Indazole ureas and method of use

Patent metadata

Field	Value
Publication number	US-9783527-B2
Application number	US-201514854433-A
Country	US
Kind code	B2
Filing date	Sep 15, 2015
Priority date	Sep 16, 2014
Publication date	Oct 10, 2017
Grant date	Oct 10, 2017

Abstract

Compounds of formula (I)

and pharmaceutically acceptable salts, esters, amides, or radiolabelled forms thereof, wherein A, R 1 and R 2 are as defined in the specification, are useful in treating conditions or disorders prevented by or ameliorated by voltage-gated sodium channels, e.g., Na v 1.7 and/or Na v 1.8. Methods for making the compounds are disclosed. Also disclosed are pharmaceutical compositions of compounds of formula (I), and methods for using such compounds and compositions.

First claim

What is claimed is:

1. A compound of formula (I):

or a pharmaceutically acceptable salt or isotopically labelled form thereof, wherein:
A is selected from the group consisting of (i), (ii), (iii), and (iv), wherein the nitrogen atom on the left side of each substructure (i), (ii), (iii), or (iv) is attached to the phenyl ring of the indazole in formula (I);

R 1a is hydrogen or C 1 -C 4 alkyl;
R 1 is selected from the group consisting of C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C 3 -C 7 cycloalkyl, phenyl and monocyclic heteroaryl, wherein the phenyl and monocyclic heteroaryl are optionally substituted with 1, 2, 3, or 4 substituents selected from the group consisting of C 1 -C 4 alkoxy, C 1 -C 4 alkyl, C 1 -C 4 haloalkoxy, C 1 -C 4 haloalkyl, and halogen;
R 2 is selected from the group consisting of hydrogen, C 1 -C 8 alkenyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, -G 1 , -G 2 , -G 3 , -G 4 , —CO 2 R 2c , —CO 2 G 1 , —C(O)R 2c , —C(O)G 1 , —C(O)G 2 , —C(O)G 3 , —C(O)G 4 , —C(O)(CR 2a R 2b ) m G 1 , —C(O)(CR 2a R 2b ) m G 2 , —C(O)(CR 2a R 2b ) m —OR 2c , —C(OH)(R 2d )—R 2c , —C(OH)(R 2d )-G 1 , —C(OH)(R 2d )—C(O)R 2c , —C(OH)(R 2d )—C(O)G 1 , —C(OH)(R 2d )—(CR 2a R 2b ) m G 1 , —SO 2 R 2c , —SO 2 G 1 , —SO 2 G 2 , —SO 2 G 3 , —SO 2 G 4 , —SO 2 —(CR 2a R 2b ) m G 1 , —SO 2 —(CR 2a R 2b ) m G 2 , —SO 2 —(CR 2a R 2b ) m G 3 , —SO 2 —(CR 2a R 2b ) m G 4 , —SO 2 NR 2d R 2e , —(CR 2a R 2b ) m —C(OH)(R 2d )-G 1 , —(CR 2a R 2b ) m —C(OH)(R 2d )-G 2 , —(CR 2a R 2b ) m —C(OH)(R 2d )-G 3 , —(CR 2a R 2b ) m —C(OH)(R 2d )-G 4 , —(CR 2a R 2b ) m —C(OH)(R 2d )—(CR 2a R 2b ) n -G 1 , —(CR 2a R 2b ) m —C(OH)(R 2d )—(CR 2a R 2b ) n -G 2 , —(CR 2a R 2b ) m —C(OH)(R 2d )—(CR 2a R 2b ) n -G 3 , —(CR 2a R 2b ) m —C(OH)(R 2d )—(CR 2a R 2b ) n -G 4 , —(CR 2a R 2b ) m C(O)R 2c , —(CR 2a R 2b ) m C(O)—(CR 2a R 2b ) n G 1 , —(CR 2a R 2b ) m C(O)(CR 2a R 2b ) n G 2 , —(CR 2a R 2b ) m C(O)(CR 2a R 2b ) n G 3 , —(CR 2a R 2b ) m C(O)(CR 2a R 2b ) n G 4 , —(CR 2a R 2b ) m CO 2 R 2c , —(CR 2a R 2b ) m CO 2 G 1 , —(CR 2a R 2b ) m C(O)G 1 , —(CR 2a R 2b ) m C(O)G 2 , —(CR 2a R 2b ) m C(O)G 3 , —(CR 2a R 2b ) m C(O)G 4 , —(CR 2a R 2b ) m C(O)NR 2d R 2e , —(CR 2a R 2b ) m C(O)NR 2d G 1 , —(CR 2a R 2b ) m C(O)NR 2d G 2 , —(CR 2a R 2b ) m C(O)NR 2d G 3 , —(CR 2a R 2b ) m C(O)NR 2d G 4 , —(CR 2a R 2b ) m C(O)N(R 2d )((CR 2a R 2b ) n G 1 ), —(CR 2a R 2b ) m C(O)N(R 2d )((CR 2a R 2b ) n G 2 ), —(CR 2a R 2b ) m C(O)N(R 2d )((CR 2a R 2b ) n G 3 ), —(CR 2a R 2b ) m C(O)N(R 2d )((CR 2a R 2b ) n G 4 ), —(CR 2a R 2b ) m SO 2 NR 2d R 2e , —(CR 2a R 2b ) m C(O)NH—(CR 2a R 2f )—C(O)NHR 2d , —CR 2a ═CHR 2a —CO 2 R 2c , —CR 2a ═CHR 2a —C(O)G 1 , and —CR 2a ═CHR 2a —C(O)G 3 ;
