3-ARYL-2H-PYRAZOLO[4,3-b]PYRIDINE COMPOUNDS AND THEIR USE AS AMPA RECEPTOR MODULATORS

Patent metadata

Field	Value
Publication number	US-2018111925-A1
Application number	US-201715790884-A
Country	US
Kind code	A1
Filing date	Oct 23, 2017
Priority date	Oct 26, 2016
Publication date	Apr 26, 2018
Grant date	—

Abstract

Provided herein are compounds of Formula (I), and pharmaceutically acceptable salts, N-oxides, or solvates thereof,

Also provided herein are pharmaceutical compositions comprising compounds of Formula (I) and methods of using compounds of Formula (I).

First claim

What is claimed:

1 . A compound of Formula (I):

wherein
R 1 is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, CH 2 CH 2 OCH 3 , C 3-8 cycloalkyl, CH 2 —C 3-8 cycloalkyl, phenyl and pyridyl;
R 2 is selected from the group consisting of: H, halo, and CH 3 ;
R 3 is C 1-6 haloalkyl;

is selected from the group consisting of: —CH═N—, —CH 2 —C(═O)—, —S—C(═O)—, and —NH—C(═O)—; and
R 5 is H or CHF 2 ; and
pharmaceutically acceptable salts, N-oxides, or solvates thereof.

2 . The compound of claim 1 , wherein R 1 is C 1-6 alkyl, C 1-6 haloalkyl, CH 2 CH 2 OCH 3 , CH 2 cyclobutyl, cyclobutyl, cyclopentyl, phenyl, or pyridin-2-yl.

3 . The compound of claim 1 , wherein R 2 is H, Cl or CH 3 .

4 . The compound of claim 1 , wherein R 3 is CF 3 .

5 . The compound of claim 1 , wherein R 3 is CF 2 H.

6 . The compound of claim 1 , wherein

is —CH═N—.

7 . The compound of claim 1 , wherein

is —CH 2 —C(═O)—.

8 . The compound of claim 1 , wherein

is —NH—C(═O)—.

9 . The compound of claim 1 , wherein

is —S—C(═O)—.

10 . The compound of claim 1 , wherein R 5 is H.

11 . The compound of claim 1 , wherein R 5 is CHF 2 .

12 . The compound of claim 1 , and pharmaceutically acceptable salts, solvates, or N-oxides thereof, having the structure of Formula (1A):

wherein
R 1 is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, CH 2 CH 2 OCH 3 , C 3-8 cycloalkyl, CH 2 —C 3-8 cycloalkyl, phenyl and pyridyl; and
R 4 is selected from the group consisting of:

