SULFONAMIDE OREXIN RECEPTOR AGONISTS AND USES THEREOF
Provided herein are compounds of Formula (I), or pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 , R 4 , A, L 1 , L 2 , Y and Z are defined herein. Also provided herein are pharmaceutical compositions comprising a compound of Formula (I) or pharmaceutically acceptable salt thereof, and methods of using a compound of Formula (I) or pharmaceutically acceptable salt thereof, e.g., in the treatment of a disease or disorder that is treatable by administration of an Orexin agonist.
1 . A compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein
A is a heteroaryl;
L 1 is —O—, —CR 5 R 6 —or a bond;
L 2 is —CR 5 R 6 ;
R 1 is alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, or —NR 7 R 8 , or R 1 and R 2 together with the atom to which they are attached form a heterocycle;
R 2 , R 3 , R 4 are independently hydrogen, alkyl, cycloalkyl, heterocyclyl, or halogen, or R 2 and R 3 together with the atom to which they are attached to form a carbocycle or heterocycle, or R 2 and R 4 together with the atom to which they are attached to form a carbocycle or heterocycle;
R 5 and R 6 are each independently hydrogen, alkyl, cycloalkyl, heterocyclyl, alkoxy, —O-cycloalkyl, —O-heterocyclyl, or halogen, or R 5 and R 6 together with the atom to which they are attached to form a carbocycle or heterocycle;
R 7 and R 8 are independently hydrogen, alkyl, cycloalkyl, or heterocyclyl, or R 7 and R 8 together with the atom to which they are attached form a heterocycle;
Y is cycloalkyl, heterocyclyl, heteroaryl or aryl; and
Z is absent, heteroaryl or aryl, wherein if L 1 is a bond or CR 5 R 6 then Z is heteroaryl or aryl; and with the proviso that the compound is not:
2 . The compound of claim 1 , wherein L 1 is —O—.
3 . The compound of claim 1 , wherein L 1 is a bond.
4 . The compound of any one of claims 1-3 , wherein R 1 is an alkyl, haloalkyl, cycloalkyl, alkylene-alkoxy, —NR 7 R 8 .
5 . The compound of claim 4 , wherein R 1 is an alkyl, haloalkyl, or —NR 7 R 8 .
6 . The compound of claim 4 , wherein R 1 is methyl.
7 . The compound of any one of claims 1-5 , wherein R 1 is —NR 7 R 8 .
8 . The compound of claim 7 , wherein R 7 and R 8 are alkyl.
9 . The compound of any one of claims 1-8 , wherein R 2 and R 3 are independently hydrogen or alkyl and R 4 is hydrogen.
10 . The compound of any one of claims 1-9 , wherein R 2 , R 3 , R 4 are hydrogen.
11 . The compound of any one of claims 1-10 , wherein Y is 3-7 membered monocyclic cycloalkyl, 5-8 membered bicyclic cycloalkyl, 4-7 membered saturated heterocyclyl, 5-8 membered bicyclic heterocyclyl, 5-6-membered heteroaryl or phenyl.
12 . The compound of any one of claims 1-11 , wherein Z is 5-10 membered heteroaryl or phenyl.
13 . The compound of claim 12 , wherein Z is phenyl substituted with one or two halogens.
14 . The compound of any one of claims 1-12 , wherein Y and Z are phenyl.
15 . The compound of any one of claims 1-12 , wherein Y is cyclohexyl and Z is phenyl.
16 . The compound of claim 11 , wherein Y is a 2-oxaspiro[4.5]decane or cyclohexyl optionally substituted one or more alkyl or cycloalkyl.
17 . The compound of claim 14 , wherein Y and Z together are:
18 . The compound of any one of claims 1-17 , wherein A is a substituted or unsubstituted monocyclic or bicyclic nitrogen-containing heteroaryl.
19 . The compound of claim 18 , wherein A is selected from the group consisting of:
wherein n is an integer from 0-6;
R 9 is hydrogen, alkyl, haloalkyl, haloalkoxy, halogen, cyano, alkoxy, cycloalkyl, heterocyclyl, or heteroaryl; and
R 11 is alkyl optionally substituted with cyano, haloalkyl, cycloalkyl or heterocyclyl.
20 . The compound of claim 19 , wherein n is 1.
21 . The compound of claim 19 , wherein n is 2.
22 . The compound of claim 19 , wherein A is
23 . The compound of claim 19 , wherein A is
24 . The compound of any one of claims 19-23 , wherein R 9 is alkyl or halogen.
25 . The compound of any one of claims 19-24 , wherein R 11 is alkyl or haloalkyl.
26 . The compound of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of compounds in Table 1.
27 . A pharmaceutical composition comprising a compound of any one of claims 1-26 and pharmaceutically acceptable excipient.
28 . A method of treating a disease or disorder that is treatable by administration of an Orexin agonist, the method comprising administering a therapeutically effective amount of the compound of any one of claims 1-26 or the composition of claim 27 .
29 . A method of treating a sleep disorder in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-26 or the composition of claim 27 .
30 . A method for treating narcolepsy in a subject in need thereof, comprising administering to the subject an effective amount of the compound of the compound of any one of claims 1-26 or the composition of claim 27 .
31 . A method for treating hypersomnia in a subject in need thereof, comprising administering to the subject an effective amount of the compound of the compound of any one of claims 1-26 or the composition of claim 27 .
32 . A method for decreasing or treating excessive sleepiness in a subject in need thereof, comprising administering to the subject an effective amount of the compound of the compound of any one of claims 1-26 or the composition of claim 27 .