IP Library › Granted Patent US 12,637,476
Granted Patent B2
US 12,637,476 · App. 18/389,467 · Granted May 26, 2026

Substituted carbamate macrocyclic compounds and related methods of treatment

Inventors: Lewis D. Pennington (Arlington, MA); Younggi Choi (Stow, MA); Hoan Huynh (Waltham, MA); Brian M. Aquila (Marlborough, MA); Ingo Andreas Mugge (Waltham, MA); Yuan Hu (Waltham, MA); James R. Woods (Waltham, MA); Brian Kenneth Raymer (Holliston, MA); Jörg Martin Bentzien (White Plains, NY); Jonathan Ward Lehmann (Burlington, MA); Michael R. Hale (Bedford, MA)
Assignee: Alkermes, Inc.
C07D498/08A61K31/439
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Quick Facts
Patent No.
US 12,637,476
App. No.
18/389,467
Granted
May 26, 2026
Kind
B2
Abstract

The present invention provides compounds useful for the treatment of narcolepsy or cataplexy in a subject in need thereof. Related pharmaceutical compositions and methods are also provided herein.

Claims (44)

1 . A compound of Formula I-A or a pharmaceutically acceptable salt thereof:

wherein:

n is 1, 2, or 3;

E is selected from the group consisting of H, hydroxyl, NR a R b , C(═O)NR a R b , C 1 -C 3 alkylene-NR a R b , C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), C 6 -C 10 aryl, C 1 -C 3 alkylene-(C 6 -C 10 aryl), 5- to 10-membered heteroaryl, and C 1 -C 3 alkylene-(5- to 10-membered heteroaryl), wherein the C 1 -C 3 alkylene-NR a R b , C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), C 6 -C 10 aryl, C 1 -C 3 alkylene-(C 6 -C 10 aryl), 5- to 10-membered heteroaryl, or C 1 -C 3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl;

T is CR 1 R 2 or O;

W is CR 4 R 5 or O;

U is CR 6 R 7 ;

X is CR 8 R 9 ;

V is CR 3 or N;

Z is (CR 12 R 13 ) m ;

R is selected from the group consisting of H, C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), C 6 -C 10 aryl, C 1 -C 3 alkylene-(C 6 -C 10 aryl), 5- to 10-membered heteroaryl, and C 1 -C 3 alkylene-(5- to 10-membered heteroaryl), wherein the C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), C 6 -C 10 aryl, C 1 -C 3 alkylene-(C 6 -C 10 aryl), 5- to 10-membered heteroaryl, or C 1 -C 3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxyl, or NR c R d ;

R a , R b , R c , and R d are each, independently, H or unsubstituted C 1 -C 3 alkyl;

m is 1, 2, 3, or 4;

and further wherein:

R 1 , R 2 , R 4 , and R 5 are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;

or, alternatively, R 2 and R 5 together with the carbon atoms to which they are attached, form a single bond;

R 3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;

or, alternatively, R 3 and R, together with the carbon atoms to which they are attached, form a C 3 -C 5 cycloalkyl;

or, alternatively, R 3 and R 4 , together with the carbon atoms to which they are attached, form a C 3 -C 5 cycloalkyl;

R 6 , R 7 , R 8 , R 9 , and R 11 are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;

each R 12 and R 13 is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with hydroxyl or one or more halogen; and

R 14 , R 15 , and R 16 are each, independently, selected from the group consisting of H, unsubstituted C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted with one or more halogen; and

each R 17 and R 18 is, independently, selected from the group consisting of H, unsubstituted C 1 -C 3 alkyl or C 1 -C 3 alkyl substituted with one or more halogen.

2 . The compound of claim 1 , wherein the compound of Formula I-A or a pharmaceutically acceptable salt thereof is a compound of Formula I or a pharmaceutically acceptable salt thereof:

3 . The compound of claim 1 , wherein n is 1 or 2.

4 . The compound of claim 1 , wherein T is CR 1 R 2 .

5 . The compound of claim 1 , wherein T is O.

6 . The compound of claim 1 , wherein W is CR 4 R 5 .

7 . The compound of claim 1 , wherein W is O.

8 . The compound of claim 1 , wherein V is CR 3 .

9 . The compound of claim 1 , wherein E is selected from the group consisting of C(═O)NR a R b , C 1 -C 3 alkylene-NR a R b , C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), C 6 -C 10 aryl, C 1 -C 3 alkylene-(C 6 -C 10 aryl), 5- to 10-membered heteroaryl, and C 1 -C 3 alkylene-(5- to 10-membered heteroaryl), wherein the C 1 -C 3 alkylene-NR a R b , C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), C 6 -C 10 aryl, C 1 -C 3 alkylene-(C 6 -C 10 aryl), 5- to 10-membered heteroaryl, or C 1 -C 3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl.

