Thioindirubins

Patent metadata

Field	Value
Publication number	US-11213510-B2
Application number	US-201816643051-A
Country	US
Kind code	B2
Filing date	Aug 30, 2018
Priority date	Sep 1, 2017
Publication date	Jan 4, 2022
Grant date	Jan 4, 2022

Abstract

Disclosed herein inter alia are compositions and methods for treating cancer using thioindirubin derivatives.

First claim

What is claimed is:

1. A compound, or pharmaceutically acceptable salt thereof, having structural Formula (I):

wherein:
n1, n2, n3, n4 and n6 are independently an integer from 0 to 4;
m2, m3, v1, v2, v3, v4 and v6 are independently 1 or 2;
z1 and z2 are independently an integer from 1 to 4;
X is ═O, ═S or ═NR 1 ;
Y is ═O, ═S or ═NR 6 ;
R 1 is hydrogen, halogen, oxo, —CX 1 3 , —CHX 1 2 , —CH 2 X 1 , —N 3 , —CN, —SO n1 R 1A , —SO v1 NR 1B R 1C , —NR 1B R 1C , —C(O)R 1D , —C(O)OR 1D , —C(O)NR 1B R 1C , —OR 1A , —OCX 1 3 , —OCHX 1 2 , —OCH 2 X 1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R 2 is hydrogen;
R 3 is independently hydrogen, halogen, —CX 3 3 , —CHX 3 2 , —CH 2 X 3 , —N 3 , —CN, —SO n3 R 3A , —SO v3 NR 3B R 3C , —NHNR 3B R 3C , —ONR 3B R 3C , —NHC(O)NHNR 3B R 3C , —NHC(O)NR 3B R 3C , —N(O) m3 , —NR 3B R 3C , —C(O)R 3D , —C(O)OR 3D , —C(O)NR 3B R 3C , —OR 3A , —NR 3B SO 2 R 3A , —NR 3B C(O)R 3D , —NR 3B C(O)OR 3D , —NR 3B OR 3D , —OCX 3 3 , —OCHX 3 2 , —OCH 2 X 3 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, at least one of R 3 is not hydrogen;
R 4 is hydrogen, halogen, oxo, —CX 4 3 , —CHX 4 2 , —CH 2 X 4 , —CN, —SO n4 R 4A , —SO v4 NR 4B R 4C , —NR 4B R 4C , —C(O)R 4D , —C(O)OR 4D , —C(O)NR 4B R 4C , —OR 4A , —OCX 4 3 , —OCHX 4 2 , —OCH 2 X 4 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R 6 is hydrogen, halogen, oxo, —CX 6 3 , —CHX 6 2 , —CH 2 X 6 , —N 3 , —CN, —SO n6 R 6A , —SO v6 NR 6B R 6C , —NR 6B R 6C , —C(O)R 6D , —C(O)OR 6D , —C(O)NR 6B R 6C , —OR 6A , —OCX 6 3 , —OCHX 6 2 , —OCH 2 X 6 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R 1A , R 1B , R 1C , R 1D , R 2A , R 2B , R 2C , R 2D , R 3A , R 3B , R 3C , R 3D , R 4A , R 4B , R 4C , R 4D , R 6A , R 6B , R 6C and R 6D are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 , —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 1B and R 1C , R 2B and R 2C , R 3B and R 3C , R 4B and R 4C and R 6B and R 6C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and
X 1 , X 2 , X 3 , X 4 and X 6 are independently —Cl, —Br, —I or —F,
provided that when X is ═O and Y is ═O, then at least one of R 2 , R 3 and R 4 is not hydrogen.

