Heteroaryl compounds for the treatment of pain

Patent metadata

Field	Value
Publication number	US-2025388543-A1
Application number	US-202318858148-A
Country	US
Kind code	A1
Filing date	Apr 21, 2023
Priority date	Apr 22, 2022
Publication date	Dec 25, 2025
Grant date	—

Abstract

Compounds, and pharmaceutically acceptable salts thereof, useful as inhibitors of sodium channels are provided. Also provided are pharmaceutical compositions comprising the compounds or pharmaceutically acceptable salts and methods of using the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions in the treatment of various disorders, including pain.

First claim

1 . A compound of formula (I) or (II)

or a pharmaceutically acceptable salt thereof, wherein:
L is O, a single bond, —C(R) 2 —, or —C(R) 2 —O—;
X 2 is N or CR 2 ;
X 3 is N or CR 3 ;
X 4 is N or CR 4 ;
X 5 is N or CR 5 ;
X 6 is N or CR 6 ;
X 7 is N or CR 7 ;
each R is independently H or C 1 -C 6 alkyl;
R 1 , R 2 , and R 3 are defined as follows:
(i) R 1 is H, halo, CN, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 6 alkylene)-OH, NR 8 R 9 , or CH(OH)(CH 2 ) m (CHOH) n (CH 2 ) p H; and
R 2 and R 3 are each independently H, halo, CN, OH, C 1 -C 6 alkyl optionally substituted with C(O)OR 8 , C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkylene)-OH, NR 8 R 9 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), C(O)NR 8 R 9 , CH(OR 8 )—C(O)NR 8 R 9 , C(O)OR 8 , CHR 8 —C(O)OR 9 , CH(OR 8 )—C(O)OR 9 , CH(OH)(CH 2 ) m (CHOH) n (CH 2 ) p H, O—(C 1 -C 6 alkylene)-O—CH 3 , C 1 -C 6 alkenyl optionally substituted with C(O)OR 8 , S(O)R 8 , C(O)C(O)NR 8 R 9 , CHR 8 —C(O)NR 8 R 9 , C(O)R 10 , S(═O)(═NR 8 )R 9 , S(O) 2 NR 8 R 9 , 3-7 membered cycloalkyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein said cycloalkyl, heterocyclyl, or heteroaryl in said 3-7 membered cycloalkyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl is optionally substituted with 1-4 substituents independently selected from oxo, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C(O)NR 8 R 9 ; or

(ii) R 2 is H; and
R 1 and R 3 , together with the carbon atoms to which they are attached, form a ring of formula:

R 4 , R 5 , R 6 , and R 7 are defined as follows:
(i) R 4 , R 5 , R 6 , and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl optionally substituted with halo;
(ii) R 4 and R 7 are each independently is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl optionally substituted with halo; and R 5 and R 6 , together with the carbon atoms to which they are attached, form a ring of formula:

(iii) R 4 and R 7 are each independently is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl optionally substituted with halo; and R 5 and R 6 , together with the carbon atoms to which they are attached, form a ring of formula:

each R 8 and R 9 is independently H or C 1 -C 6 alkyl;
each R 10 is independently C 1 -C 4 alkyl;
each R 11 is independently H, halo, C 1 -C 4 alkyl, or C 1 -C 4 haloalkyl;
R 12 and R 13 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl optionally substituted with halo;
Z 1 is 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, phenyl, 4-10 membered heterocyclyl, or 5-6 membered heteroaryl, wherein said 3-10 membered cycloalkyl, 3-10 membered cycloalkenyl, phenyl, 4-10 membered heterocyclyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-4 substituents selected from halo, OH, CH 2 OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy;
m, n, and p are each independently 0 or 1; and
q is 1, 2, or 3;
wherein when X 3 is CR 3 , and R 3 is C(O)OR 8 , then:
L is O, or
L is a bond, and X 5 is N, or
L is a bond, and X 7 is N;

wherein when X 2 or X 3 is N, then:
L is O, and Z 1 is phenyl, wherein said phenyl may be unsubstituted or may be substituted with 1-4 substituents selected from halo, OH, CH 2 OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy, or
L is a single bond, and Z 1 is 4-10 membered heterocyclyl, wherein said 4-10 membered heterocyclyl may be unsubstituted or may be substituted with 1-4 substituents selected from halo, OH, CH 2 OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy; and

wherein the compound of formula (I) is not:

