Heterocyclic compounds as biogenic amine transport modulators

Patent metadata

Field	Value
Publication number	US-9873702-B2
Application number	US-201514960012-A
Country	US
Kind code	B2
Filing date	Dec 4, 2015
Priority date	Dec 5, 2014
Publication date	Jan 23, 2018
Grant date	Jan 23, 2018

Abstract

The present disclosure relates to certain amine derivatives of fused bicyclic heterocycles that inhibit the amine reuptake function of the biogenic amine transporters, dopamine transporter (DAT), serotonin transporter (SERT) and norepinephrine transporter (NET). Compounds of the present disclosure are potent inhibitors of the reuptake of dopamine (DA), serotonin (5-hydroxytryptamine, 5-HT) and norepinephrine (NE) with full or partial maximal efficacy. The compounds with partial maximal efficacy in inhibiting reuptake of all three biogenic amines are herein referred to as partial triple uptake inhibitors (PTRIs). Compounds of the present disclosure are useful for treating depression, pain and substance abuse and relapse to substance abuse and addiction to substances such as cocaine, methamphetamine, nicotine and alcohol. 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.

First claim

What is claimed is:

1. A compound having the formula (II)

wherein
n is 0, 1 or 2;
m is 0, 1 or 2;
R 2 is H or lower alkyl group;
Ar is a phenyl or heterocyclic group;
R 3 is H, alkyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl, or heteroarylalkyl;
R 4 is H, alkyl, hydroxy, alkoxy, aryloxy, heteroaryloxy, amino, alkylamino or dialkylamino, provided that R 3 and R 4 are not simultaneously H; or
R 3 and R 4 together form a carbocycle or heterocycle;
R 5 is H, halogen, alkyl, aryl, hydroxy, alkoxy, aryloxy, amino, alkylamino or dialkylamino; and

represents a bicyclic heterocycle wherein X is a nitrogen or a carbon atom; wherein each of L and E are independently selected from CR′R″, N, O, and S; wherein each of J and G are independently selected from CR′ and N;
wherein each occurrence of R′ and R″ are independently selected from hydrogen and C1-C4 alkyl;

wherein Y is selected from S, O, CR′, CR′R″, and NR 14 ; wherein Q is selected from S, O, NR′, C═O, CR′R′″, and CR 15 ; wherein M is selected from S, O, NR′, CR′R′″, and CR 16 ;
wherein A is selected from NR′, CR′R″, and CR 17 ;
wherein R 14 is H, lower alkyl, acyl, sulfonyl, aryl, or heteroaryl; wherein each of R 15 , R 16 and R 17 are independently H, halogen, lower alkyl, hydroxy, alkoxy, aryloxy, acyl, sulfonyl, aryl, heteroaryl, amino, alkylamino or dialkylamino;
wherein each occurrence of R′″ is independently selected from hydrogen and C1-C4 alkyl, or wherein each occurrence of R′″, together with the intermediate carbon atoms, comprise a 6-membered ring,

with unsaturation allowed for appropriate valence, pharmaceutically acceptable salts thereof, deuterated forms thereof, and mixtures thereof.