2. The compound of claim 1 , wherein:
R 4 is hydrogen or substituted or unsubstituted alkyl; and
X is ═O.

3. The compound of claim 2 , wherein the compound has structural Formula (I-A):

wherein:
n3.1 and n3.2 are independently an integer from 0 to 4;
m3.1, m3.2, v3.1 and v3.2 are independently 1 or 2;
R 3.1 is hydrogen, halogen, —CX 3.1 3 , —CHX 3.1 2 , —CH 2 X 3.1 , —N 3 , —CN, —SO n3.1 R 3.1A , —SO v3.1 NR 3.1B R 3.1C , —NHNR 3.1B R 3.1C , —ONR 3.1B R 3.1C , —NHC(O)NHNR 3.1B R 3.1C , —NHC(O)NR 3.1B R 3.1C , —N(O) m3.1 , —NR 3.1B R 3.1C , —C(O)R 3.1D , —C(O)OR 3.1D , —C(O)NR 3.1B R 3.1C , —OR 3.1A , —NR 3.1B SO 2 R 3.1A , —NR 3.1B C(O)R 3.1D , —NR 3.1B C(O)OR 3.1D , —NR 3.1B OR 3.1D , —OCX 3.1 3 , —OCHX 3.1 2 , —OCH 2 X 3.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R 3.2 is hydrogen, halogen, —CX 3.2 3 , —CHX 3.2 2 , —CH 2 X 3.2 , —N 3 , —CN, —SO n3.2 R 3.2A , —SO v3.2 NR 3.2B R 3.2C , —NHNR 3.2B R 3.2C , —ONR 3.2B R 3.2C , —NHC(O)NHNR 3.2B R 3.2C , —NHC(O)NR 3.2B R 3.2C , —N(O) m3.2 , —NR 3.2B R 3.2C , —C(O)R 3.2D , —C(O)OR 3.2D , —C(O)NR 3.2B R 3.2C , —OR 3.2A , —NR 3.2B SO 2 R 3.2A , —NR 3.2B C(O)R 3.2D , —NR 3.2B C(O)OR 3.2D , —NR 3.2B OR 3.2D , —OCX 3.2 3 , —OCHX 3.2A , —OCH 2 X 3.2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl, wherein at least one of R 3.1 and R 3.2 is not hydrogen;
R 3.1A , R 3.1B , R 3.1C , R 3.1D , R 3.2A , R 3.2B , R 3.2C and R 3.2D are independently hydrogen, halogen, —CF 3 , —CCl 3 , —CBr 3 , —CI 3 —COOH, —CONH 2 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R 3.1B and R 3.1C and R 3.2B and R 3.2C substituents bonded to the same nitrogen atom may optionally be joined to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and
X 3.1 and X 3.2 are independently —Cl, —Br, —I or —F.

4. The compound of claim 1 , wherein X is ═NR 1 and wherein R 1 is —OH.

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the compound has structural Formula (I-B):

wherein:
n3.1, n3.2 and n5 are independently an integer from 0 to 4;
m3.1, m3.2, m5, v3.1, v3.2 and v5 are independently 1 or 2;
L is a bond, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, substituted or unsubstituted cycloalkylene, substituted or unsubstituted heterocycloalkylene, substituted or unsubstituted arylene or substituted or unsubstituted heteroarylene;
R 3.1 is hydrogen, halogen, —CX 3.1 3 , —CHX 3.1 2 , —CH 2 X 3.1 , —N 3 , —CN, —SO n3.1 R 3.1A , —SO v3.1 NR 3.1B R 3.1C , —NHNR 3.1B R 3.1C , —ONR 3.1B R 3.1C , —NHC(O)NHNR 3.1B R 3.1C , —NHC(O)NR 3.1B R 3.1C , —N(O) m3.1 , —NR 3.1B R 3.1C , —C(O)R 3.1D , —C(O)OR 3.1D , —C(O)NR 3.1B R 3.1C , —OR 3.1A , —NR 3.1B SO 2 R 3.1A , —NR 3.1B C(O)R 3.1D , —NR 3.1B C(O)OR 3.1D , —NR 3.1B OR 3.1D , —OCX 3.1 3 , —OCHX 3.1 2 , —OCH 2 X 3.1 , substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl;
R 3.2 is hydrogen, halogen, —CX 3.2 3 , —CHX 3.2 2 , —CH 2 X 3.2 , —N 3 , —CN, —SO n3.2 R 3.2A , —SO v3.2 NR 3.2B R 3.2C , —NHNR 3.2B R 3.2C , —ONR 32B R 32C , —NHC(O)NHNR 3.2B R 3.2C , —NHC(O)NR 3.2B R 3.2C , —N(O) m3.2 , —NR 3.2B R 3.2C , —C(O)R 3.2D , —C(O)OR 3.2D , —C(O)NR 3.2B R 3.2C , —OR

Assignees

• Hope City
• National And Kapodistrian Univ Of Athens

Inventors

• Nam Sangkil
• Horne David
• Salgia Ravi
• Skaltsounis Alexios Leandros
• Gaboriaud-Kolar Nicolas
• Gerolymatos Panagiotis
• Lougiakis Nikolaos

Classifications

• C07D409/04 Primary

  directly linked by a ring-member-to-ring-member bond · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K45/06

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

• A61P35/00

  Antineoplastic agents · CPC title

• C07D409/14

  containing three or more hetero rings · CPC title