Substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs as inhibitors of STAT protein
In one aspect, the invention relates to substituted 2-hydroxy-4-(2-(phenylsulfonamido)acetamido)benzoic acid analogs, 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.
1. A compound having a structure represented by a formula:
wherein each of m and n is 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 C3-C6 cycloalkyl, and substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 polyhaloalkoxy, C1-C6 alkylthio, C1-C6 haloalkythio, C1-C6 polyhaloalkylthio, C1-C6 alkylamino, C1-C6 dialkylamino, (C1-C6)-alkyl-(C1-C6)-alkoxy, (C1-C6)-alkyl-(C1-C6)-haloalkoxy, (C1-C6)-alkyl-(C1-C6)-polyhaloalkoxy, (C1-C6)-alkyl-(C1-C6)-alkylthio, (C1-C6)-alkyl-(C1-C6)-haloalkythio, (C1-C6)-alkyl-(C1-C6)-polyhaloalkylthio, CO 2 H, (C═O)R4, (C═O)OR 4 , and (C═O)NHR 4 ;
wherein A 2 is C3-C6 heterocycloalkyl, and substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 polyhaloalkoxy, C1-C6 alkylthio, C1-C6 haloalkythio, C1-C6 polyhaloalkylthio, C1-C6 alkylamino, C1-C6 dialkylamino, (C1-C6)-alkyl-(C1-C6)-alkoxy, (C1-C6)-alkyl-(C1-C6)-haloalkoxy, (C1-C6)-alkyl-(C1-C6)-polyhaloalkoxy, (C1-C6)-alkyl-(C1-C6)-alkylthio, (C1-C6)-alkyl-(C1-C6)-haloalkythio, (C1-C6)-alkyl-(C1-C6)-polyhaloalkylthio, CO 2 H, (C═O)R 5 , (C═O)OR 5 , and (C═O)NHR 5 ;
wherein A 3 is aryl, and substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 polyhaloalkoxy, C1-C6 alkylthio, C1-C6 haloalkythio, C1-C6 polyhaloalkylthio, C1-C6 alkylamino, C1-C6 dialkylamino, (C1-C6)-alkyl-(C1-C6)-alkoxy, (C1-C6)-alkyl-(C1-C6)-haloalkoxy, (C1-C6)-alkyl-(C1-C6)-polyhaloalkoxy, (C1-C6)-alkyl-(C1-C6)-alkylthio, (C1-C6)-alkyl-(C1-C6)-haloalkythio, (C1-C6)-alkyl-(C1-C6)-polyhaloalkylthio, CO 2 H, (C═O)R 6 , (C═O)OR 6 , and (C═O)NHR 6 ;
wherein A 4 is aryl, and substituted with 1-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 polyhaloalkoxy, C1-C6 alkylthio, C1-C6 haloalkythio, C1-C6 polyhaloalkylthio, C1-C6 alkylamino, C1-C6 dialkylamino, (C1-C6)-alkyl-(C1-C6)-alkoxy, (C1-C6)-alkyl-(C1-C6)-haloalkoxy, (C1-C6)-alkyl-(C1-C6)-polyhaloalkoxy, (C1-C6)-alkyl-(C1-C6)-alkylthio, (C1-C6)-alkyl-(C1-C6)-haloalkythio, (C1-C6)-alkyl-(C1-C6)-polyhaloalkylthio, CO 2 H, (C═O)R 7 , (C═O)OR 7 , and (C═O)NHR 7 ;
wherein A 5 is selected from C3-C6 cycloalkyl, C3-C6 heterocycloalkyl, and aryl, and substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 polyhaloalkoxy, C1-C6 alkylthio, C1-C6 haloalkythio, C1-C6 polyhaloalkylthio, C1-C6 alkylamino, C1-C6 dialkylamino, (C1-C6)-alkyl-(C1-C6)-alkoxy, (C1-C6)-alkyl-(C1-C6)-haloalkoxy, (C1-C6)-alkyl-(C1-C6)-polyhaloalkoxy, (C1-C6)-alkyl-(C1-C6)-alkylthio, (C1-C6)-alkyl-(C1-C6)-haloalkythio, (C1-C6)-alkyl-(C1-C6)-polyhaloalkylthio, CO 2 H, (C═O)R 8 , (C═O)OR 8 , and (C═O)NHR 8 ;
wherein A 6 is selected from C3-C6cycloalkyl, C3-C6heterocycloalkyl, and aryl, and substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 polyhaloalkoxy, C1-C6 alkylthio, C1-C6 haloalkythio, C1-C6 polyhaloalkylthio, C1-C6 alkylamino, C1-C6 dialkylamino, (C1-C6)-alkyl-(C1-C6)-alkoxy, (C1-C6)-alkyl-(C1-C6)-haloalkoxy, (C1-C6)-alkyl-(C1-C6)-polyhaloalkoxy, (C1-C6)-alkyl-(C1-C6)-alkylthio, (C1-C6)-alkyl-(C1-C6)-haloalkythio, (C1-C6)-alkyl-(C1-C6)-polyhaloalkylthio, CO 2 H, (C═O)R 9 , (C═O)OR 9 , and (C═O)NHR 9 ;
