# US 12,006,330 B2 · Substituted macrocyclic compounds and related methods of treatment

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 12,006,330 B2
- Document ID: US12006330B2
- Status: Granted
- Kind: B2
- Application number: 17/556,250
- Filed: 2021-12-20
- Published: 2022-06-23
- Granted: 2024-06-11
- Earliest claimed: 2020-12-21
- Assignees: Alkermes, Inc.
- Applicants: Alkermes, Inc.
- Inventors: Lewis D. Pennington; Younggi Choi; Hoan Huynh; Brian M. Aquila; Ingo Andreas Mugge; Yuan Hu; James R. Woods; Brian Kenneth Raymer; Jörg Martin Bentzien; Jonathan Ward Lehmann; Michael R. Hale; Srinivasa Karra; Roman A. Valiulin; Daljit Matharu
- Web page: https://patentgrep.com/patent/US12006330B2

## CPC

- C07D 498/04: Ortho-condensed systems
- C07D 498/14: Ortho-condensed systems
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## 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

### Claim 1

A compound of Formula I or a pharmaceutically acceptable salt thereof:
wherein:
ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl;
n is 1, 2, or 3;
E is selected from the group consisting of NRaRb, C1-C3 alkylene-NRaRb, C1-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, and C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3 alkylene-NRaRb, C1-C3alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, or C1-C3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl;
T is CR1R2 or O;
W is CR4R5 or O;
U is CR6R7;
X is CR8R9;
V is CR3 or N;
Y is O;
Z is (CR12R13)m;
each R is, independently, selected from the group consisting of halogen, deuterium, hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium;
p is 0, 1, 2, 3, or 4;
Ra and Rb are each, independently, H or unsubstituted C1-C3 alkyl;
m is 1;
and further wherein:
R1, R2, R4, and R5 are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;
or, alternatively, R2 and R5 together with the carbon atoms to which they are attached, form a single bond;
R3 is selected from the group consisting of H, deuterium, halogen, hydroxyl, and cyano;
or, alternatively, R3 and R1, together with the carbon atoms to which they are attached, form a C3-C5 cycloalkyl;
or, alternatively, R3 and R4, together with the carbon atoms to which they are attached, form a C3-C5 cycloalkyl;
R6, R7, R8, R9, and R11 are each, independently, selected from the group consisting of H, hydroxyl, halogen, and deuterium;
each R12 and R13 is, independently, selected from the group consisting of H, halogen, deuterium, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with hydroxyl or one or more halogen; and
R14, R15, and R16 are each, independently, selected from the group consisting of H, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogen; and
each R17 and R18 is, independently, selected from the group consisting of H, unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogen;
with the proviso that one or more of (a)-(f) is present:
(a) at least one R is selected from the group consisting of hydroxyl, cyano, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen or deuterium;
(b) E is NRaRb, C1-C3 alkylene-NRaRb, C2-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, or C1-C3 alkylene-(5- to 10-membered heteroaryl), wherein the C1-C3 alkylene-NRaRb, C2-C3 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, C3-C8 cycloalkyl, C1-C3 alkylene-(C3-C8 cycloalkyl), 4- to 10-membered heterocyclyl, C1-C3 alkylene-(4- to 10-membered heterocyclyl), C6-C10 aryl, C1-C3 alkylene-(C6-C10 aryl), 5- to 10-membered heteroaryl, or C1-C3 alkylene-(5- to 10-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl;
(c) E is C1 alkyl substituted with one or more halogen, hydroxyl, C1-C3 alkyl, or C1-C3 alkoxyl;
(d) at least one of R14, R15, R16, R17, and R18 is unsubstituted C1-C3 alkyl or C1-C3 alkyl substituted with one or more halogen;
(e) at least one of R1, R2, R4, R5, R6, R7, R8, R9, and Ru is hydroxyl; or
(f) at least one of R12 and R13 is C1-C3 alkyl substituted with hydroxyl.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1, 2)

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 2.

### Claim 4 (depends on 1, 2)

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 2.

### Claim 5 (depends on 1)

The compound of claim 1, wherein the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:

### Claim 6 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 8 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 9 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 10 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 11 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 12 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 13 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 14 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 15 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 16 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 20 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 22 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 23 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 24 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 25 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 26 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 27 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 28 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 29 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 30 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 31 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 32 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 33 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 34 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 35 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 36 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 37 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 38 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 39 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 40 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 41 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 42 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 43 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 44 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 45 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 46 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 47 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 48 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 49 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 50 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 51 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 52 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 53 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 54 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 55 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 56 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 57 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 58 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 59 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 60 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 61 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 62 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 63 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 64 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 65 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 66 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 67 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 68 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 69 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 70 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 71 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 72 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 73 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 74 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 75 (depends on 1)

The compound of claim 1, wherein the compound is:

### Claim 76 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 77 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 78 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 79 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 80 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 81 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 82 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 83 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 84 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 85 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 86 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 87 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 88 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 89 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 90 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 91 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 92 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 93 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 94 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 95 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 96 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 97 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 98 (depends on 1)

The compound of claim 1, wherein the compound is:
or a pharmaceutically acceptable salt thereof.

### Claim 99 (depends on 5)

A pharmaceutical composition comprising a compound of claim 5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

### Claim 100 (depends on 5, 99)

A method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of claim 5 or a pharmaceutically acceptable salt thereof, or a composition according to claim 99.

### Claim 101 (depends on 5, 99)

A method of treating cataplexy in a subject in need thereof comprising administering to the subject a compound of claim 5 or a pharmaceutically acceptable salt thereof, or a composition according to claim 99.

### Claim 102 (depends on 1)

The compound of claim 1, wherein n is 1.

### Claim 103 (depends on 1)

The compound of claim 1, wherein n is 2.

### Claim 104 (depends on 1)

The compound of claim 1, wherein ring A is phenyl.

### Claim 105 (depends on 1)

The compound of claim 1, wherein ring A is pyridinyl.

### Claim 106 (depends on 1)

The compound of claim 1, wherein T is CR1R2.

### Claim 107 (depends on 1)

The compound of claim 1, wherein T is O.

### Claim 108 (depends on 1)

The compound of claim 1, wherein W is CR4R5.

### Claim 109 (depends on 1)

The compound of claim 1, wherein W is O.

### Claim 110 (depends on 1)

The compound of claim 1, wherein V is CR3.

### Claim 111 (depends on 1)

The compound of claim 1, wherein T is CR1R2, W is CR4R5, and V is CR3.

### Claim 112 (depends on 103)

The compound of claim 103, wherein ring A is phenyl, T is CR1R2, W is CR4R5, and V is CR3.

### Claim 113 (depends on 103)

The compound of claim 103, wherein ring A is pyridinyl, T is CR1R2, W is CR4R5, and V is CR3.