Carboxamide derivatives and use thereof

Patent metadata

Field	Value
Publication number	US-9493449-B2
Application number	US-201414776527-A
Country	US
Kind code	B2
Filing date	Mar 13, 2014
Priority date	Mar 15, 2013
Publication date	Nov 15, 2016
Grant date	Nov 15, 2016

Abstract

The present disclosure provides substituted pyridyl-, pyrimidinyl-, pyrazinyl-, pyridazinyl-, and triazinyl-based carboxamides of Formula I-A: R 10 Z-HET-E I-A and the pharmaceutically acceptable salts and solvates thereof, wherein Z, HET, R 10 and E are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula I-A to treat a disorder responsive to the blockade of sodium channels. Compounds of the present disclosure are especially useful for treating pain.

First claim

What is claimed is:

1. A compound having Formula I:
Z-HET-E  I

or a pharmaceutically acceptable salt or solvate thereof, wherein:
Z is:

HET is a 6-membered nitrogen-containing heteroaryl selected from the group consisting of:

E is selected from the group consisting of:

X is selected from the group consisting of N and CR 1 ;
R 1 is selected from the group consisting of:
a) hydrogen;
b) optionally substituted heteroaryl;
c) heteroalkyl;
d) (aralkylamino)alkyl
e) (heterocyclo)alkyl;
f) optionally substituted aryl;
g) (heterocycloalkylamino)alkyl;
h) (heterocycloamino)alkyl;
i) alkanolamine;
j) hydroxyalkyl;
k) (amino)alkyl;
l) (alkylamino)alkyl;
m) (dialkylamino)alkyl;
n) (cycloalkylamino)alkyl;
o) (nitro)alkyl;
p) (carboxamido)alkyl; and
q) (haloalkylamino)alkyl;

R 2 is selected from the group consisting of:
a) hydrogen;
b) optionally substituted heteroaryl;
c) heteroalkyl;
d) (aralkylamino)alkyl
e) (heterocyclo)alkyl;
f) optionally substituted aryl;
g) (heterocycloalkylamino)alkyl;
h) (heterocycloamino)alkyl;
i) alkanolamine;
j) hydroxyalkyl;
k) (amino)alkyl;
l) (alkylamino)alkyl;
m) (dialkylamino)alkyl;
n) (cycloalkylamino)alkyl;
o) (nitro)alkyl;
p) (carboxamido)alkyl; and
q) (haloalkylamino)alkyl;

with the proviso that at least one of R 1 and R 2 is hydrogen;
R 3 is selected from the group consisting of:
a) hydrogen;
b) halo;
c) cyano;
d) haloalkyl;
e) C 1 -C 4 alkyl;
f) C 1-4 haloalkyl;
g) C 1-4 haloalkoxy; and
h) C 1-4 alkoxy;

R 4 is selected from the group consisting of:
a) hydrogen;
b) chloro;
c) cyano;
d) C 1-4 haloalkyl;
e) arylamino;
f) (arylamino)alkyl;
g) (aryloxy)alkyl;
h) (dialkylamino)alkyl;
i) alkoxyalkyl;
j) (heterocyclo)alkyl;
k) optionally substituted aryl; and
l) optionally substituted heteroaryl;

R 5 is selected from the group consisting of:
a) hydrogen;
b) chloro;
c) cyano;
d) C 1-4 haloalkyl;
e) arylamino;
f) (arylamino)alkyl;
g) (aryloxy)alkyl;
h) (dialkylamino)alkyl;
i) alkoxyalkyl;
j) (heterocyclo)alkyl;
k) optionally substituted aryl; and
l) optionally substituted heteroaryl,

