Specific AKT3 activator and uses thereof

Patent metadata

Field	Value
Publication number	US-11957673-B2
Application number	US-201816645293-A
Country	US
Kind code	B2
Filing date	Sep 6, 2018
Priority date	Sep 7, 2017
Publication date	Apr 16, 2024
Grant date	Apr 16, 2024

Abstract

Compositions and methods of selectively activating Akt3 are provided.

First claim

We claim:

1. A compound according to Formula I:

or a pharmaceutically acceptable enantiomer, or salt thereof, wherein:
rings A, B, and C are independently phenyl, pyridine, pyrimidine, pyridazine, pyrazine, triazine, quinoline, quinazoline, isoquinoline, naphthalene, naphthyridine, indole, isoindole, cinnoline, phthalazine, quinoxaline, pteridine, purine, or benzimidazole;
R 1 is selected from —(C 1 -C 30 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —(C 6 -C 20 )-aryl, or —(C 3 -C 20 )-heteroaryl groups optionally substituted by one or more substituents selected from —(C 1 -C 12 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —O—(C 1 -C 12 )-alkyl, —O—(C 3 -C 12 )-cycloalkyl, —S—(C 1 -C 12 )-alkyl, —S—(C 3 -C 12 )-cycloalkyl, —COO—(C 1 -C 12 )-alkyl, —COO—(C 3 -C 12 )-cycloalkyl, —CONH—(C 1 -C 12 )-alkyl, —CONH—(C 3 -C 12 )-cycloalkyl, —CO—(C 1 -C 12 )-alkyl, —CO—(C 3 -C 12 )-cycloalkyl, —N—[(C 1 -C 12 )-alkyl] 2 , —COOH, —OH, —SH, —SO 3 H, —CN, —NH 2 , or a halogen;
X, Y, and Z are independently —O, —NH, —S, or —N—(C 1 -C 30 )-alkyl;
R 2 is ═O, —OH, —SO 2 , —SO, or —SOCH 3 ;
R 3 on ring A is —(C 1 -C 30 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —(C 6 -C 20 )-aryl, —(C 3 -C 20 )-heteroaryl, —O—(C 1 -C 12 )-alkyl, —O—(C 3 -C 12 )-cycloalkyl, —S—(C 1 -C 12 )-alkyl, —S—(C 3 -C 12 )-cycloalkyl, —COO—(C 1 -C 12 )-alkyl, —COO—(C 3 -C 12 )-cycloalkyl, —CONH—(C 1 -C 12 )-alkyl, —CONH—(C 3 -C 12 )-cycloalkyl, —CO—(C 1 -C 12 )-alkyl, —CO—(C 3 -C 12 )-cycloalkyl, —N—[(C 1 -C 12 )-alkyl] 2 , (C 6 -C 20 )-aryl-(C 1 -C 12 )-alkyl, (C 3 -C 20 )-heteroaryl-(C 1 -C 12 )-alkyl, —COOH, —OH, —SH, —SO 3 H, —CN, —NH 2 , or a halogen; and
R 3 on ring C is hydrogen, —(C 1 -C 30 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —N—[(C 1 -C 12 )-alkyl] 2 , —COOH, —OH, —SH, —SO 3 H, —CN, —NH 2 , or a halogen,
with the proviso that:
(i) when R 1 is unsubstituted pyridine or N-substituted pyridine by -(C 1 )-alkyl, X, Y, Z are —NH, R 2 is ═O, A is quinoline or pyridine, B is phenyl or pyridine, C is phenyl, R 3 on ring C is hydrogen, then R 3 on ring A is not —COO—(C 1 )-alky, not —CO—(C 1 )-alkyl, not —N—[(C 1 )-alkyl] 2 , not —COOH, not —CN, and not —F;
(ii) when the compound has the structure of Formula III,

