N-(hydroxyalkyl (hetero)aryl) tetrahydrofuran carboxamides as modulators of sodium channels

Patent metadata

Field	Value
Publication number	US-11827627-B2
Application number	US-202217831842-A
Country	US
Kind code	B2
Filing date	Jun 3, 2022
Priority date	Jun 4, 2021
Publication date	Nov 28, 2023
Grant date	Nov 28, 2023

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-A-1):

or a pharmaceutically acceptable salt thereof, wherein:
R d is (CH 2 ) m (CHR e ) n (CH 2 ) p H;
m, n, and p are each independently 0 or 1;
R e is H, OH, halo, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 4b1 and R 4b2 are each independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 haloalkyl;
R 5b1 and R 5b2 are each independently H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, or C 1 -C 6 haloalkyl;
R 2c is H, OH, halo, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or -L 1 -L 2 -(C 3 -C 6 cycloalkyl), wherein said cycloalkyl is optionally substituted with 1-2 halo;
L 1 is a bond or O;
L 2 is a bond or C 1 -C 6 alkylene;
R 3c is H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl; or
R 2c and R 3c , together with the carbon atoms to which they are attached, form a ring of formula:

Z 1 and Z 2 are each independently O or CH 2 ;
each R is independently H or halo; and
R 4c is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy.

2. The compound of claim 1 , wherein the compound has formula (I-B-1):

or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4b1 is H or C 1 -C 6 alkyl,
optionally wherein R 4b1 is H or CH 3 .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4b2 is H or C 1 -C 6 alkyl,
optionally wherein R 4b2 is H or CH 3 .

5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5b1 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl,
optionally wherein R 5b1 is CH 3 or CF 3 .

6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5b2 is C 1 -C 6 alkyl or C 1 -C 6 haloalkyl,
optionally wherein R 5b2 is CH 3 or CF 3 .

7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 2c is OH, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy,
optionally wherein R 2c is OH, C 1 , CH 3 , OCH 3 , OCD 3 , OCH 2 CH 3 , OCH(CH 3 ) 2 , OCH 2 CH 2 F, or OCH 2 CHF 2 .

8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 3c is H, halo, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl,
optionally wherein R 3c is H, F, CH 3 , CHF 2 , or CF 3 .

9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4c is H, halo, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy,
optionally wherein R 4c is H, F, CHF 2 , OCH 2 CH 3 , OCHF 2 , OCF 3 .

10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R d is (CH 2 ) p H,
optionally wherein R d is H or CH 3 .

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R d is (CHR e ) n (CH 2 ) p H,
optionally wherein R d is CH 2 F, CH 2 OH, or CH(OH)CH 3 .

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R d is (CH 2 ) m (CHR e ) n H,
optionally wherein R d is CH 2 OCH 3 or CH 2 CH 2 OCH 3 .

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

Assignees

• Vertex Pharma

Inventors

• Beck Elizabeth Mary
• Durrant Steven John
• Skerratt Sarah
• Pullin Robert
• Etxebarria Jardi Gorka
• Shaw David Matthew
• Ahmad Nadia M
• Wray Christopher
• Virani Anisa Nizarali
• North Kiri
• Dodd James
• O'Donnell Michael Edward
• Galan Bhairavi
• Knegtel Ronald Marcellus
• Chudyk Ewa Iwona
• Pinder Joanne Louise
• Thomson Stephen Andrew
• Carvalho Meireles Lidio Marx
• Stamos Dean
• Schmidt Yvonne
• Pontillo Joseph
• Hadida Ruah Sara S
• Neubert Timothy Donald
• Hurley Dennis James
• Zhou Jinglan

Classifications

• C07D405/12 Primary

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

• A61P29/00 Primary

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

• A61K31/443

  containing a five-membered ring with oxygen as a ring hetero atom · CPC title