R 2a and R 2b , at each occurrence, are each independently selected from the group consisting of hydrogen, fluorine, C 1 -C 4 alkyl, and haloC 1 -C 4 alkyl;
R 2c is selected from the group consisting of C 2 -C 8 alkenyl, C 1 -C 8 alkyl and haloC 1 -C 8 alkyl;
R 2d , at each occurrence, is selected from the group consisting of hydrogen, C 1 -C 6 alkyl and haloC 1 -C 6 alkyl;
R 2e is selected from the group consisting of hydrogen, C 2 -C 8 alkenyl, C 1 -C 6 alkoxy, C 1 -C 4 alkoxyC 1 -C 4 alkyl, C 1 -C 6 alkyl, and haloC 1 -C 6 alkyl;
R 2f is selected from the group consisting of C 1 -C 4 alkyl, haloC 1 -C 4 alkyl and —(CR 2a R 2b ) m -G 2a ;
G 1 is C 3 -C 7 cycloalkyl, wherein the C 3 -C 7 cycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of C 1 -C 6 alkoxy, C 1 -C 4 alkyl, benzyloxy, haloC 1 -C 4 alkyl, halogen, hydroxy, hydroxyC 1 -C 4 alkyl, oxime, C 1 -C 6 alkyloxime, and oxo;
G 1a is C 3 -C 7 cycloalkyl, wherein the C 3 -C 7 cycloalkyl is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of C 1 -C 6 alkoxy, C 1 -C 4 alkyl, benzyloxy, haloC 1 -C 4 alkyl, halogen, hydroxy, hydroxyC 1 -C 4 alkyl, oxime, C 1 -C 6 alkyloxime, and oxo;
G 2 is aryl, wherein the aryl is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of C 1 -C 4 alkoxy, C 1 -C 4 alkyl, 1,3-dioxole, haloC 1 -C 4 alkyl, and halogen;
G 2a is aryl or 5-6-membered heteroaryl, wherein the aryl or 5-6-membered heteroaryl are optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of C 1 -C 4 alkoxy, C 1 -C 4 alkyl, 1,3-dioxole, haloC 1 -C 4 alkyl, and halogen;
G 3 is 4-8-membered-heterocycle, wherein the 4-8-membered-heterocycle is optionally substituted with 1, 2, 3, 4 or 5 substituents selected from the group consisting of C 1 -C 6 alkoxy, C 1 -C 4 alkoxyC 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 4 alkylcarbonyl, haloC 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfonyl, benzyl, cyano, 1,3-dioxolane, halogen, haloC 1 -C 4 alkyl, hydroxy, hydroxyC 1 -C 4 alkyl, oxo, —C(O)G 1a , —C(O)NHG 2a , —C(O)C(O)NH 2 , G 2a , —SO 2 (CR 2a R 2b ) m G 1a , and —(CR 2a R 2b ) p G 3a ;
G 3a is 4-8-membered-heterocycle, wherein the 4-8-membered-heterocycle is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of C 1 -C 4 alkoxy, C 1 -C 4 alkoxyC 1 -C 4 alkyl, C 1 -C 4 alkoxycarbonyl, C 1 -C 6 alkyl, C 1 -C 4 alkylcarbonyl, haloC 1 -C 4 alkylsulfonyl, C 1 -C 4 alkylsulfonyl, benzyl, cyano, 1,3-dioxolane, halogen, haloC 1 -C 4 alkyl, hydroxy, hydroxyC 1 -C 4 alkyl, oxo, —C(O)G 1a , —C(O)NHG 2a , —C(O)C(O)NH 2 , G 2a , and —SO 2 (CR 2a R 2b ) m G 1a ;
G 4 is 5-10-membered heteroaryl, wherein the 5-10-membered heteroaryl is optionally substituted with 1, 2, 3 or 4 substituents selected from the group consisting of C 1 -C 4 alkoxy, C 1 -C 4 alkoxyC 1 -C 4 alkyl, C 1 -C 4 alkyl, halogen, haloC 1 -C 4 alkyl, G 1a , and G 3a ;
m is 1, 2 or 3;
n is 1, 2 or 3; and
p is 1 or 2.

