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 m is an integer from 0-3 when R 2 is aryl;
wherein m=0 when R 2 is non-aryl;
wherein R 2 is selected from C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, C3-C8 haloalkenyl, C3-C8 haloalkynyl, C3-C8 polyhaloalkyl, C3-C8 polyhaloalkenyl, C3-C8 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)-alk-(C1-C6)-alkoxy, (C1-C6)-alk-(C1-C6)-haloalkoxy, (C1-C6)-alk-(C1-C6)-polyhaloalkoxy, (C1-C6)-alk-(C1-C6)-alkylthio, (C1-C6)-alk-(C1-C6)-haloalkythio, (C1-C6)-alk-(C1-C6)-polyhaloalkylthio, CO 2 H, (C═O)OR 11 , and (C═O)NHR 11 ;
wherein R 3 is aryl substituted with 0-5 groups independently selected from halo, hydroxyl, amino, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 polyhaloalkoxy, C1-C6 alkylamino, C1-C6 dialkylamino, (C1-C6)-alk-(C1-C6)-alkoxy, (C1-C6)-alk-(C1-C6)-haloalkoxy, and (C1-C6)-alk-(C1-C6)-polyhaloalkoxy; and
wherein R 11 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
or a pharmaceutically acceptable salt, hydrate, or polymorph 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 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. A method for the treatment of breast cancer or non-small cell lung cancer, comprising: administering to a subject in need thereof a therapeutically effective amount of a compound having a structure represented by a formula:
wherein m is an integer from 0-3 when R 2 is aryl;
wherein m=0 when R 2 is non-aryl;
wherein R 2 is selected from C3-C8 alkyl, C3-C8 alkenyl, C3-C8 alkynyl, C3-C8 haloalkyl, C3-C8 halo alkenyl, C3-C8 halo alkynyl, C3-C8 polyhaloalkyl, C3-C8 polyhaloalkenyl, C3-C8 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)-alk-(C1-C6)-alkoxy, (C1-C6)-alk-(C1-C6)-haloalkoxy, (C1-C6)-alk-(C1-C6)-polyhaloalkoxy, (C1-C6)-alk-(C1-C6)-alkylthio, (C1-C6)-alk-(C1-C6)-haloalkythio, (C1-C6)-alk-(C1-C6)-polyhaloalkylthio, CO 2 H, (C═O)OR 11 , and (C═O)NHR 11 ;
wherein R 3 is aryl substituted with 0-5 groups independently selected from halo, hydroxyl, amino, nitro, cyano, C1-C6 alkyl, C1-C6 haloalkyl, C1-C6 polyhaloalkyl, C1-C6 alkoxy, C1-C6 haloalkoxy, C1-C6 polyhaloalkoxy, C1-C6 alkylamino, C1-C6 dialkylamino, (C1-C6)-alk-(C1-C6)-alkoxy, (C1-C6)-alk-(C1-C6)-haloalkoxy, and (C1-C6)-alk-(C1-C6)-polyhaloalkoxy; and
wherein R 11 is selected from hydrogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 polyhaloalkyl;
or a pharmaceutically acceptable salt, hydrate, or polymorph thereof.
6. The method of claim 5 , wherein the subject has been diagnosed with breast cancer or non-small cell lung cancer prior to the administering step.
7. 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:
and
wherein R 3 is selected from a structure represented by a formula:
8. 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:
9. 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:
10. The compound of claim 1 , wherein the compound is selected from:
11. 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:
wherein R 3 is selected from a structure represented by a formula:
or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof.
12. The compound of claim 11 , wherein the compound has a structure represented by a formula:
wherein R 2 is selected from a structure represented by a formula:
wherein R 3 is selected from a structure represented by a formula:
13. The compound of claim 11 , wherein the compound has a structure represented by a formula:
wherein R 3 is selected from a structure represented by a formula:
14. The compound of claim 11 , wherein the compound is:
15. A method for the treatment of breast cancer or non-small cell lung cancer, comprising: administering to a subject in need thereof a therapeutically effective amount of 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:
wherein R 3 is selected from a structure represented by a formula:
or a pharmaceutically acceptable salt, hydrate, or polymorph thereof.
16. The method of claim 15 , wherein the subject has been diagnosed with breast cancer or non-small cell lung cancer prior to the administering step.