wherein A 7 is selected from C3-C6cycloalkyl, C3-C6heterocycloalkyl, and aryl, and substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 polyhaloalkoxy, C1-C 6 alkylthio, C1-C6 haloalkythio, C1-C6 polyhaloalkylthio, C1-C6 alkylamino, C1-C 6 dialkylamino, (C1-C6)-alkyl-(C1-C6)-alkoxy, (C1-C6)-alkyl-(C1-C6)-haloalkoxy, (C1-C6)-alkyl-(C1-C6)-polyhaloalkoxy, (C1-C6)-alkyl-(C1-C6)-alkylthio, (C1-C6)-alkyl-(C1-C6)-haloalkythio, (C1-C6)-alkyl-(C1-C6)-polyhaloalkylthio, CO 2 H, (C═O)R 10 , (C═O)OR 10 , and (C═O)NHR 10 ;
wherein A 8 is selected from C3-C6cycloalkyl, C3-C6heterocycloalkyl, and aryl, and substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 polyhaloalkoxy, C1-C6 alkylthio, C1-C6 haloalkythio, C1-C6 polyhaloalkylthio, C1-C6 alkylamino, C1-C6 dialkylamino, (C1-C6)-alkyl-(C1-C6)-alkoxy, (C1-C6)-alkyl-(C1-C6)-haloalkoxy, (C1-C6)-alkyl-(C1-C6)-polyhaloalkoxy, (C1-C6)-alkyl-(C1-C6)-alkylthio, (C1-C6)-alkyl-(C1-C6)-haloalkythio, (C1-C6)-alkyl-(C1-C6)-polyhaloalkylthio, CO 2 H, (C═O)R 11 , (C═O)OR 11 , and (C═O)NHR 11 ;
wherein L is selected from —(C═O)— and SO 2 —;
wherein R 2 is selected from C1-C6 alkyl, C2-C6alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, C2-C6 haloalkenyl, C2-C6 haloalkynyl, C1-C6 polyhaloalkyl, C2-C6 polyhaloalkenyl, C2-C6 polyhaloalkynyl; or wherein R 2 is aryl substituted with 0-5 groups independently selected from halo, hydroxyl, amino, nitro, cyano, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 polyhaloalkoxy, C1-C6 alkylthio, C1-C6 haloalkythio, C1-C6 polyhaloalkylthio, C1-C6 alkylamino, C1-C6 dialkylamino, (C1-C6)-alkyl-(C1-C6)-alkoxy, (C1-C6)-alkyl-(C1-C6)-haloalkoxy, (C1-C6)-alkyl-(C1-C6)-polyhaloalkoxy, (C1-C6)-alkyl-(C1-C6)-alkylthio, (C1-C6)-alkyl-(C1-C6)-haloalkythio, (C1-C6)-alkyl-(C1-C6)-polyhaloalkylthio, CO 2 H, (C═O)OR 11 , and (C═O)NHR 11 ;
wherein R 3 is a pentafluorophenyl; and
wherein each of R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , and R 11 is independently selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein the compound exhibits inhibition of STAT with an IC 50 of less than about 300 μM.
3. The compound of claim 1 , wherein the compound exhibits inhibition of STAT with an K i of less than about 300 μM.
4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
5. The compound of claim 1 , wherein the compound has a structure represented by a formula:
wherein R 2 is selected from a structure represented by a formula:
—(CH 2 ) 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH 2 CH═CH 2 ,
6. A compound having a structure represented by a formula:
wherein each of m is 0 and n is 0;
wherein R 1 is selected from a structure represented by a formula:
wherein R 2 is selected from a structure represented by a formula:
—CH 3 , —CH 2 (C═O)NH 2 , —CH 2 CH═CH 2 , —(CH 2 ) 2 CH 3 , —CH 2 CH(CH 3 ) 2 ,
or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.