Azetidine-substituted quinoxalines as opioid receptor like-1 modulators

Patent metadata

Field	Value
Publication number	US-9290488-B2
Application number	US-201214361876-A
Country	US
Kind code	B2
Filing date	Nov 30, 2012
Priority date	Dec 1, 2011
Publication date	Mar 22, 2016
Grant date	Mar 22, 2016

Abstract

The disclosure relates to Azetidine-Substituted Quinoxaline-Type Piperidine Compounds of Formula (I):

and pharmaceutically acceptable derivatives thereof wherein the R 1 , R 2 , R 3 , Q, Y 1 , Z, A, B, a, and b are as defined herein, compositions comprising an effective amount of an Azetidine-Substituted Quinoxaline-Type Piperidine Compound, and methods to treat or prevent a condition, such as pain, comprising administering to an animal in need thereof an effective amount of an Azetidine-Substituted Quinoxaline-Type Piperidine Compound.

First claim

What is claimed is:

1. A compound of Formula (I):

or a pharmaceutically acceptable salt thereof wherein:
Y 1 is O or S;
Q is benzo;
each R 2 is independently selected from:
(a) -halo, —CN, —NO 2 , —OT 3 , —C(═O)T 3 , —C(═O)OT 3 , —C(═O)N(T 1 )(T 2 ), —S(═O) 2 OT 3 , —S(═O)T 3 , —S(═O) 2 T 3 , —O—S(═O) 2 T 3 , —S(═O) 2 N(T 1 )(T 2 ), —N(T 1 )(T 2 ), —N(T 3 )C(═O)T 3 , —N(T 3 )C(═O)N(T 1 )(T 2 ), —N(T 3 )S(═O)T 3 , —N(T 3 )S(═O) 2 T 3 , —N(T 3 )C(═O)OT 3 , and —N(T 3 )S(═O) 2 N(T i )(T 2 ); and
(b) —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkoxy, —(C 3 -C 7 )cycloalkyl, —(C 6 -C 14 )bicycloalkyl, —(C 8 -C 20 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 7 -C 14 )bicycloalkenyl, —(C 8 -C 20 )tricycloalkenyl, -(5- or 6-membered)heterocyclyl, and -(7- to 10-membered)bicycloheterocyclyl, each of which is unsubstituted or substituted with 1, 2, or 3 independently selected R 8 groups; and
(c) -phenyl, -naphthalenyl, —(C 14 )aryl, or -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2, or 3 independently selected R 7 groups;

a is an integer selected from 0, 1, and 2;
each R 3 is independently selected from:
(a) -halo, —CN, —NO 2 , —OT 3 , —C(═O)T 3 , —C(═O)OT 3 , —C(═O)N(T 1 )(T 2 ), —S(═O) 2 OT 3 , —S(═O)T 3 , —S(═O) 2 T 3 , —O—S(═O) 2 T 3 , —S(═O) 2 N(T 1 )(T 2 ), —N(T 1 )(T 2 ), —N(T 3 )C(═O)T 3 , —N(T 3 )C(═O)N(T 1 )(T 2 ), —N(T 3 )S(═O)T 3 , —N(T 3 )S(═O) 2 T 3 , —N(T 3 )C(═O)OT 3 , and —N(T 3 )S(═O) 2 N(T 1 )(T 2 ); and
(b) —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 1 -C 6 )alkoxy, —(C 3 -C 7 )cycloalkyl, —(C 6 -C 14 )bicycloalkyl, —(C 8 -C 20 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 7 -C 14 )bicycloalkenyl, —(C 8 -C 20 )tricycloalkenyl, -(5- or 6-membered)heterocyclyl, and -(7- to 10-membered)bicycloheterocyclyl, each of which is unsubstituted or substituted with 1, 2, or 3 independently selected R 8 groups;

