STAT3 inhibitors and their anticancer use

Patent metadata

Field	Value
Publication number	US-9783513-B2
Application number	US-201314421776-A
Country	US
Kind code	B2
Filing date	Aug 16, 2013
Priority date	Aug 16, 2012
Publication date	Oct 10, 2017
Grant date	Oct 10, 2017

Abstract

In one aspect, the invention relates to substituted 6-amino-5,8-dioxo-5,8-dihydronaphthalene-1-sulfonamide analogs and derivatives thereof, substituted 4-amino-5H-naphtho[1,8-cd]isothiazol-5-one 1,1-dioxide analogs and derivatives thereof, and related compounds, which are useful as inhibitors of STAT protein activity; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders of uncontrolled cellular proliferation associated with a STAT protein activity dysfunction using the compounds and compositions. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.

First claim

What is claimed is:

1. A compound having a structure represented by a formula:

wherein R 1 is selected from hydrogen and C1-C3 alkyl;
wherein Q 1 is —NR 2a R 2b and wherein Q 2 is O; or wherein Q 1 and Q 2 are together N;
wherein each of R 2a and R 2b , when present, is independently selected from hydrogen and C1-C3 alkyl;
wherein Q 3 is selected from —(C1-C6)-Ar 1 , Ar 1 , —(C1-C6)-Cy 1 , and Cy 1 ;
wherein Ar 1 , when present, is selected from phenyl, naphthyl, monocyclic heteroaryl, and bicyclic heteroaryl; and wherein Ar 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C1-C6)NR 4a R 4b , —(C1-C6)-(C═O)R 3 , —(C1-C6)-(C═O)OR 3 , —(C1-C6)-(C═O)NR 4a R 4b , —(C1-C6)-Ar 2 , Ar 2 , —(C1-C6)-Cy 2 , Cy 2 , and —S(O) n NR 5a R 5b ;
wherein n is 0, 1, or 2;
wherein each R 3 , when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl;
wherein each of R 4a and R 4b , when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, and C1-C6 aminoalkyl;
wherein each of R 5a and R 5b , when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, and —(C═O)NR 6a R 6b ;
wherein each of R 6a and R 6b , when present, is independently selected from hydrogen and C1-C6 alkyl;
wherein each Ar 2 , when present, is independently selected from is phenyl and monocyclic heteroaryl; and wherein Ar2 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 monoalkylamino, and C1-C6 dialkylamino;
wherein each Cy 2 , when present, is independently selected from C3-C8 cycloalkyl and C2-C7 heterocycloalkyl; and wherein Cy 2 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C═O)R7, —(C═O)OR7, —(C═O)NR 8a R 8b , —(C═O)-(C1-C6 alkyl)Ar3, —(C═O)—O—(C1-C6 alkyl)Ar 3 , and —(C═O)—NR 8a —(C1-C6 alkyl)Ar 3 ;
wherein each R 7 , when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 monohaloalkyl, and C1-C6 polyhaloalkyl;
wherein each of R 8a and R 8b , when present, is independently selected from hydrogen, C1-C6 alkyl, C1-C6 monohaloalkyl, and C1-C6 polyhaloalkyl;
wherein each Ar 3 , when present, is independently selected from phenyl and monocyclic heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, and C1-C6 polyhaloalkyl;
wherein Cy 1 , when present, is selected from C3-C8 cycloalkyl and C2-C7 heterocycloalkyl; and wherein Cy 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C1-C6)NR 4a R 4b , —(C1-C6)-(C═O)R 3 , —(C1-C6)-(C═O)OR 3 , —(C1-C6)-(C═O)NR 4a R 4b , —(C1-C6)-Ar 2 , Ar 2 , —(C1-C6)-Cy 2 , Cy 2 , and —S(O) n NR 5a R 5b ;
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein Q 1 is —NH 2 .

3. The compound of claim 1 , wherein Q 1 is —NHCH 3 .

4. The compound of claim 1 , wherein Q 3 is Ar 1 .

5. The compound of claim 1 , wherein Q 3 is —(C1-C6)-Ar 1 .

6. The compound of claim 1 , wherein Ar 1 , when present, is phenyl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C1-C6)NR 4a R 4b , —(C1-C6)-(C═O)R 3 , —(C1-C6)-(C═O)OR 3 , —(C1-C6)-(C═O)NR 4a R 4b , —(C1-C6)-Ar 2 , Ar 2 , —(C1-C6)-Cy 2 , Cy 2 , and —S(O) n NR 5a R 5b .

7. The compound of claim 1 , wherein Ar 1 , when present, is phenyl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C1-C6)-Cy 2 , Cy 2 , and —S(O) n NR 5a R 5b .

8. The compound of claim 1 , wherein Ar 1 , when present, is pyridinyl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C1-C6)NR 4a R 4b , —(C1-C6)-(C═O)R 3 , —(C1-C6)-(C═O)OR 3 , —(C1-C6)-(C═O)NR 4a R 4b , —(C1-C6)-Ar 2 , Ar 2 , —(C1-C6)-Cy 2 , Cy 2 , and —S(O) n NR 5a R 5b .

9. The compound of claim 1 , wherein Cy 2 , when present, is a C2-C7 heterocycloalkyl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C═O)R 7 , —(C═O)OR 7 , —(C═O)NR 8a R 8b , —(C═O)—(C1-C6 alkyl)-Ar 3 , —(C═O)—O—(C1-C6 alkyl)-Ar 3 , and —(C═O)—NR 8a —(C1-C6 alkyl)-Ar 3 .

10. The compound of claim 1 , wherein Cy 2 , when present, is piperidinyl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C═O)R 7 , —(C═O)OR 7 , —(C═O)NR 8a R 8b , —(C═O)—(C1-C6 alkyl)-Ar 3 , —(C═O)—O—(C1-C6 alkyl)-Ar 3 , and —(C═O)—NR 8a —(C1-C6 alkyl)-Ar 3 .

11. The compound of claim 1 , wherein Cy 2 , when present, is morpholinyl and is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —CN, —OH, —NH 2 , —NO 2 , C1-C6 alkyl, C1-C6 monohaloalkyl, C1-C6 polyhaloalkyl, C1-C6 hydroxyalkyl, C1-C6 aminoalkyl, C1-C6 monoalkylamino, C1-C6 dialkylamino, —(C═O)R 7 , —(C═O)OR 7 , —(C═O)NR 8a R 8b , —(C═O)—(C1-C6 alkyl)-Ar 3 , —(C═O)—O—(C1-C6 alkyl)-Ar 3 , and —(C═O)—NR 8a —(C1-C6 alkyl)-Ar 3 .

12. The compound of claim 1 , wherein Cy 2 is unsubstituted.

13. The compound of claim 1 , wherein R 1 is hydrogen.

14. The compound of claim 1 , wherein R 1 is selected from hydrogen and methyl.

15. The compound of claim 1 , having a structure represented by a formula:

16. The compound of claim 1 , having a structure represented by a formula:

17. The compound of claim 1 , having a structure represented by a formula:

18. The compound of claim 1 , having a structure represented by a formula:

Assignees

• Ohio State Innovation Foundation
• Res Inst At Nationwide Children'S Hospital

Inventors

• Li Chenglong
• Yu Wenying
• Lin Jiayuh

Classifications

• A61P35/00

  Antineoplastic agents · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07D295/135

  with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings · CPC title