Substituted Pyrrolidinyl And Piperidinyl Compounds And Related Methods Of Treatment

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

or a pharmaceutically acceptable salt thereof;

wherein:

ring A is selected from the group consisting of phenyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl, further wherein the ring is unsubstituted or substituted with 1-3 substituents, each independently selected from C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or halogen;

X is N or CH;

Y is S(═O) 2 , C(═O), or S(═O)(═NR e );

R e is selected from the group consisting of H, C 1 -C 3 alkyl, or C 3 -C 8 cycloalkyl;

E is selected from the group consisting of 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 7-membered heteroaryl and C 1 -C 3 alkylene-(5- to 7-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 7-membered heteroaryl or C 1 -C 3 alkylene-(5- to 7-membered heteroaryl) is unsubstituted or substituted with one or more halogen, hydroxyl, NR c R d , CF 3 , CHF 2 , CH 2 F, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl;

R a and R b are each, independently, selected from the group consisting of H, C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, and 4- to 7-membered heterocyclyl, wherein the C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or 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;

or, alternatively, R a and R b , together with the N atom to which they are attached, form a 4- to 7-membered heterocyclyl or 5- to 7-membered heteroaryl, wherein the 4- to 7-membered heterocyclyl or 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxyl, NR c R d , C 1 -C 3 alkyl, C 1 -C 3 alkoxyl, or C 1 -C 3 alkyl substituted with 1-3 halogen;

R 1 is selected from the group consisting of C(═O)—C 1 -C 4 alkyl, C(═O)—C 1 -C 4 alkoxyl, C(═O)—(CR c R d ) n —C 3 -C 8 cycloalkyl, C(═O)—(CR c R d ) n -(4- to 7-membered heterocyclyl), C(═O)—(CR c R d ) n —(C 6 -C 10 aryl), C(═O)—(CR c R d ) n -(5- to 10-membered heteroaryl), C(═O)—O—(CR c R d ) n —C 3 -C 8 cycloalkyl, C(═O)—O—(CR c R d ) n -(4- to 7-membered heterocyclyl), (CR c R d ) n —(C 6 -C 10 aryl) and (CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C 1 -C 4 alkyl, C 1 -C 4 alkoxyl, C 3 -C 8 cycloalkyl, 4- to 7-membered heterocyclyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium;

R c and R d are each, independently, H, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium;

n is 0, 1, or 2;

each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 is, independently, H, halogen, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium;

or, alternatively, R 3 and R 6 , together form an unsubstituted C 1 -C 3 alkylene or a C 1 -C 3 alkylene substituted with one or more halogen;

or, alternatively, R 4 and R 5 , together form an unsubstituted C 1 -C 3 alkylene or a C 1 -C 3 alkylene substituted with one or more halogen;

m is 0 or 1;

p is 0, 1, 2, 3, or 4; and

each R 9 is, independently, selected from the group consisting of deuterium, halogen, hydroxyl, and cyano;

provided that when:

Y is S(═O) 2 ,

m is 1,

E is 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, or C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), 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, or C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl;

R 1 is (CR c R d ) n —(C 6 -C 10 aryl) or (CR c R d ) n -(5- to 10-membered heteroaryl),

n is 0 or 1,

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

ring A is unsubstituted or substituted with 1-3 substituents, each independently selected from C 1 -C 3 alkyl or halogen,

then X is N.

2 . The compound according to 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 according to claim 1 , wherein ring A is a phenyl ring, wherein the ring is unsubstituted or substituted with 1-3 substituents, each independently selected from C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or halogen.

4 - 9 . (canceled)

10 . The compound of claim 1 , wherein ring A is a pyridinyl ring, wherein the ring is unsubstituted or substituted with 1-3 substituents, each independently selected from C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or halogen.

11 - 16 . (canceled)

17 . The compound according to claim 1 , wherein ring A is a pyridazinyl ring, wherein the ring is unsubstituted or substituted with 1-3 substituents, each independently selected from C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or halogen.

18 - 23 . (canceled)

24 . The compound according to claim 1 , wherein ring A is a pyrimidinyl ring, wherein the ring is unsubstituted or substituted with 1-3 substituents, each independently selected from C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or halogen.

