Carboxamides as inhibitors of voltage-gated sodium channels

Patent metadata

Field	Value
Publication number	US-9334269-B2
Application number	US-201113575912-A
Country	US
Kind code	B2
Filing date	Feb 16, 2011
Priority date	Feb 17, 2010
Publication date	May 10, 2016
Grant date	May 10, 2016

Abstract

The present invention provides compounds that are inhibitors of voltage-gated sodium channels (Nav), in particular Nav 1.7, and are therefore useful for the treatment of diseases treatable by inhibition of these channels, in particular, chronic pain disorders. Also provided are pharmaceutical compositions containing such compounds and processes for preparing such compounds.

First claim

What is claimed is:

1. A compound of Formula (I):

where:
X is —NH;
S, T and U are independently —CR 3 — or —N—; selected from:

A is phenyl;
R 1 is hydrogen, alkyl, haloalkyl, substituted alkyl, or cycloalkyl, wherein said cycloalkyl is optionally substituted with one to three substituents-independently selected from alkyl, halo, haloalkyl, alkoxy, hydroxyl, or haloalkoxy;
R 1a is hydrogen;
R 2 is hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, cycloalkyl, halo, haloalkyl, haloalkoxy, alkoxy, alkoxyalkoxy, hydroxy, carboxy, alkoxycarbonyl, cyano, amino, monosubstituted or disubstituted amino, sulfonyl, or alkoxyalkyl;
each R 3 is hydrogen;
R 4 is hydrogen, alkyl, substituted alkyl, halo, alkoxy, hydroxy, carboxy, —CONH 2 , —CONMe 2 , cycloalkyl, or dialkylamino;
R 5 and R 6 together with the nitrogen atom to which they are attached form ring B having the formula:

wherein ring B is a heterocyclyl ring-selected from:
a) azetidin-1-yl, pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl;
b) 1,2,3,4-tetrahydroisoquinolin-2-yl substituted with R b at 6-position with haloalkoxy, cyano, cycloalkyl, halo, alkoxy, haloalkyl, or alkoxyalkoxy; or
c) 3,6-dihydro-1(2H)-pyridinyl;
wherein each aforementioned ring B is substituted with R a , R b or R c ;
wherein R a is hydrogen, alkyl, halo, haloalkyl, haloalkoxy, alkylthio, haloalkylthio, cyano, hydroxy, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, thio, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, hydroxyalkoxyalkyl, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, or acylamino and
R b and R c are independently selected from hydrogen, alkyl, substituted alkyl, substituted alkynyl, halo, haloalkyl, haloalkoxy, alkylthio, cyano, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, acylamino, sulfonylamino, aryl, heteroaryl, cycloalkyl, cycloalkenyl, heterocyclyl, aralkyl, heteroaralkyl, heterocyclylalkyl, aryloxy, heteroaryloxy, cycloalkoxy, aryloxyalkyl, aralkyloxy, aralkyloxyalkyl, aralkylthio, heteroaralkyloxy, heterocyclylalkyloxy, cycloalkylalkyloxy or cycloalkylalkyloxyalkyl;
where the aromatic or alicyclic ring in R a , R b and R c is optionally substituted with R d , R e or R f which are independently selected from alkyl, halo, haloalkyl, haloalkoxy, cyanoalkyl, alkylthio, cyano, hydroxy, alkoxy, amino, monosubstituted amino, disubstituted amino, sulfonyl, acyl, carboxy, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, hydroxyalkoxy, alkoxyalkoxy, aminoalkoxy, aminosulfonyl, aminocarbonyl, acylamino, cycloalkyl, cycloalkenyl, phenyl, phenoxy, heteroaryl, heterocyclyl, heterocyclylalkyl, aralkyl, aralkyloxy or heteroaralkyl and where the aromatic or alicyclic ring in R d , R e or R f is optionally substituted with one to three substituents independently selected from alkyl, halo, haloalkyl, haloalkyloxy, hydroxyl, alkoxy, acetylamino, alkylsulfonyl, or cyano; or a pharmaceutically acceptable salt thereof;

provided that the compound is not 3-((4-((3S)-3-benzyl-1-piperidinyl)-1,3,5-triazin-2-yl)amino)-N-methylbenzamide; 3-((4-((3R)-3-benzyl-1-piperidinyl)-1,3,5-triazin-2-yl)amino)-N-methylbenzamide; or N-methyl-3-((4-(4-(4-morpholinylcarbonyl)-1-piperidinyl)-1,3,5-triazin-2-yl)amino)benzamide.

2. The compound of claim 1 where R 1 is alkyl.

3. The compound of claim 1 where A is phenyl, R 4 is hydrogen or halo, and R 2 is hydrogen, alkyl, hydroxy, alkoxy, halo, haloalkyl, or dialkylamino.

4. The compound of claim 1 where —NR 5 R 6 is

wherein ring B is azetidinyl or piperidin-1-yl or wherein azetidin-1-yl is substituted at the 3-position of the ring and piperidin-1-yl is substituted at the 4-position of piperidin-1-yl ring, with R b where R b is aryloxy, aralkyloxy or aryloxyalkyl optionally substituted with R d , R e , or R f .

