5-Bromo-indirubins

Patent metadata

Field	Value
Publication number	US-11964941-B2
Application number	US-202016921856-A
Country	US
Kind code	B2
Filing date	Jul 6, 2020
Priority date	Mar 14, 2014
Publication date	Apr 23, 2024
Grant date	Apr 23, 2024

Abstract

Disclosed herein are compositions and methods for treating cancer, FLT3-AML, and CML.

First claim

What is claimed is:

1. A method of treating acute myeloid leukemia expressing a FLT3-kinase in a subject in need thereof, said method comprising administering an effective amount of a compound having the formula:

wherein,
L is a substituted or unsubstituted alkylene;
R 1 is —NR 2 R 3 ;
R 2 and R 3 are independently 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 R 2 and R 3 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and
R 5 and R 6 are independently hydrogen or halogen;
including pharmaceutically acceptable salts thereof,

thereby treating said acute myeloid leukemia.

2. The method of claim 1 , wherein R 2 and R 3 are independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocyloalkyl, substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl.

3. A method of treating acute myeloid leukemia expressing a FLT3-kinase in a subject in need thereof, said method comprising administering an effective amount of a compound, having formula

wherein
R 50 is hydrogen, oxo, halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CH 2 COOH, CONH 2 , NO 2 , —SH, —OCF 3 , —OCF 2 , or unsubstituted alkyl;
R 51 is hydrogen, oxo, halogen, —CF 3 , —CN, —OH, —NR 51A R 51B , —COOH, CH 2 COOH, —CONH 2 , —NO 2 , —SH, —OCF 3 , —OCHF 2 , unsubstituted alkyl, or unsubstituted heteroalkyl;
R 51A and R 51B are independently hydrogen or unsubstituted alkyl;
R 52 is halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , or unsubstituted alkyl; and
z1 and z2 are independently 0, 1, 2, 3, 4, or 5,

including pharmaceutically acceptable salts thereof; and
thereby treating said acute myeloid leukemia.

4. The method of claim 3 , wherein R 50 is hydrogen or unsubstituted alkyl.

5. The method of claim 3 , wherein R is hydrogen, oxo, halogen, —CF 3 , —CN, —OH, —COOH, —CH 2 COOH, CONH 2 , —NO 2 , or unsubstituted alkyl.

6. The method of claim 3 , wherein R 52 is halogen, —OH, —NH 2 , —COOH, —CONH 2 , or unsubstituted alkyl.

7. The method of claim 1 or 3 , wherein said FLT3-kinase is a FLT3-mutant kinase.

8. The method of claim 7 , wherein said FLT3-mutant kinase is a FLT3-TKD mutant kinase.

9. The method of claim 8 , wherein said FLT3-TKD mutant kinase comprises a mutation at an amino acid residue position corresponding to D835, I836, D839, S840, N841, or Y842 of SEQ. ID NO: 1.

10. The method of claim 7 , wherein said FLT3-mutant kinase comprises a FLT3-ITD mutant kinase.

11. A method of modulating activity of a FLT3-kinase, said method comprising contacting a FLT3-kinase with a compound having formula:

wherein,
L is a substituted or unsubstituted alkylene;
R 1 is —NR 2 R 3 ;
R 2 and R 3 are independently 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 R 2 and R 3 are optionally joined together to form a substituted or unsubstituted heterocycloalkyl or substituted or unsubstituted heteroaryl; and
R 5 and R 6 are independently hydrogen or halogen;
including pharmaceutically acceptable salts thereof,
thereby modulating said activity of said FLT3-kinase.

12. A method of modulating activity of a FLT3-kinase, said method comprising contacting a FLT3-kinase with a compound, having formula

wherein
R 50 is hydrogen, oxo, halogen, —CF 2 , —CN, —OH, —NH 2 , —COOH, —CH 2 COOH, —CONH 2 , —NO 2 , —SR, —OCF 3 , —OCHF 2 , or unsubstituted alkyl;
R 51 is hydrogen, oxo, halogen, —CF 3 , —CN, —OH, —NR 51A R 51B , —COOH, —CH 2 COOH, —CONH 2 , —NO 2 , —SH, —OCF 3 , —OCHF 2 , unsubstituted alkyl, or unsubstituted heteroalkyl;
R 51A and R 51B are independently hydrogen or unsubstituted alkyl;
R 52 is halogen, —CF 3 , —CN, —OH, —NH 2 , —COOH, —CONH 2 , or unsubstituted alkyl;

and
z1 and z2 are independently 0, 1, 2, 3, 4, or 5,

including pharmaceutically acceptable salts thereof; and
thereby modulating said activity of said FLT3-kinase.

13. The method of claim 11 or 12 , wherein said FLT3-kinase is a FLT3-mutant kinase.

14. The method of claim 13 , wherein said FLT3-mutant kinase is a FLT3-TKD mutant kinase.

15. The method of claim 14 , wherein said FLT3-TKD mutant kinase comprises a mutation at an amino acid residue position corresponding to D835, I836, D839, S840, N841, or Y842 of SEQ ID NO: 1.

16. The method of claim 11 or 12 , wherein said contacting decreases the activity of said FLT3-kinase.

Assignees

• Hope City

Inventors

• Nam Sangkil
• Horne David
• Xie Jun

Classifications

• C07D209/40 Primary

  Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone · CPC title