SALICYCLIC ACID DERIVATIVES, PHARMACEUTICALLY ACCEPTABLE SALT THEREOF, COMPOSITION THEREOF AND METHOD OF USE THEREOF

摘要

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.;

主权项

1. A compound of formula 1: or a pharmaceutically acceptable salt, solvate or prodrug thereof, wherein wherein each of m and n are independently an integer from 0-3; wherein R1 is selected from A1, A2, -(A1)-(A2), -(A2)-(A3), -(A3)-(A2), -(A3)-(A4), -(A5)-(A1)-(A7), -(A5)-(A2)-(A8), -(A5)-(A3)-(A7), and -(A5)-(A6)-L-(A7); wherein A1 is C3-6 cycloalkyl, and substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C1-6 haloalkyl, C1-6 polyhaloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 polyhaloalkoxy, C1-6 alkylthio, C1-6 haloalkythio, C1-6 polyhaloalkylthio, C1-6 alkylamino, C1-6 dialkylamino, (C1-6)-alk-(C1-6)-alkoxy, (C1-6)-alk-(C1-6)-haloalkoxy, (C1-6)-alk-(C1-6)-polyhaloalkoxy, (C1-6)-alk-(C1-6)-alkylthio, (C1-6)-alk-(C1-6)-haloalkythio, (C1-6)-alk-(C1-6)-polyhaloalkylthio, CO2H, (C═O)R5, (C═O)OR5, and (C═O)NHR5; wherein A2 is C3-6 cycloalkyl or heterocycloalkyl, substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C1-6 haloalkyl, C1-6 polyhaloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 polyhaloalkoxy, C1-6 alkylthio, C1-6 haloalkythio, C1-6 polyhaloalkylthio, C1-6 alkylamino, C1-6 dialkylamino, (C1-6)-alk-(C1-6)-alkoxy, (C1-6)-alk-(C1-6)-haloalkoxy, (C1-6)-alk-(C1-6)-polyhaloalkoxy, (C1-6)-alk-(C1-6)-alkylthio, (C1-6)-alk-(C1-6)-haloalkythio, (C1-6)-alk-(C1-6)-polyhaloalkylthio, CO2H, (C═O)R6, (C═O)OR6, and (C═O)NHR6; wherein A3 is aryl, and substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C1-6 haloalkyl, C1-6 polyhaloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 polyhaloalkoxy, C1-6 alkylthio, C1-6 haloalkythio, C1-6 polyhaloalkylthio, C1-6 alkylamino, C1-6 dialkylamino, (C1-6)-alk-(C1-6)-alkoxy, (C1-6)-alk-(C1-6)-haloalkoxy, (C1-6)-alk-(C1-6)-polyhaloalkoxy, (C1-6)-alk-(C1-6)-alkylthio, (C1-6)-alk-(C1-6)-haloalkythio, (C1-6)-alk-(C1-6)-polyhaloalkylthio, CO2H, (C═O)R7, (C═O)OR7, and (C═O)NHR7; wherein A4 is aryl, and substituted with 1-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C1-6 haloalkyl, C1-6 polyhaloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 polyhaloalkoxy, C1-6 alkylthio, C1-6 haloalkythio, C1-6 polyhaloalkylthio, C1-6 alkylamino, C1-6 dialkylamino, (C1-6)-alk-(C1-6)-alkoxy, (C1-6)-alk-(C1-6)-haloalkoxy, (C1-6)-alk-(C1-6)-polyhaloalkoxy, (C1-6)-alk-(C1-6)-alkylthio, (C1-6)-alk-(C1-6)-haloalkythio, (C1-6)-alk-(C1-6)-polyhaloalkylthio, CO2H, (C═O)R8, (C═O)OR8, and (C═O)NHR8; wherein A5 is selected from C3-6 cycloalkyl, C3-6 heterocycloalkyl, and aryl, and substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C1-6 haloalkyl, C1-6 polyhaloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 polyhaloalkoxy, C1-6 alkylthio, C1-6 haloalkythio, C1-6 polyhaloalkylthio, C1-6 alkylamino, C1-6 dialkylamino, (C1-6)-alk-(C1-6)-alkoxy, (C1-6)-alk-(C1-6)-haloalkoxy, (C1-6)-alk-(C1-6)-polyhaloalkoxy, (C1-6)-alk-(C1-6)-alkylthio, (C1-6)-alk-(C1-6)-haloalkythio, (C1-6)-alk-(C1-6)-polyhaloalkylthio, CO2H, (C═O)R9, (C═O)OR9, and (C═O)NHR9; wherein A6 is selected from C3-6 cycloalkyl, C3-6 heterocycloalkyl, and aryl, and substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C1-6 haloalkyl, C1-6 polyhaloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 polyhaloalkoxy, C1-6 alkylthio, C1-6 haloalkythio, C1-6 