b is an integer selected from 0, 1, and 2;
A and B are independently selected from:
(a) —H, —CN, —C(═O)OT 3 , and —C(═O)N(T 1 )(T 2 ); and
(b) —(C 3 -C 12 )cycloalkyl, —(C 3 -C 12 )cycloalkoxy, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, and —(C 1 -C 6 )alkoxy, each of which is unsubstituted or substituted with 1 or 2 substituents independently selected from —OH, —S(═O) 2 NH 2 , —N(R 6 ) 2 , ═NR 6 , —C(═O)OT 3 , —C(═O)N(R 6 ) 2 , —N(R 6 )C(═O)R 9 , and -(5- or 6-membered)heterocyclyl, or 1, 2, or 3 independently selected -halo; or
(c) A-B can together form a (C 2 -C 6 )bridge, which is unsubstituted or substituted with 1, 2, 3, 4, 5, 6, 7 or 8 substituents independently selected from —OH, —(C 1 -C 4 )alkyl, -halo, and —C(halo) 3 , and which bridge optionally contains —HC═CH— or —O— within the (C 2 -C 6 )bridge; wherein the A-B bridge can be in the endo- or exo- configuration with respect to the 6-membered, nitrogen-containing ring that is fused to the Q group; or
(d) A-B can together foil a —CH 2 —N(R a )—CH 2 — bridge, a

wherein the A-B bridge can be in the endo- or exo- configuration with respect to the 6-membered, nitrogen-containing ring that is fused to the Q group;
R a is —H, —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl, —CH 2 —C(═O)—R c , —(CH 2 )—C(═O)—OR c , —(CH 2 )—C(═O)—N(R c ) 2 , —(CH 2 ) 2 —O—R c , —(CH 2 ) 2 —S(═O) 2 —N(R c ) 2 , R c , or —(CH 2 ) 2 —N(R c )S(═O) 2 —R c ;
R b is selected from:
(a) —H, —(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkyl, -(3- to 7-membered)heterocyclyl, —N(R c ) 2 , —N(R c )—(C 3 -C 7 )cycloalkyl, and —N(R c )-(3- to 7-membered)heterocyclyl; and
(b) -phenyl, -naphthalenyl, and -(5- or 6-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2, or 3 independently selected R 7 groups; and
(c) —N(R c )-phenyl, —N(R c )-naphthalenyl, —N(R c )—(C 14 )aryl, and —N(R c )-(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2, or 3 independently selected R 7 groups;

each R c is independently —H or —(C 1 -C 4 )alkyl;
Z is —[(C 1 -C 10 )alkyl optionally substituted by R 13 ] h —, wherein h is 0 or 1; or —[(C 2 -C 10 )alkenyl optionally substituted by R 13 ]—; or —(C 1 -C 10 )alkyl-N(R 6 )C(═Y)—, wherein Y is O or S;
R 1 is selected from:
(a) —H, -halo, —CN, —OH, —CH 2 OH, —CH 2 CH 2 OH, —NO 2 , —N(R 6 ) 2 , —S(═O)NH 2 , —S(═O) 2 NH 2 , —C(═O)OV 1 , and —C(═O)CN; and
(b) —(C 1 -C 10 )alkyl, —(C 2 -C 10 )alkenyl, —(C 2 -C 10 )alkynyl, —O(C 1 -C 6 )alkyl, —(C 3 -C 7 )cycloalkoxy, —(C 3 -C 14 )cycloalkyl, —(C 6 -C 14 )bicycloalkyl, —(C 8 -C 20 )tricycloalkyl, —(C 5 -C 10 )cycloalkenyl, —(C 7 -C 14 )bicycloalkenyl, —(C 8 -C 20 )tricycloalkenyl, and -(3- to 7-membered)heterocyclyl, each of which is unsubstituted or substituted with 1, 2, 3, or 4 independently selected R 8 groups; and
(c)

 and
(d) -phenyl, -naphthalenyl, —(C 14 )aryl, and -(5- to 10-membered)heteroaryl, each of which is unsubstituted or substituted with 1, 2, or 3 independently selected R 7 groups; or