5. The compound in accordance with claim 1 , wherein the compound is selected from:
3-((4-(3-(4-chlorophenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-N-methylbenzamide;
2-fluoro-N-methyl-5-((4-(4-(4-phenyl-1,3-thiazol-2-yl)-1-piperidinyl)-1,3,5-triazin-2-yl)amino)benzamide;
5-((4-(3-(4-chlorophenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-2-fluoro-N-methylbenzamide;
N-methyl-3-((4-(3-((4-(trifluoromethyl)phenoxy)methyl)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)benzamide;
2-fluoro-N-methyl-5-((4-(3-(4-(trifluoromethyl)phenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)benzamide;
3-((4-(3-(4-chloro-3-methylphenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-N-methylbenzamide;
2-chloro-N-methyl-5-((4-(6-(2,2,2-trifluoroethoxy)-3,4-dihydro-2(1H)-isoquinolinyl)-1,3,5-triazin-2-yl)amino)benzamide;
3-((4-(3-(4-chloro-3-fluorophenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-N-methylbenzamide;
5-((4-(3-(4-chloro-2-fluorophenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-2-fluoro-N-methylbenzamide;
3-((4-(3-(3-chloro-4-fluorophenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-N-methylbenzamide;
3-((4-(3-(4-fluoro-2-methylphenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-N-methylbenzamide;
3-((4-(3-(3-ethylphenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-N-methylbenzamide;
3-((4-(3-(2,5-dichlorophenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-N-methylbenzamide;
3-((4-(3-(4-chloro-2-methylphenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-N-methylbenzamide;
3-((4-(3-(4-chloro-2-fluorophenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-N-methylbenzamide;
3-((4-(3-(2,3-dihydro-1H-inden-5-yloxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-N-methylbenzamide;
N-methyl-3-((4-(4-(3-(trifluoromethoxy)phenyl)-1-piperazinyl)-1,3,5-triazin-2-yl)amino)benzamide;
N-methyl-3-((4-(4-(4-phenyl-1,3-thiazol-2-yl)-1-piperidinyl)-1,3,5-triazin-2-yl)amino)benzamide;
3-((4-(3-(3-chlorophenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-N-methylbenzamide;
N-methyl-3-((4-(4-(4-(2-phenyl-1,3-thiazol-4-yl)-1-piperidinyl)-1,3,5-triazin-2-yl)amino)benzamide;
2-chloro-N-methyl-5-((4-(4-(4-phenyl-1,3-thiazol-2-yl)-1-piperidinyl)-1,3,5-triazin-2-yl)amino)benzamide;
3-((4-(3-(4-chlorophenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-N-(2-methoxyethyl)benzamide;
3-((4-(3-(2-chlorophenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-N-methylbenzamide;
3-((4-(3-(2-chloro-4-methylphenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-N-methylbenzamide;
N-methyl-3-((4-(3-phenoxy-1-azetidinyl)-1,3,5-triazin-2-yl)amino)benzamide;
N-methyl-3-((4-(4-(4-methylphenyl)-1-piperazinyl)-1,3,5-triazin-2-yl)amino)benzamide;
N-methyl-3-((4-(3-(4-(trifluoromethyl)phenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)benzamide;
3-((4-(4-(4-chlorophenyl)carbonyl)-1-piperidinyl)-1,3,5-triazin-2-yl)amino)-N-methylbenzamide;
3-((4-(3-(4-chlorophenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-5-fluoro-N-methylbenzamide;
3-((4-(3-(4-fluorophenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-N-(2-methoxyethyl)benzamide;
3-((4-(3-(3,4-dichlorophenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-N-methylbenzamide;
3-((4-(3-((4-chlorophenoxy)methyl)-1-azetidinyl)-1,3,5-triazin-2-yl)amino)-N-methylbenzamide;
N-methyl-3-((4-(6-(2,2,2-trifluoroethoxy)-3,4-dihydro-2(1H)-isoquinolinyl)-1,3,5-triazin-2-yl)amino)benzamide;
N-methyl-3-((4-(3-(4-(1-methylethyl)phenoxy)-1-azetidinyl)-1,3,5-triazin-2-yl)amino

Assignees

• Bregman Howard
• Buchanan John L
• Chakka Nagasree
• Dimauro Erin F
• Du Bingfan
• Nguyen Hanh Nho
• Zheng Xiao Mei
• Amgen Inc

Inventors

• Bregman Howard
• Buchanan John L
• Chakka Nagasree
• Dimauro Erin F
• Du Bingfan
• Nguyen Hanh Nho
• Zheng Xiao Mei

Classifications

• A61P43/00

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

• C07D251/48

  Two nitrogen atoms · CPC title

• C07D403/04

  directly linked by a ring-member-to-ring-member bond · CPC title

• C07D471/10 Primary

  Spiro-condensed systems · CPC title

• C07D213/74

  Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals · CPC title