13 . A compound selected from the group consisting of:
5-(2-Methyl-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 7-Methyl-5-(2-methyl-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)indolin-2-one; 5-[2-(Difluoromethyl)-5-(trifluoromethyl)pyrazolo[4,3-b]pyridin-3-yl]-7-methyl-indolin-2-one; 5-(2-Ethyl-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5-(2-Isopropyl-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5-(2-(Cyclobutylmethyl)-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5-(2-Cyclopentyl-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 2-Cyclopentyl-3-(7-methyl-1H-indazol-5-yl)-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridine; 5-(2-Phenyl-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)-1,3-dihydro-2H-benzo[d]imidazol-2-one; 5-(2-Phenyl-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)indolin-2-one; 3-(1H-Indazol-5-yl)-2-phenyl-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridine; 2-Cyclobutyl-3-(1H-indazol-5-yl)-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridine; 3-(1H-Indazol-5-yl)-2-(2-methoxyethyl)-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridine; 3-(1H-Indazol-5-yl)-2-(pyridin-2-yl)-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridine; 2-Methyl-3-(7-methyl-1H-indazol-5-yl)-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridine; 3-(7-Chloro-1H-indazol-5-yl)-2-methyl-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridine; 5-(2-Ethyl-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)-7-methylindolin-2-one; 7-Chloro-5-(2-ethyl-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)indolin-2-one; 2-Ethyl-3-(7-methyl-1H-indazol-5-yl)-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridine; 3-(7-Chloro-1H-indazol-5-yl)-2-ethyl-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridine; 5-(2-Isopropyl-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)-7-methylindolin-2-one; 7-Chloro-5-(2-isopropyl-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)indolin-2-one; 2-Isopropyl-3-(7-methyl-1H-indazol-5-yl)-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridine; 3-(7-Chloro-1H-indazol-5-yl)-2-isopropyl-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridine; 5-(2-Cyclobutyl-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)-7-methylindolin-2-one; 7-Chloro-5-(2-cyclobutyl-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)indolin-2-one; 2-Cyclobutyl-3-(7-methyl-1H-indazol-5-yl)-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridine; 3-(7-Chloro-1H-indazol-5-yl)-2-cyclobutyl-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridine; 7-Chloro-5-(2-(difluoromethyl)-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)indolin-2-one; 2-(Difluoromethyl)-3-(7-methyl-1H-indazol-5-yl)-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridine; 3-(7-Chloro-1H-indazol-5-yl)-2-(difluoromethyl)-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridine; 5-(Difluoromethyl)-2-isopropyl-3-(7-methyl-1H-indazol-5-yl)-2H-pyrazolo[4,3-b]pyridine; 7-Chloro-5-(5-(difluoromethyl)-2-isopropyl-2H-pyrazolo[4,3-b]pyridin-3-yl)indolin-2-one; 7-(Difluoromethyl)-2-isopropyl-3-(7-methyl-1H-indazol-5-yl)pyrazolo[4,3-b]pyridine; 3-(7-Chloro-1H-indazol-5-yl)-2-isopropyl-pyrazolo[4,3-b]pyridine; and 5,7-Bis(difluoromethyl)-2-isopropyl-3-(7-methyl-1H-indazol-5-yl)pyrazolo[4,3-b]pyridine; and pharmaceutically acceptable salts, N-oxides or solvates thereof.

14 . A compound selected from the group consisting of:
6-(2-Isopropyl-5-(trifluoromethyl)-2H-pyrazolo[4,3-b]pyridin-3-yl)benzo[d]thiazol-2(3H)-one; 3-(7-Chloro-1H-indazol-5-yl)-5-(difluoromethyl)-2-isopropyl-2H-pyrazolo[4,3-b]pyridine; 5-(5-(Difluoromethyl)-2-isopropyl-2H-pyrazolo[4,3-b]pyridin-3-yl)-7-methylindolin-2-one; and 6-(5-(Difluoromethyl)-2-isopropyl-2H-pyrazolo[4,3-b]pyridin-3-yl)benzo[d]thiazol-2(3H)-one; and pharmaceutically acceptable salts, N-oxides or solvates thereof.

15 . A pharmaceutical composition comprising:
(A) an effective amount of at least one compound of Formula (I):

wherein
R 1 is selected from the group consisting of: C 1-6 alkyl, C 1-6 haloalkyl, CH 2 CH 2 OCH 3 , C 3-8 cycloalkyl, CH 2 —C 3-8 cycloalkyl, phenyl and pyridyl;
R 2 is selected from the group consisting of: H, halo, and CH 3 ;
R 3 is C 1-6 haloalkyl;

is selected from the group consisting of: —CH═N—, —CH 2 —C(═O)—, —S—C(═O)—, and —NH—C(═O)—; and
R 5 is H or CHF 2 ; and
pharmaceutically acceptable salts, N-oxides or solvates of compounds of Formula (I); and
(B) at least one pharmaceutically acceptable excipient.

16 . A pharmaceutical composition comprising an effective amount of at least one compound of claim 13 and at least one pharmaceutically acceptable excipient.

17 . A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by AMPA receptor activity, comprising administering to a subject in need of such treatment an effective amoun

Assignees

• Janssen Pharmaceutica Nv

Inventors

• Ameriks Michael K
• Laforteza Brian Ngo
• Savall Brad M
• Wade Warren Stanfield
• Meyer Stephen Todd
• GYURIS Márió

Classifications

• C07D471/04

  Ortho-condensed systems · CPC title

• C07D417/14 Primary

  containing three or more hetero rings · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• A61P25/00

  Drugs for disorders of the nervous system · CPC title