Substituted benzo[f]imidazo[1,5-a][1,4]diazepines as GABA(a) receptor modulators

Patent metadata

Field	Value
Publication number	US-12054491-B2
Application number	US-202217886403-A
Country	US
Kind code	B2
Filing date	Aug 11, 2022
Priority date	Aug 16, 2016
Publication date	Aug 6, 2024
Grant date	Aug 6, 2024

Abstract

The present invention describes substituted benzo[f]imidazo[1,5-a][1,4]diazepines of the formula (I):

wherein R 1 , R 2 , R 2′ , R 3 , and X are as disclosed herein. These compounds target alpha-4 and alpha-5 GABAa receptors and are useful for the treatment of airway hyperresponsiveness and inflammation in asthma.

First claim

We claim:

1. A method for reducing airway constriction in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R 1 is C(O)OH;
R 2 is C 1-4 alkyl, CF 3 , or CCl 3 ;
R 2′ is H, C 1-4 alkyl, CF 3 , or CCl 3 ;
R 3 is Cl, Br, or cyclopropyl; and
X is CF, CCl, CBr, CI, or N.

2. The method of claim 1 , wherein the compound, or stereoisomer thereof, is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

3. The method of claim 2 , wherein the compound, or stereoisomer thereof, is:

or a pharmaceutically acceptable salt thereof.

4. A method for reducing development of disease in a subject having risk factors associated with lung inflammation, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R 1 is C(O)OH;
R 2 is C 1-4 alkyl, CF 3 , or CCl 3 ;
R 2′ is H, C 1-4 alkyl, CF 3 , or CCl 3 ;
R 3 is Cl, Br, or cyclopropyl; and
X is CF, CCl, CBr, CI, or N.

5. The method of claim 4 , wherein the compound, or stereoisomer thereof, is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

6. The method of claim 5 , wherein the compound, or stereoisomer thereof, is:

or a pharmaceutically acceptable salt thereof.

7. A method for reducing lung inflammation in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R 1 is C(O)OH;
R 2 is C 1-4 alkyl, CF 3 , or CCl 3 ;
R 2′ is H, C 1-4 alkyl, CF 3 , or CCl 3 ;
R 3 is Cl, Br, or cyclopropyl; and
X is CF, CCl, CBr, CI, or N.

8. The method of claim 7 , wherein the compound, or stereoisomer thereof, is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

9. The method of claim 8 , wherein the compound, or stereoisomer thereof, is:

or a pharmaceutically acceptable salt thereof.

10. A method for treating lung disease in a subject, wherein the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof,
wherein:
R 1 is C(O)OH;
R 2 is C 1-4 alkyl, CF 3 , or CCl 3 ;
R 2′ is H, C 1-4 alkyl, CF 3 , or CCl 3 ;
R 3 is Cl, Br, or cyclopropyl; and
X is CF, CCl, CBr, CI, or N.

11. The method of claim 10 , wherein the compound, or stereoisomer thereof, is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

12. The method of claim 11 , wherein the compound, or stereoisomer thereof, is:

or a pharmaceutically acceptable salt thereof.

Assignees

• Uwm Res Foundation Inc
• Univ Columbia

Inventors

• Arnold Alexander E
• Stafford Douglas C
• Cook James M
• Emala Charles W
• Forkuo Gloria
• Jahan Rajwana
• Kodali Revathi
• Li Guanguan
• Stephen Michael Rajesh

Classifications

• C07D487/04 Primary

  Ortho-condensed systems · CPC title

• A61P11/06

  Antiasthmatics · CPC title

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P11/08

  Bronchodilators · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title