2. A compound selected from the group consisting of:
2-(2-(Dimethylamino)pyrimidin-5-yl)-N-(2,2-diphenylethyl)quinazolin-4-amine;
N-(2,2-Diphenylethyl)-2-(1H-indol-5-yl)quinazolin-4-amine;
N-(3,3-Diphenylpropyl)-2-(1H-indol-5-yl)quinazolin-4-amine;
N-(2,2-Diphenylethyl)-2-(1H-indol-5-yl)-6,7-dimethoxyquinazolin-4-amine;
N-(2,2-Diphenylethyl)-2-(2-methoxypyrimidin-5-yl)quinazolin-4-amine;
N-(2,2-Diphenylethyl)-2-(2-(methylthio)pyrimidin-5-yl)quinazolin-4-amine;
N-(2,2-Diphenylethyl)-2-(pyridin-4-yl)quinazolin-4-amine;
N-(2,2-Diphenylethyl)-2-(2-(methylamino)pyrimidin-5-yl)quinazolin-4-amine;
N-(2,2-Diphenylethyl)-2-(1H-imidazol-1-yl)quinazolin-4-amine;
N-(2,2-Diphenylethyl)-2-(quinolin-6-yl)quinazolin-4-amine;
N-(2,2-Diphenylethyl)-2-(imidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine;
N-(2,2-Diphenylethyl)-2-(1-methyl-1H-benzo[d]imidazol-6-yl)quinazolin-4-amine;
N-(2,2-Diphenylethyl)-2-(2-methyl-2H-indazol-5-yl)quinazolin-4-amine;
N-(2,2-Diphenylethyl)-2-(1-methyl-1H-indazol-5-yl)quinazolin-4-amine;
2-(6-(Dimethylamino)pyridin-3-yl)-N-(2,2-diphenylethyl)quinazolin-4-amine;
2-(Benzo[d]thiazol-6-yl)-N-(2,2-diphenylethyl)quinazolin-4-amine;
N-(2,2-Diphenylethyl)-2-(1-methyl-1H-indol-5-yl)quinazolin-4-amine;
5-(4-((2,2-Diphenylethyl)amino)quinazolin-2-yl)indolin-2-one;
2-((2-(2-(Dimethylamino)pyrimidin-5-yl)quinazolin-4-yl)amino)-1,1-diphenylethanol;
2-((2-(1H-Indol-5-yl)quinazolin-4-yl)amino)-1,1-diphenylethanol;
N-(2,2-Diphenylethyl)-2-(indolin-5-yl)quinazolin-4-amine;
2-(6-Aminopyridin-3-yl)-N-(2,2-diphenylethyl)quinazolin-4-amine;
N-(2,2-Diphenylethyl)-2-(imidazo[1,2-a]pyrimidin-6-yl)quinazolin-4-amine;
2-(2,3-Dimethylimidazo[1,2-a]pyridin-6-yl)-N-(2,2-diphenylethyl)quinazolin-4-amine;
N-Benzhydryl-2-(6-(dimethylamino)pyridin-3-yl)quinazolin-4-amine;
2-(6-(Dimethylamino)pyridin-3-yl)-N-(3,3-diphenylpropyl)quinazolin-4-amine;
2-(Imidazo[1,2-a]pyridin-6-yl)-N-(2-phenyl-2-(pyridin-2-yl)ethyl)quinazolin-4-amine;
2-((2-(Imidazo[1,2-a]pyridin-6-yl)quinazolin-4-yl)amino)-1,1-diphenylethanol;
2-(Imidazo[1,2-a]pyrimidin-6-yl)-N-(2-phenyl-2-(pyridin-2-yl)ethyl)quinazolin-4-amine;
2-((2-(Imidazo[1,2-a]pyrimidin-6-yl)quinazolin-4-yl)amino)-1,1-diphenylethanol;
N-(2-Cyclohexyl-2-phenylethyl)-2-(imidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine;
N-(2-Cyclohexyl-2-phenylethyl)-2-(imidazo[1,2-a]pyrimidin-6-yl)quinazolin-4-amine;
2-([1,2,4]Triazolo[1,5-a]pyridin-6-yl)-N-(2,2-diphenylethyl)quinazolin-4-amine;
2-(Imidazo[1,2-a]pyridin-6-yl)-N-(2-phenyl-2-(pyridin-4-yl)ethyl)quinazolin-4-amine;
2-(Imidazo[1,2-a]pyrimidin-6-yl)-N-(2-phenyl-2-(pyridin-4-yl)ethyl)quinazolin-4-amine;
2-(Imidazo[1,2-a]pyridin-6-yl)-N-(2-phenyl-2-(1H-pyrrol-2-yl)ethyl)quinazolin-4-amine;
N-(2,2-Diphenylethyl)-2-(7-methylimidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine;
N-(2,2-Diphenylethyl)-2-(1H-pyrrolo[2,3-b]pyridin-5-yl)quinazolin-4-amine;
N-(2,2-Diphenylethyl)-7-fluoro-2-(imidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine hydrochloride;
2-(Imidazo[1,2-a]pyrimidin-6-yl)-N-(2-(4-methylpiperazin-1-yl)-2-phenylethyl)quinazolin-4-amine;
2-(1H-Indol-5-yl)-N-(2-phenyl-2-(pyridin-3-yl)ethyl)quinazolin-4-amine;
2-(Imidazo[1,2-a]pyridin-6-yl)-N-(2-phenyl-2-(pyridin-3-yl)ethyl)quinazolin-4-amine;