with the provisos:
1) when X is CR 1 and R 1 is hydrogen or hydroxyalkyl, then:
i) R 2 is selected from the group consisting of optionally substituted heteroaryl; heteroalkyl; (aralkylamino)alkyl (heterocyclo)alkyl; optionally substituted aryl; (heterocycloalkylamino)alkyl; (heterocycloamino)alkyl; alkanolamine; hydroxyalkyl; (amino)alkyl; (alkylamino)alkyl; (dialkylamino)alkyl; (cycloalkylamino)alkyl; (nitro)alkyl; (carboxamido)alkyl; and (haloalkylamino)alkyl; or
ii) R 4 is selected from the group consisting of arylamino; (arylamino)alkyl; (aryloxy)alkyl; (dialkylamino)alkyl; (heterocyclo)alkyl; optionally substituted aryl; and optionally substituted heteroaryl; or
iii) R 5 is selected from the group consisting of arylamino; (arylamino)alkyl; (aryloxy)alkyl; (dialkylamino)alkyl; (heterocyclo)alkyl; optionally substituted aryl; and optionally substituted heteroaryl; or
2) when X is CR 1 and R 2 is hydrogen, then:
i) R 1 is selected from the group consisting of optionally substituted heteroaryl; heteroalkyl; (aralkylamino)alkyl; (heterocyclo)alkyl; optionally substituted aryl; (heterocycloalkylamino)alkyl; (heterocycloamino)alkyl; alkanolamine; (amino)alkyl; (alkylamino)alkyl; (dialkylamino)alkyl; (cycloalkylamino)alkyl; (nitro)alkyl; (carboxamido)alkyl; and (haloalkylamino)alkyl; or
ii) R 4 is selected from the group consisting of arylamino; (arylamino)alkyl; (aryloxy)alkyl; (dialkylamino)alkyl; (heterocyclo)alkyl; optionally substituted aryl; and optionally substituted heteroaryl; or
iii) R 5 is selected from the group consisting of arylamino; (arylamino)alkyl; (aryloxy)alkyl; (dialkylamino)alkyl; (heterocyclo)alkyl; optionally substituted aryl; and optionally substituted heteroaryl.

2. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein HET is selected from the group consisting of HET-1, HET-2, HET-3, HET-4, HET-12, HET-13, HET-19, HET-20, HET-21, and HET-22.

3. The compound of claim 1 having Formula II:

or a pharmaceutically acceptable salt or solvate thereof.

4. The compound of claim 3 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 5 is selected from the group consisting of hydrogen; chloro; and C 1-4 haloalkyl.

5. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having Formula III:

wherein:
R 1 is selected from the group consisting of:
a) optionally substituted heteroaryl;
b) heteroalkyl;
c) (aralkylamino)alkyl;
d) (heterocyclo)alkyl;
e) optionally substituted aryl;
f) (heterocycloalkylamino)alkyl;
g) (heterocycloamino)alkyl;
h) alkanolamine;
i) (amino)alkyl;
j) (alkylamino)alkyl;
k) (dialkylamino)alkyl;
l) (cycloalkylamino)alkyl;
m) (nitro)alkyl; and
n) (carboxamido)alkyl.

6. The compound of claim 5 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 is selected from the group consisting of:
a) optionally substituted heteroaryl;
b) (heterocyclo)alkyl; and
c) (dialkylamino)alkyl.

7. The compound of claim 6 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is selected from the group consisting of halo, cyano, and haloalkyl.

8. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having Formula IV:

wherein R 2 is selected from the group consisting of heteroaryl; (heterocyclo)alkyl; and (haloalkylamino)alkyl.

9. The compound of claim 8 , or a pharmaceutically acceptable salt or solvate thereof, wherein R 3 is selected from the group consisting of cyano and haloalkyl.

10. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having Formula V:

wherein R 4 is selected from the group consisting of:
a) arylamino;
b) (arylamino)alkyl;
c) (aryloxy)alkyl;
d) (dialkylamino)alkyl;
e) (heterocyclo)alkyl;
f) optionally substituted aryl; and
g) optionally substituted heteroaryl.

11. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, having Formula VI:

wherein R 5 is selected from the group consisting of:
a) arylamino;
b) (arylamino)alkyl;
c) (aryloxy)alkyl;
d) (dialkylamino)alkyl;
e) (heterocyclo)alkyl;
f) optionally substituted aryl; and
g) optionally substituted heteroaryl.

12. The compound of claim 1 , or a pharmaceutically acceptable salt or solvate thereof, wherein E is:

Assignees

• Purdue Pharma Lp

Inventors

• Yao Jiangchao
• Tafesse Laykea

Classifications

• A61P25/00

  Drugs for disorders of the nervous system · CPC title

• A61P29/00

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

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D239/26

  with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms · CPC title

• C07D417/12 Primary

  linked by a chain containing hetero atoms as chain links · CPC title