Heteroaryl compounds for the treatment of pain

Patent metadata

Field	Value
Publication number	US-12503439-B2
Application number	US-202318137939-A
Country	US
Kind code	B2
Filing date	Apr 21, 2023
Priority date	Apr 22, 2022
Publication date	Dec 23, 2025
Grant date	Dec 23, 2025

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

What is claimed is:

1 . A compound of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:
L is —O—, a single bond, —O—C(R) 2 —, —C(R) 2 —, —C(R) 2 —O—, or —N(R)—;
each R is independently H, halo, or C 1 -C 6 alkyl;

X 2 , Y 1 , Y 2 , and Y 3 are defined as follows:
(i) X 2 is CR 2 , Y 1 is CR 1a , Y 2 is CR 2a , and Y 3 is CR 3a ; or
(ii) X 2 is N, Y 1 is CR 1a , Y 2 is CR 2a , and Y 3 is CR 3a ; or
(iii) X 2 is CR 2 , Y 1 is N, Y 2 is CR 2a , and Y 3 is CR 3a ; or
(iv) X 2 is CR 2 , Y 1 is CR 1a , Y 2 is N, and Y 3 is CR 3a ; or
(v) X 2 is CR 2 , Y 1 is CR 1a , Y 2 is + N—O − , and Y 3 is CR 3a ; or
(vi) X 2 is CR 2 , Y 1 is CR 1a , Y 2 is CR 2a , and Y 3 is N;

X 4 , X 5 , X 6 , and X 7 are defined as follows:
(i) X 4 is CR 4 , X 5 is CR 5 , X 6 is CR 6 , and X 7 is CR 7 ; or
(ii) X 4 is N, X 5 is CR 5 , X 6 is CR 6 , and X 7 is CR 7 ; or
(iii) X 4 is CR 4 , X 5 is N, X 6 is CR 6 , and X 7 is CR 7 ; or
(iv) X 4 is CR 4 , X 5 is CR 5 , X 6 is N, and X 7 is CR 7 ; or
(v) X 4 is CR 4 , X 5 is CR 5 , X 6 is CR 6 , and X 7 is N; or
(vi) X 4 is CR 4 , X 5 is N, X 6 is CR 6 , and X 7 is N; or
(vii) X 4 is CR 4 , X 5 is N, X 6 is N, and X 7 is CR 7 ; or
(viii) X 4 is CR 4 , X 5 is CR 5 , X 6 is N, and X 7 is N;
R 2 is H, halo, C 1 -C 6 alkyl, (C 1 -C 6 alkylene)-NR 8 R 9 , C 2 -C 6 alkenyl, C 1 -C 6 alkoxy, (C 1 -C 6 alkylene)-OH, C(O)OR 8 , or CH(OH)(CH 2 ) m (CHOH) n (CH 2 ) p H;

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

or

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

R 8 and R 9 are each independently H or C 1 -C 6 alkyl;
each R 10 is independently H or halo;
R 1a is H, halo, CN, C 1 -C 6 alkyl, OH, C(O)NR 12 R 13 , C 1 -C 6 alkoxy, NR 12 R 13 , NR 8 C(O)NR 8 R 9 , (C 1 -C 6 alkylene)-C(O)NR 8 R 9 , (C 1 -C 6 alkylene)-OH, C(O)OR 12 , OR 12 , CH(OH)(CH 2 ) m (CHOH) n (CH 2 ) p H, N═S(═O)(CH 3 ) 2 , N═S(═O)R′R″, 5-10 membered heteroaryl, or 4-10 membered heterocyclyl, wherein the heterocyclyl or heteroaryl in said 5-10 membered heteroaryl or 4-10 membered heterocyclyl is optionally substituted with 1-4 substituents selected from OH, halo, oxo, C(O)NR 8 R 9 , NR 8 R 9 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, (C 1 -C 6 alkylene)-OH, (C 1 -C 6 alkylene)-O—(C 1 C 6 alkyl), and (C 1 -C 6 alkylene)-NR 8 R 9 ;
R′ and R″, together with the S atom to which they are attached, form a 4-7 membered heterocyclyl;
R 11 , R 2a , and R 3a are each independently H, halo, CN, C 1 -C 6 alkyl, C(O)NR 8 R 9 , or C 1 -C 6 alkoxy;
R 12 and R 13 are each independently H, C(O)(C 1 -C 6 alkyl), (C 1 -C 6 alkylene)-NR 8 R 9 , CH 2 CH(OH)(CH 2 ) m (CHOH) n (CH 2 ) p H, C 1 -C 6 alkyl optionally substituted with one or more OH, indanyl, (C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), (C 1 -C 6 alkylene)-phenyl, (C 1 -C 6 alkylene)-(5-membered heterocyclyl), C 4 -C 7 cycloalkyl, C 6 -C 10 aryl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl, wherein the indanyl, (C 1 -C 6 alkylene)-(C 3 -C 6 cycloalkyl), (C 1 -C 6 alkylene)-phenyl, (C 1 -C 6 alkylene)-(5 membered heterocyclyl), C 4 -C 7 cycloalkyl, C 6 -C 10 aryl, 5-6 membered heteroaryl, or 4-7 membered heterocyclyl is optionally substituted with 1-4 substituents selected from OH, oxo, C 1 -C 6 alkyl, (C 1 -C 6 alkylene)-OH, and C 1 -C 6 alkoxy;
Z 1 is, 3-7 membered cycloalkenyl, phenyl, 4-10 membered heterocyclyl, or 5-6 membered heteroaryl, wherein said 3-7 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, CD 3 , C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, CH 2 OH, C(O)H, 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 2 is N, then:
(i) L is O, and Z 1 is phenyl, wherein said phenyl is substituted with 2-4 substituents selected from halo, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy; or
(ii) L is a single bond, and Z 1 is 4-10 membered heterocyclyl, wherein said 4-10 membered heterocyclyl is substituted with 2-4 substituents selected from halo, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy; and

wherein when X 2 , X 4 , X 5 , X 6 and X 7 are each CH, L is a single bond, and Z 1 is phenyl, then said phenyl is substituted with 1-4 substituents selected from halo, OH, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, and C 1 -C 6 haloalkoxy.

2 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein:
R 1a is H, halo, CN, C 1 -C 6 alkyl, OH, C(O)NR 12 R 13 , C 1 -C 6 alkoxy, NR 12 R 13 , (C 1 -C 6 alkylene)-C(O)NR 8 R 9 , (C 1 -C 6 alkylene)-OH, C(O)OR 12 , CH(OH)(CH 2 ) m (CHOH) n (CH 2 ) p H, or N═S(═O)(CH 3 ) 2; and R 12 and R 13 are each independently H, C(O)(C 1 -C 6 alkyl), (C 1 -C 6 alkylene)-NR 8 R 9 , CH 2 CH(OH)(CH 2 ) m (CHOH) n (CH 2 ) p H, or C 1 -C 6 alkyl optionally substituted with one or more OH.

3 . The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 , R 5 , R 6 , and R 7 are each independently H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, or C 3 -C 6 cycloalkyl optionally substituted with one or more alkyl, halo, or OH.

4 . The compound of claim 1 , wherein the compound is selected from:

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 Fredrick
• 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
• Dodd James
• Simpson Iain

Classifications

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• C07D401/14

  containing three or more hetero rings · CPC title

• C07D401/04

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

• C07D239/91

  with aryl or aralkyl radicals attached in position 2 or 3 · CPC title