2-(Imidazo[1,2-a]pyrimidin-6-yl)-N-(2-phenyl-2-(pyridin-3-yl)ethyl)quinazolin-4-amine;
N-(2,3-Diphenylpropyl)-2-(imidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine;
2-(1-Methyl-1H-indol-5-yl)-N-(2-phenyl-2-(pyridin-3-yl)ethyl)quinazolin-4-amine;
N-(5-(4-((2,2-Diphenylethyl)amino)quinazolin-2-yl)pyridin-2-yl)methanesulfonamide;
2-(7-Methylimidazo[1,2-a]pyridin-6-yl)-N-(2-phenyl-2-(1H-pyrrol-2-yl)ethyl)quinazolin-4-amine;
N-(2,2-Diphenylethyl)-2-(quinolin-8-yl)quinazolin-4-amine;
N-(2,3-Diphenylpropyl)-2-(imidazo[1,2-a]pyrimidin-6-yl)quinazolin-4-amine;
2-(7-Methylimidazo[1,2-a]pyridin-6-yl)-N-(2-phenyl-2-(pyridin-4-yl)ethyl)quinazolin-4-amine;
2-((2-(7-Methylimidazo[1,2-a]pyridin-6-yl)quinazolin-4-yl)amino)-1,1-diphenylethanol;
1-(2-((2-(Imidazo[1,2-a]pyridin-6-yl)quinazolin-4-yl)amino)-1-(4-methoxyphenyl)ethyl)cyclohexanol;
2-(7-Methylimidazo[1,2-a]pyridin-6-yl)-N-(2-(pyridin-3-yl)-2-(1H-pyrrol-2-yl)ethyl)quinazolin-4-amine;
N-(2,2-Di(pyridin-4-yl)ethyl)-2-(7-methylimidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine;
(S)-2-(7-Methylimidazo[1,2-a]pyridin-6-yl)-N-(2-phenyl-2-(1H-pyrrol-1-yl)ethyl)quinazolin-4-amine;
2-(6,7-Dihydro-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)-N-(2,2-diphenylethyl)quinazolin-4-amine;
N-(2,2-Diphenylpropyl)-2-(imidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine;
N-(1,2-Diphenylethyl)-2-(imidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine;
N-(1,3-Diphenylpropyl)-2-(imidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine;
N-(1,3-Diphenylpropyl)-2-(7-methylimidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine;
2-(Imidazo[1,2-a]pyridin-6-yl)-N-(3-methyl-2-phenylbutyl)quinazolin-4-amine;
N-(3-Methyl-2-phenylbutyl)-2-(7-methylimidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine;
N-(1,2-Diphenylethyl)-2-(7-methylimidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine;
N-(2,2-Di(pyridin-4-yl)ethyl)-2-(6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-5(4H)-yl)quinazolin-4-amine;
2-(7-Methylimidazo[1,2-a]pyridin-6-yl)-N-(2-phenoxy-2-phenylethyl)quinazolin-4-amine;
N-(2,2-Diphenylpropyl)-2-(7-methylimidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine;
N-(2-Cyclopropyl-2-phenylethyl)-2-(7-methylimidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine;
N-(2-Benzyl-3-phenylpropyl)-2-(7-methylimidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine;
2-(7-Methylimidazo[1,2-a]pyridin-6-yl)-N-(2-phenylpropyl)quinazolin-4-amine;
2-(7-Methylimidazo[1,2-a]pyridin-6-yl)-N-(2-(pyridin-4-yl)-2-(1H-pyrrol-2-yl)ethyl)quinazolin-4-amine;
2-((2-(7-Methylimidazo[1,2-a]pyridin-6-yl)quinazolin-4-yl)amino)-1-phenylethanol;
N-(2-Methoxy-2-phenylethyl)-2-(7-methylimidazo[1,2-a]pyridin-6-yl)quinazolin-4-amine;
2-(7-Methylimidazo[1,2-a]pyridin-6-yl)-N-(2-phenylbutyl)quinazolin-4-amine;
N-(2,2-Diphenylethyl)-2-(isoindol

Assignees

• Ananthan Subramaniam
• Rothman Richard B
• Southern Res Inst
• Us Health

Inventors

• Ananthan Subramaniam
• Rothman Richard B

Classifications

• A61P25/30

  for treating abuse or dependence · CPC title

• A61P25/32

  Alcohol-abuse · CPC title

• A61P25/24

  Antidepressants · CPC title

• A61P25/04

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

• A61P25/34

  Tobacco-abuse · CPC title