OX2R compounds
Methods and compositions for agonizing a type-2 orexin receptor (OX2R) in a cell determined to be in need thereof, including the general method of (a) administering to a subject a cyclic guanidinyl OX2R agonist and (b) detecting a resultant enhanced wakefulness or increased resistance to diet-induced accumulation of body fat, or abbreviated recovery from general anesthesia or jet lag.
1. A method of treating a subject suffering from or diagnosed with a disease, disorder, or medical condition mediated by orexin receptor activity, wherein the disease, disorder, or medical condition is a disorder of the sleep-wake cycle, insomnia, restless legs syndrome, jet-lag, disturbed sleep, a sleep disorder secondary to neurological disorders, mania, depression, manic depression, schizophrenia, a pain syndromes, fibromyalgia, neuropathic pain, catatonia, Parkinson's disease, Tourette's syndrome, anxiety, delirium, dementia, overweight, obesity or a condition related to overweight or obesity, insulin resistance, type II diabetes, hyperlipidemia, gallstones, angina, hypertension, breathlessness, tachycardia, infertility, sleep apnea, back and joint pain, varicose veins, osteoarthritis, arrhythmias, angina pectoris, acute heart failure, ulcers, irritable bowel syndrome, diarrhea, gastroesophageal reflux, post-traumatic stress disorder, panic disorders, attention deficit disorders, cognitive deficiencies, or substance abuse, the method comprising administering to the subject in need thereof an effective amount of a compound of formula (A):
or a pharmaceutically acceptable salt thereof, wherein:
Y 1 , Y 2 , Y 3 , and Y 4 , are each independently N or CR 6 , wherein no more than two of Y 1 , Y 2 , