Esters and carbamates as modulators of sodium channels

Patent metadata

Field	Value
Publication number	US-12440481-B2
Application number	US-202017421945-A
Country	US
Kind code	B2
Filing date	Jan 9, 2020
Priority date	Jan 10, 2019
Publication date	Oct 14, 2025
Grant date	Oct 14, 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), (II), or (III)

or a pharmaceutically acceptable salt thereof, wherein:
Q is C(O)OR o or NR n C(O)OR o ;
R n is H or C 1 -C 6 alkyl;
each R o is independently C 1 -C 6 alkyl;
R 1a is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 3a is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy or C(O)OR o ;
R 4a is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or —W—R w ;
R 1b is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 3b is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 4b is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 2c is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 3c is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
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;
R 5 is H, halo, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or —W—(CH 2 ) n —R w ;
R 6 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or —W—(CH 2 ) n —R w ;
R 7 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or —W—(CH 2 ) n —R w ;
R 9 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 10 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 11 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 12 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 13 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
each W is independently O or a single bond;
each R w is independently 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl, wherein said 3-6 membered cycloalkyl, phenyl, or 5-6 membered heteroaryl may be unsubstituted or may be substituted with 1-3 substituents selected from a group consisting of halo, C 1 -C 6 alkyl, and C 1 -C 6 haloalkyl; and
n is 0 or 1;
wherein the compound of formula (I), (II), or (III) is not methyl 5-(2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinate or methyl 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinate.

2. The compound of claim 1 , wherein:
the compound is of formula (I) or (II);
R 1a is H;
R 3a is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy;
R 4a is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or C 1 -C 6 haloalkoxy; and
R 5 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or —W—(CH 2 ) n —R w .

3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is C(O)OR o .

4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein Q is NHC(O)OR o .

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

or a pharmaceutically acceptable salt thereof, wherein R o , R 1a , R 3a , R 4a , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13 , W, R w , and n are as defined in claim 1 or 2 .

6. The compound of claim 1 , wherein the compound has formula (II-A)

or a pharmaceutically acceptable salt thereof, wherein R o , R 1b , R 3b , R 4b , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13 , W, R w , and n are as defined in claim 1 or 2 ;
wherein the compound of formula (II-A) is not methyl 5-(2-(2,4-dimethoxyphenoxy)-5-(trifluoromethyl)benzamido)picolinate or methyl 5-(4,5-dichloro-2-(4-fluoro-2-methoxyphenoxy)benzamido)picolinate.

7. The compound of claim 1 , wherein the compound has formula (III-A)

or a pharmaceutically acceptable salt thereof, wherein R o , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13 , W, R w , and n are as defined in claim 1 .

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

or a pharmaceutically acceptable salt thereof, wherein R n , R o , R 1a , R 3a , R 4a , R 5 , R 6 , R 7 , R 9 , R 10 , R 11 , R 12 , R 13 , W, R w , and n are as defined in claim 1 or 2 .

9. The compound of claim 5 , wherein R 1a is H, F, or CH 3 ; R 3a is H; and R 4a is H, C 1 -C 6 alkyl, or cyclopropyl.

10. The compound of claim 6 , or a pharmaceutically acceptable salt thereof, wherein R 1b , R 3b , and R 4b are each H.

11. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 5 is H, halo, OH, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or —W—(CH 2 ) n —R w .

12. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 6 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, 3-6 membered cycloalkyl, or —W—(CH 2 ) n —R w .

13. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkoxy, or —W—(CH 2 ) n —R w .

14. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 9 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkoxy.

15. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 10 is H or F.

16. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 11 is H, halo, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 1 -C 6 haloalkyl, or C 1 -C 6 haloalkoxy.

17. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 12 is H.

18. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 13 is H.

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

or a pharmaceutically acceptable salt thereof.

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

or a pharmaceutically acceptable salt thereof.

21. The compound of claim 1 , wher

Assignees

• Vertex Pharma

Inventors

• Thomson Stephen Andrew
• Ahmad Nadia
• Anderson Corey
• Arumugam Vijayalaksmi
• Asgian Iuliana Luci
• Camp Joanne Louise
• Fanning Lev Tyler Dewey
• Hadida Ruah Sara Sabina
• Hurley Dennis
• Schmidt Yvonne
• Shaw David
• Patel Urvi
• Carvalho Meireles Lidio Marx

Classifications

• C07D213/79

  Acids; Esters · CPC title

• C07C65/24

  polycyclic · CPC title

• C07B2200/05

  Isotopically modified compounds, e.g. labelled · CPC title

• A61K31/192

  having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid  {(cannabinoids A61K31/658)} · CPC title

• C07D213/56

  Amides · CPC title