Small molecule mediated transcriptional induction of E-cadherin

Patent metadata

Field	Value
Publication number	US-9783510-B2
Application number	US-201514828230-A
Country	US
Kind code	B2
Filing date	Aug 17, 2015
Priority date	Aug 22, 2014
Publication date	Oct 10, 2017
Grant date	Oct 10, 2017

Abstract

In one aspect, the invention relates to N-acetamidoalkyl-5-arylisoxazole-3-carboxamide analogs, derivatives thereof, and related compounds, which are useful as mediators of transcriptional induction of E-cadherin; synthesis methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders associated with E-cadherin activity 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 m is an integer selected from 2, 3, and 4 and Ar 1 is aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —N 3 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino, or
wherein m is 3 and Ar 1 is heteroaryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —N 3 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino;
wherein n is an integer selected from 0 and 1;
wherein p is an integer selected from 0, 1, 2, 3, and 4;
wherein Q is selected from NR 6 , O, and S;
wherein R 6 is selected from hydrogen and C1-C4 alkyl;

wherein R 1 is selected from hydrogen and C1-C4 alkyl;
wherein each of R 2 and R 3 is independently selected from hydrogen and C1-C4 alkyl;
wherein each occurrence of R 4a and R 4b is independently selected from hydrogen, halogen, —OH, —CN, —N 3 , —NH 2 , and C1-C4 alkyl, or wherein each of R 4a and R 4b are optionally covalently bonded and, together with the intermediate atoms, comprise a 3- to 5-membered cycle;
wherein R 5 is selected from Cy 2 and Ar 2
wherein Cy 2 , when present, is selected from cycloalkyl and heterocycloalkyl, and Cy 2 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —N 3 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that when m is 2 then Cy 2 is not cycloalkyl;
wherein Ar 2 , when present, is selected from aryl and heteroaryl, and Ar 2 is substituted with 0, 1, 2, or 3 substituents independently selected from halogen, —OH, —CN, —N 3 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4 dialkylamino, Cy 3 , Ar 3 , and —NH(C═O)(C1-C4 alkyl)Cy 3 , provided that when m is 2 then Ar 2 is not substituted or unsubstituted phenyl, substituted or unsubstituted furanyl, or substituted or unsubstituted pyridinyl;
wherein Cy 3 , when present, is selected from cycloalkyl and heterocycloalkyl, and Cy 3 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —N 3 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino;
wherein Ar 3 , when present, is phenyl substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —N 3 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino;

provided that when m is 3, n is 0, and p is 0, that Ar 2 , when present, is not a structure represented by a formula:

or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein Ar 2 is aryl, and Ar 2 is substituted with 0, 1, 2, or 3 substituents independently selected from halogen, —OH, —CN, —N 3 , —NH 2 , C1-C3 alkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4 dialkylamino, Cy 3 , and Ar 3 .

3. The compound of claim 1 , wherein Ar 2 is heteroaryl, and Ar 2 is substituted with 0, 1, 2, or 3 substituents independently selected from halogen, —OH, —CN, —N 3 , —NH 2 , C1-C3 alkyl, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, C1-C4 dialkylamino, Cy 3 , and Ar 3 .

4. The compound of claim 1 , wherein Ar 1 is aryl, and Ar 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —N 3 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino.

5. The compound of claim 1 , wherein Ar 1 is phenyl, and Ar 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —N 3 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino.

6. The compound of claim 1 , wherein Ar 1 is heteroaryl, and Ar 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —N 3 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino.

7. The compound of claim 1 , wherein Ar 1 is thiophenyl, and Ar 1 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —N 3 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino.

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

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

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

wherein each of R 20a , R 20b , R 20c , R 20d , and R 20e are independently selected from hydrogen, halogen, —OH, —CN, —N 3 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that at least two of R 20a , R 20b , R 20c , R 20d , and R 20e are hydrogen.

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

wherein each of R 20b , R 20c , and R 20d are hydrogen and each of R 20a and R 20e are independently selected from hydrogen, halogen, —OH, —CN, —N 3 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino.

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

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

wherein each of R 30a , R 30b , and R 30c are independently selected from hydrogen, halogen, —OH, —CN, —N 3 , —NH 2 , C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino.

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

15. A compound having a structure selected from:

or a pharmaceutically acceptable salt thereof.

16. The compound of claim 1 , wherein m is 3.

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

wherein p is an in

Assignees

• Univ Vanderbilt

Inventors

• Lindsley Craig W
• Waterson Alex G
• Beauchamp R Daniel

Classifications

• C07D487/04

  Ortho-condensed systems · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D261/18 Primary

  Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen · CPC title

• C07D401/12

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

• C07D495/04

  Ortho-condensed systems · CPC title