Granted Patent B2

US 12,533,341 · App. 17/783,531 · Granted Jan 27, 2026

Inventors: Andrey Bortsov (Durham, NC); Sharat Chandra (Durham, NC); Ru-Rong Ji (Durham, NC)

Assignee: Duke University

A61K31/4045A61K9/0019A61P17/04

Abstract

Claims (35)

1 . A method of treating a condition selected from the group consisting of itch, pain, and combinations thereof, the method comprising administering a therapeutically effective amount of a Nav1.7 inhibitor to a subject in need thereof, wherein the Nav1.7 inhibitor is an N-substituted indole, wherein the N-substituted indole is a compound according to Formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R 1 is -L 1 -R 1a ;

-L 1 - is selected from the group consisting of —(CH 2 ) n —, —NHS(O) 2 —, —NHC(O)—, and —S(O) 2 —, wherein subscript n is 1, 2, 3, 4, 5, or 6;

R 1a is selected from the group consisting of C 6-14 aryl, C 3-8 cycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, (C 6-14 aryl) sulfonyl, (C 1-8 alkyl) sulfonyl, (C 3-8 cycloalkyl)sulfonyl, C 2-8 alkyl, C 2-8 alkenyl, and C 2-8 alkynyl, each of which is optionally substituted with one or more R 1b ;

each R 1b is independently selected from the group consisting of halogen, —CN, —NO 2 , —NHR 1c , —N═C(OH)R 1d , —N 3 , —OH, —SH, —SO 3 H, C 1-8 alkyl, C 1-8 alkoxy, C 2-8 alkenyl, C 2-8 alkynyl, C 3-10 cycloalkyl, —COOR 1c , —C(O)NHR 1c , and —C(O)R 1d , wherein each R 1c is independently selected from the group consisting of H and C 1-4 alkyl and each R 1d is independently C 1-4 alkyl;

subscript x is 0, 1, 2, 3, or 4;

each R 2 is independently selected from the group consisting of halogen, —CN, —NO 2 , —NHR 1c , —N 3 , —OH, —SH, —SO 3 H, C 1-8 alkyl, C 1-8 alkoxy, —COOR 1c , —C(O)NHR 1c , and —C(O)R 1d ;

R 3 is -L 3 -R 3a ;

-L 3 - is selected from the group consisting of a bond, —O—, —O(CH 2 ) n —, —(CH 2 ) n —, —NHC(O)—, —NHS(O) 2 —, and —S(O) 2 —, wherein subscript n is 1,2, 3,4, 5, or 6;

R 3a is selected from the group consisting of C 6-14 aryl, C 3-8 cycloalkyl, 5- to 10-membered heteroaryl, 3- to 10-membered heterocyclyl, (C 6-14 aryl)sulfonyl, (C 1-8 alkyl)sulfonyl, (C 3-8 cycloalkyl)sulfonyl, C 1-8 alkyl, C 2-8 alkenyl, and C 2-8 alkynyl, each of which is optionally substituted with one or more R 3b ;

each R 3b is independently selected from the group consisting of halogen, —CN, —NO 2 , —NHR 3c , —N 3 , —OH, —SH, —SO 3 H, C 1-8 alkyl, C 1-8 alkoxy, —COOR 3c , —C(O)NHR 3c , and —C(O)R 3d , wherein each R 3c is independently selected from the group consisting of H and C 1-4 alkyl and each R 3d is independently C 1-4 alkyl;

R 4 is selected from the group consisting of H and C 1-6 alkyl;

subscript y is 2, 1, 3, 4, 5, or 6;

subscript z is 0 or 1;

R 5 is selected from the group consisting of H and C 1-6 alkyl;

alternatively, R 4 and R 5 are taken together to form 4- to 10-membered heterocyclylene;

R 6 is selected from the group consisting of 5- to 10-membered heterocyclyl, 3- or 4-membered heterocyclyl, 5- to 10-membered heteroaryl, C 3-8 cycloalkyl, C 6-14 aryl, and C 7-22 arylalkyl, each of which is optionally substituted with one or more R 6a ; and

each R 6a is independently selected from the group consisting of halogen, —CN, —NO 2 , —NHR 6b , —N 3 , —OH, —SH, —SO 3 H, C 1-8 alkyl, C 1-8 alkoxy, —COOR 6b , —C(O)NHR 6b , and —C(O)R 6c , wherein each R 6b is independently selected from the group consisting of H and C 1-4 alkyl and each R 6c is independently C 1-4 alkyl.

2 . The method of claim 1 , wherein -L 1 - is -CH 2 -, and R 1a is phenyl which is optionally substituted with one or more R 1b .

3 . The method of claim 1 , wherein -L 3 - is selected from the group consisting of —O— and —OCH 2 —, and R 3a is phenyl which is optionally substituted with one or more R 3b .

4 . The method of claim 1 , wherein subscript y is 1 or 2.

5 . The method of claim 1 , wherein R 4 is H.

6 . The method of claim 1 , wherein R 6 is selected from the group consisting of pyrrolidin-1-yl, furan-2-yl, phenyl, pyridin-4-yl, and benzhydryl, each of which is optionally substituted with one or more R 6a .

7 . The method of claim 1 , wherein subscript x is 0.

8 . The method of claim 1 , wherein subscript z is 1 and R 4 and R 5 are taken together to form piperazin-1,4-diyl.

9 . The method of claim 1 , wherein the Nav1.7 inhibitor is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

10 . The method of claim 1 , wherein the Nav1.7 inhibitor is selected from the group consisting of:

and pharmaceutically acceptable salts thereof.

11 . The method of claim 1 , wherein the condition is itch.

12 . The method of claim 11 , wherein the itch comprises histamine-induced acute itch, lymphoma-induced chronic itch, allergic itch, infection-induced itch, liver- or kidney-induced itch, diabetes-induced itch, skin disorder-induced itch, opioid-induced itch, itch associated with Nav1.7 gain-of function mutations, or a combination thereof.

13 . The method of claim 1 , wherein the condition is pain.

14 . The method of claim 13 , wherein the pain comprises neuropathic pain, inflammatory pain, cancer pain, or a combination thereof.

15 . The method of claim 1 , wherein the Nav1.7 inhibitor is administered intrathecally or intraperitoneally.

Assignments (1)

Continuity (2)

References Cited (82)