—Z—R 1 is 3,3-diphenylpropyl- optionally substituted at the 3 carbon of the propyl with —CN, —C(═O)N(R 6 ) 2 , —C(═O)OV 1 , or -tetrazolyl; or
—Z—R 1 is —(C 1 -C 4 )alkyl substituted with tetrazolyl;
each R 5 is independently —(C 1 -C 4 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, -(5- or 6-membered)heteroaryl, —(C 1 -C 6 )alkyl-C(═O)OR 9 , —OR 9 , —SR 9 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, ═O, ═S, -halo, —N 3 , —NO 2 , —CH═N(R 9 ), —N(R 9 )(C 1 -C 6 )alkyl-C(═O)OR 9 , —N(R 9 ) 2 , —N(R 9 )OH, —N(R 9 )S(═O)R 12 , —N(R 9 )S(═O) 2 R 12 , —N(R 9 )C(═O)R 12 , —N(R 9 )C(═O)OR 12 , —C(═O)R 9 , —C(═O)OR 9 , —OC(═O)R 9 , —OC(═O)OR 9 , —S(═O)R 9 , or —S(═O) 2 R 9 ;
each R 6 is independently —H, —(C 1 -C 6 )alkyl, or —(C 3 -C 7 )cycloalkyl, or two R 6 groups attached to the same nitrogen atom can together form a 5- to 8-membered ring, wherein the number of atoms in the ring includes the nitrogen atom, and in which one of the 5- to 8-membered ring carbon atoms is optionally replaced by O, S, or N(T 3 );
each R 7 is independently —(C 1 -C 4 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —OR 9 , —SR 9 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, -halo, —N 3 , —NO 2 , —CH═N(R 9 ), —N(R 9 ) 2 , —N(R 9 )OH, —N(R 9 )S(═O)R 12 , —N(R 9 )S(═O) 2 R 12 , —N(R 9 )C(═O)R 12 , —N(R 9 )C(═O)N(T 1 )(T 2 ), —N(R 9 )C(═O)OR 12 , —C(═O)R 9 , —C(═O)N(T 1 )(T 2 ), —C(═O)OR 9 , —OC(═O)R 9 , —OC(═O)N(T 1 )(T 2 ), —OC(═O)OR 9 , —S(═O)R 9 , or —S(═O) 2 R 9 ;
each R 8 is independently —(C 1 -C 4 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, -(5- or 6-membered)heteroaryl, —(C 1 -C 6 )alkyl-C(═O)OR 9 , —N(R 9 )(C 1 -C 6 )alkyl-C(═O)OR 9 , —OR 9 , —SR 9 , —C(halo) 3 , —CH(halo) 2 , —CH 2 (halo), —CN, ═O, ═S, -halo, —N 3 , —NO 2 , —CH═N(R 9 ), —N(R 9 ) 2 , —N(R 9 )OH, —N(R 9 )S(═O)R 12 , —N(R 9 )S(═O) 2 R 12 , —N(R 9 )C(═O)R 12 , —N(R 9 )C(═O)N(T 1 )(T 2 ), —N(R 9 )C(═O)OR 12 , —C(═O)R 9 , —C(═O)N(T 1 )(T 2 ), —C(═O)OR 9 , —OC(═O)R 9 , —OC(═O)N(T 1 )(T 2 ), —OC(═O)OR 9 , —S(═O)R 9 , or —S(═O) 2 R 9 ;
each R 9 is independently —H, —(C 1 -C 6 )alkyl, —(C 2 -C 6 )alkenyl, —(C 2 -C 6 )alkynyl, —(C 3 -C 8 )cycloalkyl, —(C 5 -C 8 )cycloalkenyl, -phenyl, -benzyl, -(3- to 7-membered)heterocyclyl, —C(halo) 3 , —CH(halo) 2 , or —CH 2 (halo);
if h is 0, then R 11 can be —H, —CN, —C(═O)OR 9 , or —C(═O)N(R 6 ) 2 or R 11 can be —(C 1 -C 4 )alkyl which is unsubstituted or substituted with —OH, —(C 1 -C 4 )alkoxy, —N(R 6 ) 2 , —C(═O)OR 9 , or —C(═O)N(R 6 ) 2

Assignees

• Purdue Pharma Lp
• Shionogi & Co

Inventors

• Tafesse Laykea
• Tsuno Naoki
• Zhou Xiaoming

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P43/00

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

• A61P25/36

  Opioid-abuse · CPC title

• A61P25/04

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

• A61P25/08

  Antiepileptics; Anticonvulsants · CPC title