polyhaloalkylthio, C1-6 alkylamino, C1-6 dialkylamino, (C1-6)-alk-(C1-6)-alkoxy, (C1-6)-alk-(C1-6)-haloalkoxy, (C1-6)-alk-(C1-6)-polyhaloalkoxy, (C1-6)-alk-(C1-6)-alkylthio, (C1-6)-alk-(C1-6)-haloalkythio, (C1-6)-alk-(C1-6)-polyhaloalkylthio, CO2H, (C═O)R10, (C═O)OR10, and (C═O)NHR10; wherein A7 is selected from C3-6 cycloalkyl, C3-6 heterocycloalkyl, and aryl, and substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, cyano, C1-6 haloalkyl, C1-6 polyhaloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 polyhaloalkoxy, C1-6 alkylthio, C1-6 haloalkythio, C1-6 polyhaloalkylthio, C1-6 alkylamino, C1-6 dialkylamino, (C1-6)-alk-(C1-6)-alkoxy, (C1-6)-alk-(C1-6)-haloalkoxy, (C1-6)-alk-(C1-6)-polyhaloalkoxy, (C1-6)-alk-(C1-6)-alkylthio, (C1-6)-alk-(C1-6)-haloalkythio, (C1-6)-alk-(C1-6)-polyhaloalkylthio, CO2H, (C═O)R11, (C═O)OR11, and (C═O)NHR11; wherein A8 is selected from C3-6 cycloalkyl, C3-6 heterocycloalkyl, and aryl, and substituted with 0-3 groups selected from halo, hydroxyl, amino, nitro, C1-6 haloalkyl, C1-6 polyhaloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 polyhaloalkoxy, C1-6 alkylthio, C1-6 haloalkythio, C1-6 polyhaloalkylthio, C1-6 alkylamino, C1-6 dialkylamino, (C1-6)-alk-(C1-6)-alkoxy, (C1-6)-alk-(C1-6)-haloalkoxy, (C1-6)-alk-(C1-6)-polyhaloalkoxy, (C1-6)-alk-(C1-6)-alkylthio, (C1-6)-alk-(C1-6)-haloalkythio, (C1-6)-alk-(C1-6)-polyhaloalkylthio, CO2H, (C═O)R12, (C═O)OR12, and (C═O)NHR12; wherein L is selected from —(C=0)- and —SO2—; wherein R2 is selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C1-6 haloalkyl, C2-6 haloalkenyl, C2-6 haloalkynyl, C1-6 polyhaloalkyl, C2-6 polyhaloalkenyl, C2-6 polyhaloalkynyl; or wherein R2 is aryl, and substituted with 0-5 groups independently selected from halo, hydroxyl, amino, nitro, cyano, C1-6 haloalkyl, C1-6 polyhaloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 polyhaloalkoxy, C1-6 alkylthio, C1-6 haloalkythio, C1-6 polyhaloalkylthio, C1-6 alkylamino, C1-6 dialkylamino, (C1-6)-alk-(C1-6)-alkoxy, (C1-6)-alk-(C1-6)-haloalkoxy, (C1-6)-alk-(C1-6)-polyhaloalkoxy, (C1-6)-alk-(C1-6)-alkylthio, (C1-6)-alk-(C1-6)-haloalkythio, (C1-6)-alk-(C1-6)-polyhaloalkylthio, CO2H, (C═O)OR12, and (C═O)NHR12; wherein R3 is aryl substituted with 0-5 groups independently selected from halo, hydroxyl, amino, nitro, cyano, C1-6 alkyl, C1-6 haloalkyl, C1-6 polyhaloalkyl, C1-6 alkoxy, C1-6 haloalkoxy, C1-6 polyhaloalkoxy, C1-6 alkylamino, C1-6 dialkylamino, (C1-6)-alk-(C1-6)-alkoxy, (C1-6)-alk-(C1-6)-haloalkoxy, and (C1-6)-alk-(C1-6)-polyhaloalkoxy; wherein each of R5, R6, R7, R8, R9, R10, R11, and R11 is independently selected from hydrogen, C1-6 alkyl, C1-6 haloalkyl, and C1-6 polyhaloalkyl; or a pharmaceutically acceptable salt, hydrate, solvate, or polymorph thereof, wherein R2 is selected from the group consisting of: Wherein R3 is selected from the structure represented by formula: Wherein R4 is a structure represented by formula: wherein R13 is selected from the group consisting of —OH, —COR16, —CN, —CH2PO(OH)2, —CH2P(O)3(CH2CH3)2, —NO2, —NHR17, and 1H-tetrazole; R16 is selected from the group consisting of: —OH, —O—C(1-2)alkyl, —OCH2OC(O)CH3, —OCH2OC(O)t-Butyl, and —NHOH, R17 is selected from the group consisting of: —H, —C(O)C(O)CH2CH3, —C(O)C(O)OH, and —C(O)CH2-1H-tetrazole R14 is —H or when R13 is —COOH, R14 is —F, —OC(O)CH3; and R13 is —H when R14 is —OH or both R14 and R15 are —COOH.