein

R 3 is independently selected from hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted amino, optionally substituted C 1 -C 8 alkylamino C 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;

Z 1 is selected from CR 8 and N, wherein

R 8 is selected from hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted amino, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;

Z 2 is selected from CH and N;

Y is selected from CO, SO, SO 2 , CR 4 R 5 , CONR 4 , and SO 2 NR 4 , wherein

R 4 and R 5 is independently selected from hydrogen and optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted amino, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 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″, R′SR″, R′NR 6 R″, R′OC(O)R″, R′OC(O)OR″, R′OCONR 6 R″, R′C(O)R″, R′C(O)OR″, R′CONR 6 R″, R'S(O)R″, R'S(O) 2 R″, R′SO 2 NR 6 R″, R′NR 7 C(O)OR″, R′NR 7 C(O)R″, R′NR 7 C(O)NR 6 R″, R′NR 7 S(O)R″, R′NR 7 S(O) 2 R″, and R′NR 7 S(O) 2 NR 6 R″, wherein

R′ and R″ are independently selected from null, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 alkylene, optionally substituted C 2 -C 8 alkenylene, optionally substituted C 2 -C 8 alkynylene, optionally substituted C 1 -C 8 haloalkylene, optionally substituted C 1 -C 8 hydroxyalkylene, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkylene, optionally substituted (C 1 -C 8 alkylene)O(C 1 -C 8 alkylene), optionally substituted (C 1 -C 8 alkylene)N(C 1 -C 8 alkylene), optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted C 3 -C 13 fused carbocyclyl, optionally substituted C 3 -C 13 fused heterocyclyl, optionally substituted C 3 -C 13 bridged carbocyclyl, optionally substituted C 3 -C 13 bridged heterocyclyl, optionally substituted C 3 -C 13 spiro carbocyclyl, optionally substituted C 3 -C 13 spiro heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl;

R 6 and R 7 are independently selected from hydrogen, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl, or

R′ and R″, R 6 and R 7 , R′ and R 6 , R′ and R 7 , R″ and R 6 , R″ and R 7 together with the atom to which they are connected form a 4-20 membered heterocyclyl ring;

R 1 is selected from selected from hydrogen, halogen, and optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted amino, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted aryl, and optionally substituted heteroaryl; and

R 2 is selected from hydrogen, halogen, cyano, nitro, hydroxyl, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxy, or optionally substituted C 1 -C 8 alkoxy C 1 -C 8 alkyl, optionally substituted amino, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl; and

e. a compound selected from the group consisting of:

11. The bivalent ligand of claim 10 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′NR 9 R″, wherein

R′ is optionally substituted C 1 -C 8 alkyl;

R 9 is hydrogen;

R″ is null;

R 1 is optionally substituted aryl;

R 2 is hydrogen;

R 3 is optionally substituted C 1 -C 8 alkyl;

R 4 is hydrogen; and

R 5 is hydrogen.

12. The bivalent compound of claim 10 wherein the AKT ligand comprises:

13. The bivalent ligand of claim 10 wherein the AKT ligand comprises:

wherein

A is CR 3 , wherein

B and X are each N, wherein

R 3 is optionally substituted amino;

Z 1 is CR, wherein

R 8 is hydrogen;

Z 2 is CH;

Y is CONR 4 , wherein

R 4 is hydrogen;

E is connected to the “linker” moiety of the bivalent compound, and is R′—R″, wherein

R′ is optionally substituted C 1 -C 8 alkyl;

R″ is null;

R 1 is optionally substituted aryl; and

R 2 is hydrogen.