2. The compound of claim 1 , wherein, A is (i)

3. The compound of claim 2 , wherein R 1 is selected from the group consisting of C 1 -C 8 alkyl and C 3 -C 7 cycloalkyl.

4. The compound of claim 3 , wherein R 2 is selected from the group consisting of hydrogen, C 1 -C 8 alkenyl, C 1 -C 6 alkoxyC 1 -C 6 alkyl, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, —CO 2 R 2c , —C(O)R 2c , —C(O)(CR 2a R 2b ) m —OR 2c , —C(OH)(R 2d )—R 2c , —C(OH)(R 2d )—C(O)R 2c , —SO 2 R 2c , —SO 2 NR 2d R 2e , —(CR 2a R 2b ) m —C(OR 2d )(R 2d )—R 2e , —(CR 2a R 2b ) m C(O)R 2c , —(CR 2a R 2b ) m CO 2 R 2c , —(CR 2a R 2b ) m C(O)NR 2d R 2e , —(CR 2a R 2b ) m SO 2 NR 2d R 2e , —(CR 2a R 2b ) m C(O)NH—(CR 2a R 2f )—C(O)NHR 2d , and —CR 2a ═CHR 2a —CO 2 R 2c .

5. The compound of claim 3 , wherein R 2 is selected from the group consisting of -G 1 , -G 2 , -G 3 , -G 4 , —CO 2 G 1 , —C(O)G 1 , —C(O)G 2 , —C(O)G 3 , —C(O)G 4 , —C(O)(CR 2a R 2b ) m G 1 , —C(O)(CR 2a R 2b ) m G 2 , —C(OH)(R 2d )-G 1 , —C(OH)(R 2d )—C(O)G 1 , —C(OH)(R 2d )—(CR 2a R 2b ) m G 1 , —SO 2 G 1 , —SO 2 G 2 , —SO 2 G 3 , —SO 2 G 4 , —SO 2 —(CR 2a R 2b ) m G 1 , —SO 2 —(CR 2a R 2b ) m G 2 , —SO 2 —(CR 2a R 2b ) m G 3 , —SO 2 —(CR 2a R 2b ) m G 4 , —(CR 2a R 2b ) m G 1 , —(CR 2a R 2b ) m G 2 , —(CR 2a R 2b ) m G 3 , —(CR 2a R 2b ) m G 4 , —(CR 2a R 2b ) m —C(OH)(R 2d )-G 1 , —(CR 2a R 2b ) m —C(OH)(R 2d )-G 2 , —(CR 2a R 2b ) m —C(OH)(R 2d )-G 3 , —(CR 2a R 2b ) m —C(OH)(R 2d )-G 4 , —(CR 2a R 2b ) m —C(OH)(R 2d )—(CR 2a R 2b ) n -G 1 , —(CR 2a R 2b ) m —C(OH)(R 2d )—(CR 2a R 2b ) n -G 2 , —(CR 2a R 2b ) m —C(OH)(R 2d )—(CR 2a R 2b ) n -G 3 , —(CR 2

Assignees

• Abbvie Inc

Inventors

• Daanen Jerome F
• Degoey David A
• Frost Jennifer M
• Koenig John R
• Latshaw Steve
• Matulenko Mark
• Scanio Marc
• Shi Lei
• Bunnelle William H

Classifications

• A61P43/00

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

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P29/00

  Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] · CPC title

• A61P25/04

  Centrally acting analgesics, e.g. opioids · CPC title

• A61P1/04

  for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants · CPC title