25 - 30 . (canceled)

31 . The compound according to claim 1 , wherein ring A is a pyrazinyl ring, wherein the ring is unsubstituted or substituted with 1-3 substituents, each independently selected from C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or halogen.

32 - 37 . (canceled)

38 . The compound according to claim 1 , wherein ring A is a triazinyl ring, wherein the ring is unsubstituted or substituted with 1-3 substituents, each independently selected from C 1 -C 3 alkyl, C 3 -C 5 cycloalkyl, or halogen.

39 - 49 . (canceled)

50 . The compound according to claim 1 , wherein p is 0, 1, or 2.

51 . (canceled)

52 . The compound according to claim 1 , wherein E is NR a R b .

53 . The compound according to claim 1 , wherein E is C 1 -C 3 alkylene-NR a R b .

54 - 73 . (canceled)

74 . The compound according to claim 1 , wherein E is 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, or C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl), 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, or C 1 -C 3 alkylene-(4- to 10-membered heterocyclyl) is unsubstituted or substituted with one or more halogen, hydroxyl, NR c R d , CF 3 , CHF 2 , CH 2 F, C 1 -C 3 alkyl, or C 1 -C 3 alkoxyl.

75 - 89 . (canceled)

90 . The compound according to claim 1 , wherein Y is S(═O) 2 .

91 . The compound according to claim 1 , wherein Y is C(═O).

92 - 93 . (canceled)

94 . The compound according to claim 1 , wherein X is CH.

95 . The compound according to claim 1 , wherein R 1 is selected from the group consisting of C(═O)—C 1 -C 4 alkyl, C(═O)—C 1 -C 4 alkoxyl, C(═O)—(CR c R d ) n —C 3 -C 8 cycloalkyl, C(═O)—(CR c R d ) n -(4- to 7-membered heterocyclyl), C(═O)—(CR c R d ) n —(C 6 -C 10 aryl), and C(═O)—(CR c R d ) n -(5- to 10-membered heteroaryl), wherein the C 1 -C 4 alkyl, C 1 -C 4 alkoxyl, C 3 -C 8 cycloalkyl, 4- to 7-membered heterocyclyl, C 6 -C 10 aryl, or 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.

96 - 134 . (canceled)

135 . The compound according to claim 1 , wherein R 1 is (CR c R d ) n -(5- to 10-membered heteroaryl) wherein the 5- to 10-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.

136 - 140 . (canceled)

141 . The compound according to claim 1 , wherein R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(5- to 7-membered heteroaryl) wherein the phenyl or 5- to 7-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.

142 - 146 . (canceled)

147 . The compound according to claim 1 , wherein R 1 is (CR c R d ) n -(phenyl) or (CR c R d ) n -(6-membered heteroaryl) wherein the phenyl or 6-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.

148 - 152 . (canceled)

153 . The compound according to claim 1 , wherein R 1 is (CR c R d ) n -(6-membered heteroaryl) wherein the 6-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.

154 - 158 . (canceled)

159 . The compound according to claim 1 , wherein R 1 is (CR c R d ) n -(5-membered heteroaryl) wherein the 5-membered heteroaryl is unsubstituted or substituted with one or more halogen, hydroxyl, unsubstituted C 1 -C 3 alkyl, or C 1 -C 3 alkyl substituted with one or more halogen or deuterium.

160 - 225 . (canceled)

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

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

228 . 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 thereof.

229 . 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 thereof.

230 - 233 . (canceled)

234 . A pharmaceutical composition comprising a compound of claim 2 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

235 . A method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of claim 2 or a pharmaceutically acceptable salt thereof, or a composition thereof.

236 . A method of treating cataplexy in a subject in need thereof comprising administering to the subject a compound of claim 2 or a pharmaceutically acceptable salt thereof, or a composition thereof.

237 . A pharmaceutical composition comprising a compound of claim 226 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

238 . A method of treating narcolepsy in a subject in need thereof comprising administering to the subject a compound of claim 226 or a pharmaceutically acceptable salt thereof, or a composition thereof.

239 . A method of treating cataplexy in a subject in need thereof comprising administering to the subject a compound of claim 226 or a pharmaceutically acceptable salt thereof, or a composition thereof.