SMALL MOLECULE INHIBITORS OF IL-6 AND USES THEREOF

摘要

In one aspect, the invention relates to substituted 2-(1H-indol-3-yl)ethanol analogs and substituted 3,3a,8,8a-tetrahydro-2H-furo[2,3-b]indole analogs, derivatives thereof, and related compounds, which are useful as inhibitors of IL-6 mediated activation of the Jak2/STAT3 pathway; synthetic methods for making the compounds; pharmaceutical compositions comprising the compounds; and methods of treating disorders of uncontrolled cellular proliferation associated with a IL6 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.

主权项

1. A compound having a structure represented by a formula: wherein m and n are integers independently selected from 1, 2, 3, 4, 5, and 6; wherein p is an integer selected from 1, 2 and 3; and wherein q is an integer selected from 0 and 1; wherein each of R1 and R2, when present, is independently selected from H and —OH; wherein R3 is selected from:
hydrogen, wherein L1 is —O— or —NH—;wherein L2 is CH2 or (C═O); andwherein R10 is selected from hydrogen, C1-C8 alkyl, C1-C8 alkoxy, —NR21R22, —O—Ar1, —NH—Ar1, —O—Cy1, and —NH—Cy1;
wherein Ar1 is phenyl or heteroaryl, and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NO2, —NH2, —NHCH3, —N(CH3)2, —NHCH2CH3, —N(CH2CH3)2, —N(CH3)(CH2CH3), C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy;wherein Cy1 is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NO2, —NH2, —NHCH3, —N(CH3)2, —NHCH2CH3, —N(CH2CH3)2, —N(CH3)(CH2CH3), C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy;wherein each of R21 and R22 is independently selected from hydrogen and C1-C6 alkyl; wherein R4 is selected from C1-C8 alkyl, C1-C8 alkoxy, —NR23R24, —O—Ar2, —NH—Ar2, —O-Cy2, and —NH-Cy2;
wherein Ar2 is phenyl or heteroaryl, and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NO2, —NH2, —NHCH3, —N(CH3)2, —NHCH2CH3, —N(CH2CH3)2, —N(CH3)(CH2CH3), C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy;wherein Cy2 is C3-C6 cycloalkyl or C2-C5 heterocycloalkyl, and substituted with 0, 1, 2, or 3 groups independently selected from halogen, —OH, —NO2, —NH2, —NHCH3, —N(CH3)2, —NHCH2CH3, —N(CH2CH3)2, —N(CH3)(CH2CH3), C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkoxy;wherein each of R23 and R24 is independently selected from hydrogen and C1-C6 alkyl; wherein each of R5, R6, R7, and R8 is independently selected from hydrogen, halogen, —OH, —NO2, —NR25R26, C1-C6 alkyl, C1-C6 haloalkyl, —(C1-C6 alkyl)-OH, and C1-C6 alkoxy; and
wherein each of R25 and R26 is independently selected from hydrogen and C1-C6 alkyl; wherein R11, when present, is selected from hydrogen and C1-C8 alkyl; or a pharmaceutically acceptable salt, solvate, or polymorph thereof.