10 . The compound of claim 1 , wherein E is selected from the group consisting of C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), C 6 -C 10 aryl, C 1 -C 3 alkylene-(C 6 -C 10 aryl), 5- to 10-membered heteroaryl, and C 1 -C 3 alkylene-(5- to 10-membered heteroaryl), wherein the C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), C 6 -C 10 aryl, C 1 -C 3 alkylene-(C 6 -C 10 aryl), 5- to 10-membered heteroaryl, or C 1 -C 3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl.

11 . The compound of claim 1 , wherein E is selected from the group consisting of C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, and C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), wherein the C 1 -C 3 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, C 3 -C 8 cycloalkyl, or C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl.

12 . The compound of claim 1 , wherein E is selected from the group consisting of 4- to 10-membered heterocyclyl, C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), C 6 -C 10 aryl, C 1 -C 3 alkylene-(C 6 -C 10 aryl), 5- to 10-membered heteroaryl, and C 1 -C 3 alkylene-(5- to 10-membered heteroaryl), wherein the 4- to 10-membered heterocyclyl, C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), C 6 -C 10 aryl, C 1 -C 3 alkylene-(C 6 -C 10 aryl), 5- to 10-membered heteroaryl, or C 1 -C 3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl.

13 . The compound of claim 1 , wherein E is selected from the group consisting of 4- to 7-membered heterocyclyl and C 1 -C 3 alkylene-(4- to 7-membered heterocyclyl), wherein the 4- to 7-membered heterocyclyl or C 1 -C 3 alkylene-(4- to 7-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl.

14 . The compound of claim 1 , wherein R is selected from the group consisting of C 1 -C 3 alkyl, C 2 -C 4 alkenyl, and C 2 -C 4 alkynyl, wherein the C 1 -C 3 alkyl, C 2 -C 4 alkenyl, or C 2 -C 4 alkynyl is unsubstituted or substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxyl, or NR c R d .

15 . The compound of claim 1 , wherein R is selected from the group consisting of C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), C 6 -C 10 aryl, C 1 -C 3 alkylene-(C 6 -C 10 aryl), 5- to 10-membered heteroaryl, and C 1 -C 3 alkylene-(5- to 10-membered heteroaryl), wherein the C 3 -C 8 cycloalkyl, C 1 -C 3 alkylene-(C 3 -C 8 cycloalkyl), 4- to 10-membered heterocyclyl, C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), C 6 -C 10 aryl, C 1 -C 3 alkylene-(C 6 -C 10 aryl), 5- to 10-membered heteroaryl, or C 1 -C 3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, C 1 -C 3 alkoxyl, or NR c R d .

16 . The compound of claim 1 , wherein T is CR 1 R 2 , W is CR 4 R 5 , and V is CR 3 .

17 . The compound of claim 1 , wherein m is 1 or 2.

18 . The compound of claim 1 , wherein m is 1.

19 . A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of:

20 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

21 . A method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a composition according to claim 20 .

22 . A method of treating cataplexy in a subject in need thereof comprising administering to the subject a compound of claim 1 or a pharmaceutically acceptable salt thereof, or a composition according to claim 20 .

Assignments (6)
SECURITY INTEREST Recorded Feb 13, 2026
From: ALKERMES, INC.
To: JPMORGAN CHASE BANK, N.A. AS ADMINISTRATIVE AGENT
Reel/Frame 073790/0950 →
RELEASE OF SECURITY INTEREST IN PATENTS PREVIOUSLY RECORDED AT REEL/FRAME (072656/0509) Recorded Feb 13, 2026
From: JPMORGAN CHASE BANK, N.A., AS ADMINISTRATIVE AGENT
To: ALKERMES, INC.
Reel/Frame 074858/0481 →
SECURITY INTEREST Recorded Oct 23, 2025
From: ALKERMES, INC.
To: JPMORGAN CHASE BANK, N.A. AS ADMINISTRATIVE AGENT
Reel/Frame 072656/0509 →
RELEASE OF PATENT SECURITY AGREEMENTS Recorded Dec 24, 2024
From: MORGAN STANLEY SENIOR FUNDING, INC.
To: ALKERMES, INC.
Reel/Frame 069771/0616 →
SECURITY INTEREST Recorded Jun 14, 2024
From: ALKERMES, INC.
To: MORGAN STANLEY SENIOR FUNDING, INC.
Reel/Frame 067726/0001 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 3, 2024
From: PENNINGTON, LEWIS D.; CHOI, YOUNGGI; HUYNH, HOAN; AQUILA, BRIAN M.; MUGGE, INGO ANDREAS; HU, YUAN; WOODS, JAMES R.; RAYMER, BRIAN KENNETH; BENTZIEN, JÖRG MARTIN; LEHMANN, JONATHAN WARD; HALE, MICHAEL R.
To: ALKERMES, INC.
Reel/Frame 066990/0203 →
Continuity (3)
Continuation PCTUS2022030841 · May 25, 2022
Provisional Application 63193256 · May 26, 2021
Related Publication 20240174689A1 · May 30, 2024
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