IP Library › Granted Patent US 12,440,481
Granted Patent B2
US 12,440,481 · App. 17/421,945 · Granted Oct 14, 2025

Esters and carbamates as modulators of sodium channels

Inventors: Stephen Andrew Thomson (Del Mar, CA); Nadia Ahmad (Didcot, GB); Corey Anderson (Brighton, MA); Vijayalaksmi Arumugam (San Marcos, CA); Iuliana Luci Asgian (San Diego, CA); Joanne Louise Camp (Didcot, GB); Lev Tyler Dewey Fanning (San Marcos, CA); Sara Sabina Hadida Ruah (La Jolia, CA); Dennis Hurley (San Marcos, CA); Yvonne Schmidt (San Diego, CA); David Shaw (Oxford, GB); Urvi Patel (San Diego, CA); Lidio Marx Carvalho Meireles (San Marcos, CA)
Assignee: VERTEX PHARMACEUTICALS INCORPORATED
A61K31/44A61K31/192C07C65/24C07D213/79C07B2200/05
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Quick Facts
Patent No.
US 12,440,481
App. No.
17/421,945
Granted
Oct 14, 2025
Kind
B2
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.

Claims (61)

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 , wherein the compound is selected from:

or a pharmaceutically acceptable salt thereof.

22. A pharmaceutical composition comprising the compound of claim 1 , or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers or vehicles.

23. A method of treating or lessening the severity in a subject of chronic pain, gut pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postsurgical pain, visceral pain, incontinence, comprising administering to the subject an effective amount of the compound of claim 1 , or a pharmaceutically acceptable salt thereof.

Assignments (6)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 20, 2025
From: CARVALHO MEIRELES, LIDIO MARX
To: VERTEX PHARMACEUTICALS INCORPORATED
Reel/Frame 071462/0301 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 20, 2025
From: AHMAD, NADIA; CAMP, JOANNE LOUISE; SHAW, DAVID
To: VERTEX PHARMACEUTICALS (EUROPE) LIMITED
Reel/Frame 071462/0425 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 20, 2025
From: VERTEX PHARMACEUTICALS (EUROPE) LIMITED
To: VERTEX PHARMACEUTICALS INCORPORATED
Reel/Frame 071462/0465 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 20, 2025
From: ANDERSON, COREY; ARUMUGAM, VIJAYALAKSMI; ASGIAN, IULIANA LUCI; FANNING, LEV TYLER DEWEY; HADIDA RUAH, SARA SABINA; HURLEY, DENNIS; SCHMIDT, YVONNE; PATEL, URVI
To: VERTEX PHARMACEUTICALS (SAN DIEGO) LLC
Reel/Frame 071462/0608 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jun 20, 2025
From: VERTEX PHARMACEUTICALS (SAN DIEGO) LLC
To: VERTEX PHARMACEUTICALS INCORPORATED
Reel/Frame 071462/0680 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 6, 2021
From: THOMSON, STEPHEN ANDREW
To: VERTEX PHARMACEUTICALS INCORPORATED
Reel/Frame 057102/0904 →
Continuity (2)
Provisional Application 62790886 · Jan 10, 2019
Related Publication 20220110923A1 · Apr 14, 2022
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