14. The bivalent compound of claim 10 wherein the AKT ligand comprises:

15. The bivalent compound of claim 10 , wherein the AKT ligand comprises:

16. The bivalent compound of claim 10 , wherein the AKT ligand comprises:

17. The bivalent compound of claim 10 , wherein the AKT ligand comprises:

18. The bivalent compound of claim 1 , wherein the degradation/disruption tag is selected from the group consisting of:

wherein

V, W, and X are independently selected from CR 2 and N;

Y is selected from CO, CH 2 , and N═N;

Z is selected from CH 2 , NH and O; and

R 1 and R 2 are independently selected from hydrogen, halogen, cyano, nitro, and C 1 -C 5 alkyl;

wherein

R 1 and R 2 are independently hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxyalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 hydroxyalkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 heterocyclyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl;

wherein

R 1 and R 2 are independently selected from hydrogen, hydroxyl, amino, cyano, nitro, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, and optionally substituted C 2 -C 8 alkynyl, optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 aminoalkyl, optionally substituted C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted 3-10 membered carbocyclyl, and optionally substituted 4-10 membered heterocyclyl;

R 3 is selected from hydrogen, optionally substituted C(O)C 1 -C 8 alkyl, optionally substituted C(O)C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C(O)C 1 -C 8 haloalkyl, optionally substituted C(O)C 1 -C 8 hydroxyalkyl, optionally substituted C(O)C 1 -C 8 aminoalkyl, optionally substituted C(O)C 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C(O)(3-10 membered carbocyclyl), optionally substituted C(O)(4-10 membered heterocyclyl), optionally substituted C(O)C 2 -C 8 alkenyl, optionally substituted C(O)C 2 -C 8 alkynyl, optionally substituted C(O)OC 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C(O)OC 1 -C 8 haloalkyl, optionally substituted C(O)OC 1 -C 8 hydroxyalkyl, optionally substituted C(O)OC 1 -C 8 aminoalkyl, optionally substituted C(O)OC 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C(O)O(3-10 membered carbocyclyl), optionally substituted C(O)O(4-10 membered heterocyclyl), optionally substituted C(O)OC 2 -C 8 alkenyl, optionally substituted C(O)OC 2 -C 8 alkynyl, optionally substituted C(O)NC 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C(O)NC 1 -C 8 haloalkyl, optionally substituted C(O)NC 1 -C 8 hydroxyalkyl, optionally substituted C(O)NC 1 -C 8 aminoalkyl, optionally substituted C(O)NC 1 -C 8 alkylaminoC 1 -C 8 alkyl, optionally substituted C(O)N(3-10 membered carbocyclyl), optionally substituted C(O)N(4-10 membered heterocyclyl), optionally substituted C(O)NC 2 -C 8 alkenyl, optionally substituted C(O)NC 2 -C 8 alkynyl, optionally substituted P(O)(OH) 2 , optionally substituted P(O)(OC 1 -C 8 alkyl) 2 , and optionally substituted P(O)(OC 1 -C 8 aryl) 2 ;

wherein

V, W, X, and Z are independently selected from CR 4 and N; and

R 1 , R 2 , R 3 , and R 4 are independently selected from hydrogen, halogen, cyano, nitro, optionally substituted C 1 -C 8 alkyl, optionally substituted C 2 -C 8 alkenyl, and optionally substituted C 2 -C 8 alkynyl; optionally substituted C 1 -C 8 alkoxyC 1 -C 8 alkyl, optionally substituted C 1 -C 8 haloalkyl, optionally substituted C 1 -C 8 hydroxyalkyl, optionally substituted C 1 -C 8 alkoxy, optionally substituted C 1 -C 8 alkylamino, 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.

19. The bivalent compound of claim 1 , 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 pharmaceutically acceptable salts and enantiomers thereof.

20. 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.

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

22. The bivalent compound of claim 21 , wherein the AKT ligand is selected from the group consisting of GSK690693, GSK2110183, GSK2141795, AZD5363, GDC-0068, MK-2206, and ARQ-092.

