Modulators of TNF-alpha activity

Inventors: Toufike Kanouni (Palm Beach Gardens, FL); Yoshiyuki Fukase (San Diego, CA)

Assignee: FORWARD THERAPEUTICS, INC.

A61K31/395 C07D405/04

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Quick Facts

Patent No.: US 12691095
App. No.: 19/370,127
Granted: Jul 28, 2026
Kind: B2

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Abstract

Provided herein are inhibitors of TNF-alpha, pharmaceutical compositions comprising the inhibitory compounds, and methods for using the TNF-alpha inhibitory compounds for the treatment of diseases or disorders.

Claims (52)

1 . A compound selected from the group consisting of:

(7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-1-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one;

(7R,14R)-11-(4-(dimethylphosphoryl)-2,5-difluorophenyl)-1-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one;

(7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-1,3-difluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one;

(7R,14R)-11-(4-(dimethylphosphoryl)-2,3-difluorophenyl)-1-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one;

(7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-1,2-difluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one;

(7R,14R)-11-(4-(dimethylphosphoryl)phenyl)-1-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one;

(7R,14R)-11-(4-(dimethylphosphoryl)-2-fluorophenyl)-1-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one;

(7R,14R)-11-(4-(dimethylphosphoryl)phenyl)-1,10-difluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one;

(7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-1-fluoro-7-methyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one;

(7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-1,10-difluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one;

(7R,14R)-11-(3-amino-4-(dimethylphosphoryl)phenyl)-1-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one; and

(7R,14R)-11-(4-(dimethylphosphoryl)-3-(methylamino)phenyl)-1-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one;

or a pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof.

2 . The compound of claim 1 , wherein the compound is (7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-1-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one, or a pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof.

3 . The compound of claim 1 , wherein the compound is (7R,14R)-11-(4-(dimethylphosphoryl)-2,5-difluorophenyl)-1-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one, or a pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof.

4 . The compound of claim 1 , wherein the compound is (7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-1,3-difluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one, or a pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof.

5 . The compound of claim 1 , wherein the compound is (7R,14R)-11-(4-(dimethylphosphoryl)-2,3-difluorophenyl)-1-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one, or a pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof.

6 . The compound of claim 1 , wherein the compound is (7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-1,2-difluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one, or a pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof.

7 . The compound of claim 1 , wherein the compound is (7R,14R)-11-(4-(dimethylphosphoryl)phenyl)-1-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one, or a pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof.

8 . The compound of claim 1 , wherein the compound is (7R,14R)-11-(4-(dimethylphosphoryl)-2-fluorophenyl)-1-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one, or a pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof.

9 . The compound of claim 1 , wherein the compound is (7R,14R)-11-(4-(dimethylphosphoryl)phenyl)-1,10-difluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one, or a pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof.

10 . The compound of claim 1 , wherein the compound is (7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-1-fluoro-7-methyl-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one, or a pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof.

11 . The compound of claim 1 , wherein the compound is (7R,14R)-11-(4-(dimethylphosphoryl)-3-fluorophenyl)-1,10-difluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one, or a pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof.

12 . The compound of claim 1 , wherein the compound is (7R,14R)-11-(3-amino-4-(dimethylphosphoryl)phenyl)-1-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one, or a pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof.

13 . The compound of claim 1 , wherein the compound is (7R,14R)-11-(4-(dimethylphosphoryl)-3-(methylamino)phenyl)-1-fluoro-6-(methyl-d3)-6,7-dihydro-7,14-methanobenzo[f]benzo[4,5]imidazo[1,2-a][1,4]diazocin-5(14H)-one, or a pharmaceutically acceptable salt, solvate, deuteroisotope, or N-oxide thereof.

14 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient, and a compound selected from the group consisting of: