Isoxazole analogs as mediators of transcriptional induction of E-cadherin

Patent metadata

Field	Value
Publication number	US-9505729-B2
Application number	US-201514828286-A
Country	US
Kind code	B2
Filing date	Aug 17, 2015
Priority date	Aug 22, 2014
Publication date	Nov 29, 2016
Grant date	Nov 29, 2016

Abstract

In one aspect, the invention relates to N-((arylamino)alkyl)-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 3 and 4;
wherein n is an integer selected from 0 and 1;
wherein Q is selected from NR 5 , O, and S;
wherein R 5 , when present, is selected from hydrogen and C1-C4 alkyl;

wherein each of R 1 and R 2 is independently selected from hydrogen and C1-C4 alkyl;
wherein R 3 is selected from hydrogen and (CHR 6 ) p Ar 2 ;
wherein p, when present, is an integer selected from 0 and 1;
wherein R 6 , when present, is selected from hydrogen and C1-C4 alkyl;

wherein Ar 2 , when present, is selected from aryl and heteroaryl, and Ar 2 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —N 3 , —NH 2 , —C(O)(C1-C4 alkyl), C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino;
wherein R 4 is selected from CH 2 Ar 3 and Ar 4 ;
wherein Ar 3 , when present, is selected from aryl and heteroaryl, and Ar 3 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —N 3 , —NH 2 , —C(O)(C1-C4 alkyl), C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that when R 2 is hydrogen then Ar 3 , when present, cannot be a structure selected from:

wherein Ar 4 , when present, is selected from aryl and heteroaryl, and Ar 4 is substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —CN, —N 3 , —NH 2 , —C(O)(C1-C4 alkyl), C1-C4 alkyl, C1-C4 alkoxy, C1-C4 monohaloalkyl, C1-C4 polyhaloalkyl, C1-C4 alkylamino, and C1-C4 dialkylamino, provided that when R 2 is hydrogen then Ar 4 , when present, cannot be a structure selected from:

and
wherein Ar 1 , when present, is selected from aryl and heteroaryl, and wherein Ar 1 , when present, 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,
or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1 , wherein R 3 is (CHR 6 ) p Ar 2 .

3. The compound of claim 1 , wherein R 3 is (CH 2 ) p Ar 2 .

4. The compound of claim 1 , wherein R 4 is CH 2 Ar 3 .

5. The compound of claim 1 , wherein R 4 is Ar 4 .

6. 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.

7. 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.

8. The compound of claim 1 , wherein R 2 is hydrogen and Ar 3 is not substituted or unsubstituted pyridinyl.

9. The compound of claim 1 , wherein R 2 is hydrogen and Ar 4 is not substituted or unsubstituted pyridinyl, phenyl, or benzo[d]isothiazole.

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

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

12. 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.

13. 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.

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 the compound has a structure represented by a formula:

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

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

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

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

Assignees

• Univ Vanderbilt

Inventors

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

Classifications

• C07D231/14

  with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms · CPC title

• C07D413/12

  linked by a chain containing hetero atoms as chain links · 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

• C07D471/04

  Ortho-condensed systems · CPC title