IP Library › Patent Application 18376020

Patent Application

App. No. 18/376,020

SUBSTITUTED AMIDE MACROCYCLIC COMPOUNDS WITH OREXIN-2 RECEPTOR AGONIST ACTIVITY

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Patent No.: US None
App. No.: 18/376,020

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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.

Claims (116)

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 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 ;

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

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

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; 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 n is 1 or 2.

3 . (canceled)

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

5 . (canceled)

6 . The compound of claim 4 , wherein Y is O or absent.

7 - 11 . (canceled)

12 . The compound of any claim 1 , wherein T is CR 1 R 2 or O.

13 . (canceled)

14 . The compound of claim 1 , wherein W is CR 4 R 5 or O.

15 . (canceled)

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

17 . The compound of any 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.

18 - 21 . (canceled)

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

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

24 . (canceled)

25 . The compound of claim 1 , wherein ring A is phenyl, T is CR 1 R 2 , W is CR 4 R 5 , and V is CR 3 .

26 . The compound of claim 25 , wherein Y is absent or O.

27 . (canceled)

28 . The compound of claim 25 , wherein m is 1 or 2.

29 . (canceled)

30 . The compound of claim 1 , wherein ring A is pyridinyl, T is CR 1 R 2 , W is CR 4 R 5 , and V is CR 3 .

31 . The compound of claim 30 , wherein Y is absent or O.

32 . (canceled)

33 . The compound of claim 30 , wherein m is 1 or 2.

34 . (canceled)

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

36 . A compound of Formula II or a pharmaceutically acceptable salt thereof: