Salicylic acid derivatives, pharmaceutically acceptable salt thereof, composition thereof and method of use thereof

Patent metadata

Field	Value
Publication number	US-10377780-B2
Application number	US-201715475108-A
Country	US
Kind code	B2
Filing date	Mar 30, 2017
Priority date	May 25, 2012
Publication date	Aug 13, 2019
Grant date	Aug 13, 2019

Abstract

The present invention relates to novel compounds, compositions containing same and methods for inhibiting STAT3 and/or STAT5 activity or for the treatment of a STAT3 or STAT5-dependent cancer using said compounds;

or a pharmaceutically acceptable salt, solvate or prodrug thereof.

First claim

The invention claimed is:

1. A compound of formula I:

or a pharmaceutically acceptable salt, solvate or prodrug thereof,
wherein each of m and n are independently an integer from 0-3;
wherein R 1 is selected from A 1 , A 2 , -(A 1 )-(A 2 ), -(A 2 )-(A 3 ), -(A 3 )-(A 2 ), -(A 3 )-(A 4 ), -(A 5 )-(A 1 )-(A 7 ), -(A 5 )-(A 2 )-(A 8 ), -(A 5 )-(A 3 )-(A 7 ), and -(A 5 )-(A 6 )-L-(A 7 );
wherein A 1 is C 3-6 cycloalkyl, and substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C 1-6 haloalkyl, C 1-6 polyhaloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 polyhaloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 1-6 polyhaloalkylthio, C 1-6 alkylamino, C 1-6 dialkylamino, (C 1-6 )-alkyl-(C 1-6 )-alkoxy, (C 1-6 )-alkyl-(C 1-6 )-haloalkoxy, (C 1-6 )-alkyl-(C 1-6 )-polyhaloalkoxy, (C 1-6 )-alkyl-(C 1-6 )-alkylthio, (C 1-6 )-alkyl-(C 1-6 )-haloalkylthio, (C 1-6 )-alkyl-(C 1-6 )-polyhaloalkylthio, CO 2 H, (C═O)R 5 , (C═O)OR 5 , and (C═O)NHR 5 ;
wherein A 2 is C 3-6 cycloalkyl or heterocycloalkyl, substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C 1-6 haloalkyl, C 1-6 polyhaloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 polyhaloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 1-6 polyhaloalkylthio, C 1-6 alkylamino, C 1-6 dialkylamino, (C 1-6 )-alkyl-(C 1-6 )-alkoxy, (C 1-6 )-alkyl-(C 1-6 )-haloalkoxy, (C 1-6 )-alkyl-(C 1-6 )-polyhaloalkoxy (C 1-6 )-alkyl-(C 1-6 )-alkylthio, (C 1-6 )-alkyl-(C 1-6 )-haloalkylthio, (C 1-6 )-alkyl-(C 1-6 )-polyhaloalkylthio, CO 2 H, (C═O)R 6 , (C═O)OR 6 , and (C═O)NHR 6 ;
wherein A 3 is aryl, and substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C 1-6 haloalkyl, C 1-6 polyhaloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 polyhaloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 1-6 polyhaloalkylthio, C 1-6 alkylamino, C 1-6 dialkylamino, (C 1-6 )- alkyl-(C 1-6 )-alkoxy, (C 1-6 )-alkyl-(C 1-6 )-haloalkoxy, (C 1-6 )-alkyl-(C 1-6 )-polyhaloalkoxy, (C 1-6 )-alkyl-(C 1-6 )-alkylthio, (C 1-6 )-alkyl-(C 1-6 )- haloalkylthio, (C 1-6 )-alkyl-(C 1-6 )-polyhaloalkylthio, CO 2 H, (C═O)R 7 , (C═O)OR 7 , and (C═O)NHR 7 ;
wherein A 4 is aryl, and substituted with 1-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C 1-6 haloalkyl, C 1-6 polyhaloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 polyhaloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 1-6 polyhaloalkylthio, C 1-6 alkylamino, C 1-6 dialkylamino, (C 1-6 )-alkyl-(C 1-6 )-alkoxy, (C 1-6 )-alkyl-(C 1-6 )-haloalkoxy, (C 1-6 )-alkyl-(C 1-6 )-polyhaloalkoxy, (C 1-6 )-alkyl-(C 1-6 )-alkylthio, (C 1-6 )-alkyl-(C 1-6 )-haloalkylthio, (C 1-6 )-alkyl-(C 1-6 )-polyhaloalkylthio, CO 2 H, (C═O)R 8 , (C═O)OR 8 , and (C═O)NHR 8 ;
wherein A 5 is selected from C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, and aryl, and substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C 1-6 haloalkyl, C 1-6 polyhaloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 polyhaloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 1-6 polyhaloalkylthio, C 1-6 alkylamino, C 1-6 dialkylamino, (C 1-6 )-alkyl-(C 1-6 )-alkoxy, (C 1-6 )-alkyl-(C 1-6 )-haloalkoxy, (C 1-6 )-alkyl-(C 1-6 )-polyhaloalkoxy, (C 1-6 )-alkyl-(C 1-6 )-alkylthio, (C 1-6 )-alkyl-(C 1-6 )-haloalkylthio, (C 1-6 )-alkyl-(C 1-6 )-polyhaloalkylthio, CO 2 H, (C═O)R 9 , (C═O)OR 9 , and (C═O)NHR 9 ;
wherein A 6 is selected from C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, and aryl, and substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C 1-6 haloalkyl, C 1-6 polyhaloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 polyhaloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 1-6 polyhaloalkylthio, C 1-6 alkylamino, C 1-6 dialkylamino, (C 1-6 )-alkyl-(C 1-6 )-alkoxy, (C 1-6 )-alkyl-(C 1-6 )-haloalkoxy, (C 1-6 )-alkyl-(C 1-6 )-polyhaloalkoxy, (C 1-6 )-alkyl-(C 1-6 )-alkylthio, (C 1-6 )-alkyl-(C 1-6 )-haloalkylthio, (C 1-6 )-alkyl-(C 1-6 )-polyhaloalkylthio, CO 2 H, (C═O)R 10 , (C═O)OR 10 , and (C═O)NHR 10 ;
wherein A 7 is selected from C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, and aryl, and substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C 1-6 haloalkyl, C 1-6 polyhaloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 polyhaloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 1-6 polyhaloalkylthio, C 1-6 alkylamino, C 1-6 dialkylamino, (C 1-6 )-alkyl-(C 1-6 )-alkoxy, (C 1-6 )-alkyl-(C 1-6 )-haloalkoxy, (C 1-6 )-alkyl-(C 1-6 )-polyhaloalkoxy, (C 1-6 )-alkyl-(C 1-6 )-alkylthio, (C 1-6 )-alkyl-(C 1-6 )-haloalkylthio, (C 1-6 )-alkyl-(C 1-6 )-polyhaloalkylthio, CO 2 H, (C═O)R 11 , (C═O)OR 11 , and (C═O)NHR 11 ;
wherein A 8 is selected from C 3-6 cycloalkyl, C 3-6 heterocycloalkyl, and aryl, and substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, C 1-6 haloalkyl, C 1-6 polyhaloalkyl, C 1-6 alkoxy, C 1-6 haloalkoxy, C 1-6 polyhaloalkoxy, C 1-6 alkylthio, C 1-6 haloalkylthio, C 1-6 polyhaloalkylthio, C 1-6 alkylamino, C 1-6 dialkylamino, (C 1-6 )-alkyl-(C 1-6 )-alkoxy, (C 1-6 )-alkyl-(C 1-6 )-haloalkoxy, (C 1-6 )-alkyl-(C 1-6 )-polyhaloalkoxy, (C 1-6 )-alkyl-(C 1-6 )-alkylthio, (C 1-6 )-alkyl-(C 1-6 )-haloalkylthio, (C 1-6 )-alkyl-(C 1-6 )-polyhaloalkylthio, CO 2 H, (C═O)R 12 , (C═O)OR 12 , and (C═O)NHR 12 ;
wherein L is selected from —(C═O)— and —SO 2 —;
wherein each of R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , and R 12 is independently selected from hydrogen, C 1-6 alkyl, C 1-6 haloalkyl, and C 1-6 polyhaloalkyl; or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof,
wherein R 2 is selected from the group consisting of:

