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US 12,753,188 B2Granted
Substituted macrocyclic compounds and related methods of treatment
AssigneeAlkermes, Inc.
InventorsLewis 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
Life of this patent
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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.
Claims22
A compound of Formula I-A 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 R11 is hydroxyl;
- or
- (f) at least one of R12 and R13 is C1-C3 alkyl substituted with hydroxyl.
32 more elements
A compound of Formula II-A 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 2, 3, 4, or 5 when Y is absent;
- or
- m is 1, 2, 3, or 4 when Y is NR10 or O;
- 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;
- R10 is selected from the group consisting of H, unsubstituted C1-C3 alkyl, and C1-C3 alkyl substituted with one or more halogen;
- 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 R11 is hydroxyl;
- or
- (f) at least one of R12 and R13 is C1-C3 alkyl substituted with hydroxyl.
35 more elements
Dependencies are inferred from the claim text.