R 1 is unsubstituted pyridine, N-substituted pyridine by -(C 1 -C 3 )-alkyl, or pyrimidine substituted by -(C 1 )-alkyl and —NH 2 , X, Y, Z are —NH, R 2 is ═O, then R 4 is not halogen, not —(C 1 )-alkyl, not —O—(C 1 )-alkyl, not —NH 2 , and not —N—[(C 1 )-alkyl] 2 ;
(iii) when R 1 is unsubstituted pyridine, unsubstituted quinoline, quinoline substituted by —NH 2 , —NO 2 , or —N—[(C 1 )-alkyl] 2 , or pyrimidine substituted by -(C 1 )-alkyl and —NH 2 , X, Y, Z are —NH, R 2 is ═O, A is pyridine, naphthalene, or pyrimidine, B is phenyl, C is phenyl, R 3 on ring C is hydrogen, then R 3 on ring A is not —(C 1 -C 2 )-alkyl and not —NH 2 ;
(iv) when R 1 is acridine, X, Y, Z are —NH, R 2 is ═O, A is pyridine or pyrimidine substituted by —(C 1 )-alkyl and —NH 2 , B is phenyl, C is phenyl, R 3 on ring C is hydrogen, then R 3 on ring A is not -(C 1 )-alkyl; and
(v) when A is pyridine, phenyl, pyrimidine, or quinazoline, B is phenyl or pyridine, C is phenyl, pyridine, or pyrimidine, X is —O or —S, Z is —O, —S, or —NH, Y is —NH, R 2 is ═O, R 3 on ring A is -(C 1 )-alkyl, —CN, —CF 3 , pyrimidine, phenyl, —NH 2 , halogen, or —CONH-(C 1 )-alkyl, R 3 on ring C is hydrogen, halogen, or -(C 1 )-alkyl, then R 1 is not -(C 1 -C 5 )-alkyl, not phenyl, not -(C 1 -C 3 )-alkyl substituted by halogen, -(C 3 )-cycloalkyl, —N-[(C 1 )-alkyl] 2 , or -(C 4 )-heterocycloalkyl.

2. A compound according to Formula II:

or a pharmaceutically acceptable enantiomer, or salt thereof, wherein:
R 1 is (C 1 -C 30 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —(C 6 -C 20 )-aryl, or —(C 3 -C 20 )-heteroaryl groups optionally substituted by one or more substituents selected from —(C 1 -C 12 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —O—(C 1 -C 12 )-alkyl, —O—(C 3 -C 12 )-cycloalkyl, —S—(C 1 -C 12 )-alkyl, —S—(C 3 -C 12 )-cycloalkyl, —COO—(C 1 -C 12 )-alkyl, —COO—(C 3 -C 12 )-cycloalkyl, —CONH—(C 1 -C 12 )-alkyl, —CONH—(C 3 -C 12 )-cycloalkyl, —CO—(C 1 -C 12 )-alkyl, —CO—(C 3 -C 12 )-cycloalkyl, —N—[(C 1 -C 12 )-alkyl] 2 , —COOH, —OH, —SH, —SO 3 H, —CN, —NH 2 , or a halogen;
X, Y, and Z are independently O, —NH, —S, or, —N—(C 1 -C 30 )-alkyl;
R 2 is ═O, —OH, —SO 2 , —SO, or —SOCH 3 ; and
R 3 is selected from —(C 1 -C 30 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —(C 6 -C 20 )-aryl, or —(C 3 -C 20 )-heteroaryl —O—(C 1 -C 12 )-alkyl, —O—(C 3 -C 12 )-cycloalkyl, —S—(C 1 -C 12 )-alkyl, —S—(C 3 -C 12 )-cycloalkyl, —COO—(C 1 -C 12 )-alkyl, —COO—(C 3 -C 12 )-cycloalkyl, —CONH—(C 1 -C 12 )-alkyl, —CONH—(C 3 -C 12 )-cycloalkyl, —CO—(C 1 -C 12 )-alkyl, —CO—(C 3 -C 12 )-cycloalkyl, —N—[(C 1 -C 12 )-alkyl] 2 , (C 6 -C 20 )-aryl-(C 1 -C 12 )-alkyl, (C 3 -C 20 )-heteroaryl-(C 1 -C 12 )-alkyl, —COOH, —OH, —SH, —SO 3 H, —CN, —NH 2 , or a halogen,
with the proviso that
(i) when R 1 is quinoline substituted by —NH 2 , —NO 2 , or —N-[(C 1 )-alkyl] 2 , X, Y, Z are —NH, then R 3 on ring A is not -(C 1 -C 2 )-alkyl and not —NH 2 ; and
(ii) when R 1 is acridine, X, Y, Z are —NH, then R 3 on ring A is not -(C 1 )-alkyl.