wherein R 3 is selected from the structure represented by formula:

wherein R 4 is a structure represented by formula:

wherein R 13 is selected from the group consisting of —H, —OH, —COR 16 , —CN, —CH 2 PO(OH) 2 , —CH 2 P(O) 3 (CH 2 CH 3 ) 2 , —NO 2 , —NHR 17 , and 1H-tetrazole;
R 16 is selected from the group consisting of: —OH, —O—C( 1-2 )alkyl, —OCH 2 OC(O)CH 3 , and —OCH 2 OC(O)t-Butyl;
R 17 is selected from the group consisting of: —H, —C(O)C(O)CH 2 CH 3 , —C(O)C(O)OH, and —C(O)CH 2 -1H-tetrazole;
R 14 is —H or —COOH or when R 13 is —COR 16 and R 16 is OH, R 14 is —F, or —OC(O)CH 3 ; and
R 15 is H, —OH, or —COOH or when R 13 is —COR 16 and R 16 is OH, R 15 is —F, or —OC(O)CH 3 ;
wherein R 13 is —H when R 15 is —OH or both R 14 and R 15 are —COOH, and
R 14 and R 15 are —H when R 3 is

 and R 13 is —OH.

2. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein m=0 and R 2 is —CH 3 .

3. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 1 is -(A 3 )-(A 2 ), A 2 and A 3 both having the definition as in claim 1 .

4. The compound of claim 3 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein n is 1, A 2 is cyclohexyl and A 3 is aryl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein R 3 is pentafluorobenzene.

6. A compound that is com

Assignees

• Governing Council Univ Toronto
• Uti Lp
• Univ Indiana Res & Tech Corp

Inventors

• Gunning Patrick Thomas
• Haftchenary Sina
• Page Brent David George
• Weiss Samuel
• Luchman Hema Artee
• Fishel Melissa L

Classifications

• A61P43/00

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

• A61P35/02

  specific for leukemia · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• C07F9/40 Primary

  Esters thereof · CPC title

• C07F9/3882

  Arylalkanephosphonic acids (C07F9/3839 takes precedence) · CPC title