2 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, halo, CN, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 6 alkylene)-OH, NR 8 R 9 , or CH(OH)(CH 2 ) m (CHOH) n (CH 2 ) p H; and R 2 and R 3 are each independently H, halo, CN, OH, C 1 -C 6 alkyl optionally substituted with C(O)OR 8 , C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkylene)-OH, NR 8 R 9 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), C(O)NR 8 R 9 , CH(OR 8 )—C(O)NR 8 R 9 , C(O)OR 8 , CHR 8 —C(O)OR 9 , CH(OR 8 )—C(O)OR 9 , CH(OH)(CH 2 ) m (CHOH) n (CH 2 ) p H, O—(C 1 -C 6 alkylene)-O—CH 3 , C 1 -C 6 alkenyl optionally substituted with C(O)OR 8 , S(O)R 8 , C(O)C(O)NR 8 R 9 , CHR 8 —C(O)NR 8 R 9 , C(O)R 10 , S(═O)(═NR 8 )R 9 , S(O) 2 NR 8 R 9 , 3-7 membered cycloalkyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl, wherein said cycloalkyl, heterocyclyl, or heteroaryl in said 3-7 membered cycloalkyl, 4-7 membered heterocyclyl, or 5-6 membered heteroaryl is optionally substituted with 1-4 substituents independently selected from oxo, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, and C(O)NR 8 R 9 .

3 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, halo, CN, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 6 alkylene)-OH, NR 8 R 9 , or CH(OH)(CH 2 ) m (CHOH) n (CH 2 ) p H; and R 2 and R 3 are each independently H, halo, CN, OH, C 1 -C 6 alkyl optionally substituted with C(O)OR 8 , C 2 -C 6 alkynyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, (C 1 -C 6 alkylene)-OH, NR 8 R 9 , (C 1 -C 6 alkylene)-O—(C 1 -C 6 alkyl), C(O)NR 8 R 9 , CH(OR 8 )—C(O)NR 8 R 9 , C(O)OR 8 , CHR 8 —C(O)OR 9 , CH(OR 8 )—C(O)OR 9 , CH(OH)(CH 2 ) m (CHOH) n (CH 2 ) p H, O—(C 1 -C 6 alkylene)-O—CH 3 , C 1 -C 6 alkenyl optionally substituted with C(O)OR 8 , S(O)R 8 , C(O)C(O)NR 8 R 9 , CHR 8 —C(O)NR 8 R 9 , C(O)R 10 , S(═O)(═NR 8 )R 9 , or S(O) 2 NR 8 R 9 .

4 . The compound of formula (I) of claim 1 , wherein the compound has formula (I-A)

or a pharmaceutically acceptable salt thereof, wherein:
R 1 is H, halo, CN, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 6 alkylene)-OH, or NR 8 R 9 ;
R 4 , R 5 , R 6 , and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 3 -C 6 cycloalkyl optionally substituted with halo; and
Z 1 is 5-10 membered cycloalkyl, phenyl, 4-10 membered heterocyclyl, or 5-6 membered heteroaryl, wherein said 5-10 membered cycloalkyl, phenyl, 4-10 membered heterocyclyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-4 substituents selected from CH 2 OH, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.

5 . The compound of formula (I) of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
at least one of X 4 , X 5 , X 6 , or X 7 is N; and/or X 4 is CR 4 and X 7 is CR 7 ; and/or X 5 is N; and/or R 3 is C 1 -C 6 alkyl; and/or R 2 and R 3 are each independently H, halo, CN, OH, C 1 -C 6 alkyl optionally substituted with C(O)OR 8 , C 1 -C 6

Assignees

• Vertex Pharma

Inventors

• Miller Mark Thomas
• Hurley Dennis James
• Neubert Timothy Donald
• Arumugam Vijayalaksmi
• Hadida Ruah Sara Sabina
• Mccartney Jason
• Zhou Jinglan
• Chau Jaclyn
• Demoret Robert Martin
• Ghirmai Senait G
• Valiulin Roman Askatovich
• Kintzer Alexander Frederik
• Slochower David Robert
• Aertgeerts Kathleen
• Beck Elizabeth Mary
• MUI James Jun Bon
• Wright Miranda Adele
• Knegtel Ronald Marcellus Alphonsus
• Chudyk Ewa Iwona
• Pinder Joanne Louise
• Jacques Reece
• Dodd James
• Simpson Iain

Classifications

• C07D495/04

  Ortho-condensed systems · CPC title

• C07D491/048

  the oxygen-containing ring being five-membered · CPC title

• C07D487/08

  Bridged systems · CPC title

• C07D413/14

  containing three or more hetero rings · CPC title

• C07D413/04

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