Substituted 1H-indazol-1-ol analogs as inhibitors of beta catenin/Tcf protein-protein interactions

Patent metadata

Field	Value
Publication number	US-9284299-B2
Application number	US-201314377839-A
Country	US
Kind code	B2
Filing date	Feb 10, 2013
Priority date	Feb 10, 2012
Publication date	Mar 15, 2016
Grant date	Mar 15, 2016

Abstract

In one aspect, the invention relates to substituted 1H-benzo[d][1,2,3]triazol-1-ol analgoues, derivatives thereof, and related compound; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders, e.g. various tumors and cancers, associated with β-catenin/Tcf protein-protein interaction 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 A 1 is selected from —N═, —NH—, and —CR 2a ═;
wherein A 2 is selected from ═N—, (C═O), (C═S), and ═CR 2b —;
wherein A 3 is selected from —N(OH)— and —O—;
provided that valency is satisfied for A 1 , A 2 , and A 3 ;

wherein L is selected from —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —OCH 2 —, —NHCH 2 —, —CH 2 NHCH 2 —, and —CH 2 OCH 2 —;
wherein B 1 is selected from —N═, —O—, and —S—; wherein B 2 is selected from ═N—, (C═O), (C═S), and (S═O);
provided that valency is satisfied for B 1 and B 2 ;

wherein each of R 1a , R 1b , and R 1c is independently selected from hydrogen, halogen, —OH, —NH 2 , C1-C3 haloalkyl, C1-C3 polyhaloalkyl, and C1-C3 alkoxy; and
wherein each of R 2a and R 2b is independently selected from hydrogen, halogen, —OH, —NH 2 , C1-C3 haloalkyl, C1-C3 polyhaloalkyl, and C1-C3 alkoxy;
or pharmaceutically acceptable salt, ester, hydrate, solvate, or polymorph thereof.

2. The compound of claim 1 , wherein the compound has a structure represented by a formula:

3. The compound of claim 1 , wherein the compound has a structure represented by a formula selected from:

4. The compound of claim 1 , wherein the compound has a structure represented by a formula selected from:

5. The compound of claim 1 , wherein the compound has a structure represented by a formula selected from:

6. The compound of claim 1 , wherein the compound has a structure represented by a formula selected from:

7. The compound of claim 1 , wherein the compound has a structure represented by a formula selected from:

8. The compound of claim 1 , wherein L is selected from —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —OCH 2 —, and —CH 2 OCH 2 —.

9. The compound of claim 1 , wherein L is selected from —CH 2 —, —(CH 2 ) 2 —, and —(CH 2 ) 3 —.

10. The compound of claim 1 , wherein L is selected from —OCH 2 —, and —CH 2 OCH 2 —.

11. A method for the treatment of a disorder of uncontrolled cellular proliferation associated with β-catenin/Tcf protein-protein interaction dysfunction in a mammal comprising the step of administering to the mammal an effective amount of at least one compound having a structure represented by a formula:

wherein A 1 is selected from —N═, —NH—, and —CR 2a ═;
wherein A 2 is selected from ═N—, (C═O), (C═S), and ═CR 2b —;
wherein A 3 is selected from —N(OH)— and —O—;
provided that valency is satisfied for A 1 , A 2 , and A 3 ;

wherein L is selected from —CH 2 —, —(CH 2 ) 2 —, —(CH 2 ) 3 —, —OCH 2 —, —NHCH 2 —, —CH 2 NHCH 2 —, and —CH 2 OCH 2 —;
wherein B 1 is selected from —N═, —O—, and —S—; wherein B 2 is selected from ═N—, (C═O), and (C═S);
provided that valency is satisfied for B 1 and B 2 ;

wherein each of R 1a , R 1b , and R 1c is independently selected from hydrogen, halogen, —OH, —NH 2 , C1-C3 haloalkyl, C1-C3 polyhaloalkyl, and C1-C3 alkoxy; and
wherein each of R 2a and R 2b is independently selected from hydrogen, halogen, —OH, —NH 2 , C1-C3 haloalkyl, C1-C3 polyhaloalkyl, and C1-C3 alkoxy;
or pharmaceutically acceptable salt, ester, hydrate, solvate, or polymorph thereof.

12. The method of claim 11 , wherein the mammal has been diagnosed with a need for treatment of a disorder prior to the administering step.

13. The method of claim 11 , further comprising the step of identifying a mammal in need of treatment of the disorder.

14. The method of claim 12 or claim 13 , wherein the disorder is associated with a Wnt signaling pathway dysregulation.

15. The method of claim 11 , wherein the disorder of uncontrolled cellular proliferation is a cancer.

16. The method of claim 15 , wherein the cancer is selected from a colorectal cancer, breast cancer, prostate cancer, hepatic carcinoma, a melanoma, and lung cancer.

17. The method of claim 11 , wherein the disorder is characterized by fibrosis.

18. The method of claim 17 , wherein the fibrotic disorder is selected from pulmonary fibrosis, liver fibrosis, and polycystic kidney disease.

Assignees

• Univ Utah Res Found

Inventors

• Ji Haitao
• Yu Binxun
• Zhang Min
• Guo Wenxing

Classifications

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D403/12

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

• C07D413/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title