SUBSTITUTED FUSED BICYCLIC MACROCYCLIC COMPOUNDS AND RELATED METHODS OF TREATMENT
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.
1 . A compound of Formula I-A or a pharmaceutically acceptable salt thereof:
wherein:
fused ring A is a C 4 -C 8 cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C 4 -C 8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C 1 -C 3 alkoxyl, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen or deuterium;
is a single bond or double bond;
J and L are each, independently, C or N;
M is N or CR 19 ;
Q is N or CR 20 ;
G is C(═O) or S(═O) 2 ;
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;
Y is NR 10 , O or absent;
Z is (CR 12 R 13 ) m ;
R a and R b 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 1 , 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;
R 10 is selected from the group consisting of H, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen;
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;
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; and
R 19 and R 20 are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen or deuterium.
2 - 16 . (canceled)
17 . A compound of Formula II-A or a pharmaceutically acceptable salt thereof:
wherein:
fused ring A is a C 4 -C 8 cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C 4 -C 8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C 1 -C 3 alkoxyl, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen or deuterium;
is a single bond or double bond;
J and L are each, independently, C or N;
M is N or CR 19 ;
Q is N or CR 20 ;
G is C(═O) or S(═O) 2 ;
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;
Y is NR 10 , O or absent;
Z is (CR 12 R 13 ) m ;
R a and R b 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 1 , 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;
R 10 is selected from the group consisting of H, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen;
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;
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; and
R 19 and R 20 are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen or deuterium.
18 - 32 . (canceled)
33 . A compound of Formula III-A or a pharmaceutically acceptable salt thereof:
wherein:
fused ring A is a C 4 -C 8 cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C 4 -C 8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C 1 -C 3 alkoxyl, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen or deuterium;
is a single bond or double bond;
J and L are each, independently, C or N;
M is N or CR 19 ;
Q is N or CR 20 ;
G is C(═O) or S(═O) 2 ;
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;
Y is NR 10 , O or absent;
Z is (CR 12 R 13 ) m ;
R a and R b 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 1 , 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;
R 10 is selected from the group consisting of H, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen;
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;
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; and
R 19 and R 20 are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen or deuterium.
34 - 48 . (canceled)
49 . A compound of Formula IV-A or a pharmaceutically acceptable salt thereof:
wherein:
fused ring A is a C 4 -C 8 cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C 4 -C 8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C 1 -C 3 alkoxyl, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen or deuterium;
is a single bond or double bond;
J and L are each, independently, C or N;
M is N or CR 19 ;
Q is N or CR 20 ;
G is C(═O) or S(═O) 2 ;
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;
Y is NR 10 , O or absent;
Z is (CR 12 R 13 ) m ;
R a and R b are each, independently, H or unsubstituted C 1 -C 3 alkyl;
m is 2, 3, 4, or 5 when Y is absent; or
m is 1, 2, 3, or 4 when Y is NR 10 or O;
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 1 , 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;
R 10 is selected from the group consisting of H, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen;
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;
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; and
R 19 and R 20 are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen or deuterium.
50 - 64 . (canceled)
65 . A compound of Formula V-A or a pharmaceutically acceptable salt thereof:
wherein:
fused ring A is a C 4 -C 8 cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C 4 -C 8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C 1 -C 3 alkoxyl, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen or deuterium;
is a single bond or double bond;
J and L are each, independently, C or N;
M is N or CR 19 ;
Q is N or CR 20 ;
G is C(═O) or S(═O) 2 ;
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;
Y is NR 10 , O or absent;
Z is (CR 12 R 13 ) m ;
R a and R b are each, independently, H or unsubstituted C 1 -C 3 alkyl;
m is 2, 3, 4, or 5 when Y is absent; or
m is 1, 2, 3, or 4 when Y is NR 10 or O;
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 1 , 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;
R 10 is selected from the group consisting of H, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen;
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;
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; and
R 19 and R 20 are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen or deuterium.
66 - 80 . (canceled)
81 . A compound of Formula VI-A or a pharmaceutically acceptable salt thereof:
wherein:
fused ring A is a C 4 -C 8 cycloalkyl, a 4- to 7-membered heterocyclyl, or a 5- to 8-membered heteroaryl, wherein the C 4 -C 8 cycloalkyl, 4- to 7-membered heterocyclyl, or 5- to 8-membered heteroaryl is unsubstituted or substituted with one or more halogen, deuterium, hydroxyl, cyano, C 1 -C 3 alkoxyl, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen or deuterium;
is a single bond or double bond;
J and L are each, independently, C or N;
M is N or CR 19 ;
Q is N or CR 20 ;
G is C(═O) or S(═O) 2 ;
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;
Y is NR 10 , O or absent;
Z is (CR 12 R 13 ) m ;
R a and R b are each, independently, H or unsubstituted C 1 -C 3 alkyl;
m is 2, 3, 4, or 5 when Y is absent; or
m is 1, 2, 3, or 4 when Y is NR 10 or O;
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 1 , 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;
R 10 is selected from the group consisting of H, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen;
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;
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; and
R 19 and R 20 are each, independently, selected from the group consisting of H, halogen, deuterium, hydroxyl, cyano, unsubstituted C 1 -C 3 alkyl, and C 1 -C 3 alkyl substituted with one or more halogen or deuterium.
82 - 96 . (canceled)
97 . A compound or a pharmaceutically acceptable salt thereof selected from the group consisting of:
98 . A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
99 . 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 98 .
100 . 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 98 .
101 - 104 . (canceled)
105 . A pharmaceutical composition comprising a compound of claim 17 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
106 . A method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of claim 17 or a pharmaceutically acceptable salt thereof, or a composition according to claim 105 .
107 . A method of treating cataplexy in a subject in need thereof comprising administering to the subject a compound of claim 17 or a pharmaceutically acceptable salt thereof, or a composition according to claim 105 .
108 . A pharmaceutical composition comprising a compound of claim 33 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
109 . A method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of claim 33 or a pharmaceutically acceptable salt thereof, or a composition according to claim 108 .
110 . A method of treating cataplexy in a subject in need thereof comprising administering to the subject a compound of claim 33 or a pharmaceutically acceptable salt thereof, or a composition according to claim 108 .
111 . A pharmaceutical composition comprising a compound of claim 49 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
112 . A method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of claim 49 or a pharmaceutically acceptable salt thereof, or a composition according to claim 111 .
113 . A method of treating cataplexy in a subject in need thereof comprising administering to the subject a compound of claim 49 or a pharmaceutically acceptable salt thereof, or a composition according to claim 111 .
114 . A pharmaceutical composition comprising a compound of claim 65 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
115 . A method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of 65 or a pharmaceutically acceptable salt thereof, or a composition according to claim 114 .
116 . A method of treating cataplexy in a subject in need thereof comprising administering to the subject a compound of claim 65 or a pharmaceutically acceptable salt thereof, or a composition according to claim 114 .
117 . A pharmaceutical composition comprising a compound of claim 81 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
118 . A method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of 81 or a pharmaceutically acceptable salt thereof, or a composition according to claim 117 .
119 . A method of treating cataplexy in a subject in need thereof comprising administering to the subject a compound of claim 81 or a pharmaceutically acceptable salt thereof, or a composition according to claim 117 .