3. A compound according to Formula III:

or a pharmaceutically acceptable enantiomer, or salt thereof, wherein:
R 1 is (C 1 -C 30 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —(C 6 -C 20 )-aryl, or —(C 3 -C 20 )-heteroaryl groups optionally substituted by one or more substituents selected from —(C 1 -C 12 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —O—(C 1 -C 12 )-alkyl, —O—(C 3 -C 12 )-cycloalkyl, —S—(C 1 -C 12 )-alkyl, —S—(C 3 -C 12 )-cycloalkyl, —COO—(C 1 -C 12 )-alkyl, —COO—(C 3 -C 12 )-cycloalkyl, —CONH—(C 1 -C 12 )-alkyl, —CONH—(C 3 -C 12 )-cycloalkyl, —CO—(C 1 -C 12 )-alkyl, —CO—(C 3 -C 12 )-cycloalkyl, —N—[(C 1 -C 12 )-alkyl] 2 , —COOH, —OH, —SH, —SO 3 H, —CN, —NH 2 , or a halogen;
X, Y, and Z are independently —O, —NH, —S, or —N—(C 1 -C 30 )-alkyl;
R 2 is ═O, —OH, —SO 2 , —SO, or —SOCH 3 ; and
R 4 is selected from —(C 1 -C 12 )-alkyl, —(C 3 -C 12 )-cycloalkyl, —(C 3 -C 12 )-heterocycloalkyl, —O—(C 1 -C 12 )-alkyl, —O—(C 3 -C 12 )-cycloalkyl, —S—(C 1 -C 12 )-alkyl, —S —(C 3 -C 12 )-cycloalkyl, —COO—(C 1 -C 12 )-alkyl, —COO—(C 3 -C 12 )-cycloalkyl, —CONH—(C 1 -C 12 )-alkyl, —CONH—(C 3 -C 12 )-cycloalkyl, —CO—(C 1 -C 12 )-alkyl, —CO—(C 3 -C 12 )-cycloalkyl, —N—[(C 1 -C 12 )-alkyl] 2 , —(C 6 -C 20 )-aryl, —(C 6 -C 20 )-aryl-(C 1 -C 12 )-alkyl, —(C 3 -C 20 )-heteroaryl, —(C 3 -C 20 )-heteroaryl-(C 1 -C 12 )-alkyl, —COOH, —OH, —SH, —SO 3 H, —CN, —NH 2 , or a halogen,
with the proviso that:
when R 1 is unsubstituted pyridine, N-substituted pyridine by —(C 1 -C 3 )-alkyl, or pyrimidine substituted by —(C 1 )-alkyl and —NH 2 , X, Y, Z are —NH, R 2 is ═O, then R 4 is not halogen, not —(C 1 )-alkyl, not —O—(C 1 )-alkyl, not —NH 2 , not —CN, not —COOH, and not —N—[(C 1 )-alkyl] 2 .

4. A method of increasing an immune suppressive response in a subject in need thereof comprising administering to the subject the compound of claim 1 , or a co

Assignees

• Univ Res Inst Inc Augusta

Inventors

• Khleif Samir
• Mkrtichyan Mikayel

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61P3/04

  Anorexiants; Antiobesity agents · CPC title

• A61P31/00

  Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics · CPC title

• A61K35/17

  Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes (when activated by a specific antigen A61K39/00) · CPC title

• C07D401/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title