23. The bivalent compound of claim 21 , 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, and LCL161.

24. The bivalent compound of claim 21 , wherein the AKT ligand [PI] comprises:

wherein

A, B, and X are independently N, CH, or CR 6 ,

Y is CH 2 , CO, SO, SO 2 , CR 7 R 8 , CONR 7 , or SO 2 NR 7 , E is NH, NR 9 , O, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkoxyalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 hydroxyalkyl, C 3 -C 8 cycloalkyl, C 3 -C 7 heterocyclyl, C 2 -C 8 alkenyl, C 2 -C 8 alkynyl, OR 9 , SR 9 , NR 9 R 10 , CN, NO 2 , (CR 9 R 10 ) m NR 11 R 12 , (CR 9 R 10 ) m C(O)R 11 , (NR 9 R 10 ) m NR 11 R 12 , (NR 9 R 10 ) m C(O)R 11 , COR 9 , CO 2 R 9 , CONR 9 R 10 , NR 9 COR 10 , NR 9 SOR 10 , NR 9 SO 2 R 10 , SOR 9 , SO 2 R 9 , SO 2 NR 9 R 10 , (CR 9 R 10 ) m -aryl, or (CR 9 R 10 ) m -heteroaryl,

R 1 is H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkoxyalkyl, aryl, C 1 -C 8 alkylaryl, haloaryl, arylalkyl, heteroaryl, or heteroarylalkyl,

R 2 , R 3 , R 4 , and R 6 are independently hydrogen, halogen, amino, C 1 -C 8 alkylamino, arylamino, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, or C 1 -C 8 alkoxyalkyl,

R 5 , R 7 , and R 8 are independently H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, or C 1 -C 8 alkoxyalkyl,

R 9 and R 10 , R 11 and R 12 can independently form 4-8 membered alkyl or heterocyclyl rings,

m=0-8,

and

n=0-8.

25. The bivalent compound of claim 21 , wherein the AKT ligand [PI] comprises:

wherein

A, B, and X are independently N or CR 3 ,

Y is CH 2 , CO, SO, SO 2 , CR 4 R 5 , CONR 4 , or SO 2 NR 4 ,

Z 1 -Z 2 is CR 10 ═CH, N+CH, or CR 10 ═N,

R 1 is hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkoxyalkyl, aryl, C 1 -C 8 alkylaryl, haloaryl, arylalkyl, heteroaryl, or heteroarylalkyl,

R 2 , R 3 , and R 4 are independently hydrogen, halogen, amino, C 1 -C 8 alkylamino, arylamino, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, or C 1 -C 8 alkoxyalkyl,

R 6 and R 7 , R 8 and R 9 can independently form 4-8 membered alkyl or heterocyclyl rings,

R 10 is hydrogen, halogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkoxyalkyl,

m=0-8,

and

n=0-8.

26. The bivalent compound of claim 21 , wherein [PI] the AKT ligand is selected from the group consisting of:

27. The bivalent compound of claim 21 , wherein the degradation tag [EL] is selected from the group consisting of:

wherein

V, W, and X are independently CR 2 or N,

Y is CO or CH 2 ,

Z is CH 2 , NH, or O,

R 1 is hydrogen, methyl, or fluoro, and

R 2 is hydrogen, halogen, or C 1 -C 8 alkyl;

wherein R 1 and R 2 are independently hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxyalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 hydroxyalkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 heterocyclyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl; and

wherein R 1 , R 2 , R 3 , and R 4 are independently hydrogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxyalkyl, C 1 -C 8 haloalkyl, C 1 -C 8 hydroxyalkyl, C 3 -C 7 cycloalkyl, C 3 -C 7 heterocyclyl, C 2 -C 8 alkenyl, or C 2 -C 8 alkynyl, and

V, W, X, and Z are independently CR 4 or N.

28. The bivalent compound of claim 21 , wherein the linker is selected from the group consisting of:

wherein X is C═O or CH 2 ,

Y is C═O or CH 2 , and

n is 0-15;

wherein X is C═O or CH 2 ,

Y is C═O or CH 2 ,

m is 0-15,

n is 0-6, and

o is 0-15; and

wherein

X is C═O or CH 2 ,

Y is C═O or CH 2 ,

m is 0-15, and

n is 0-15.

29. The bivalent compound of claim 21 , wherein the linker is Formula C and R is selected from the group consisting of:

30. 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.

Continuity (2)

Provisional Application 62639240 · Mar 6, 2018

Related Publication 20200399266A1 · Dec 24, 2020

Cited By (1)

US 12,274,697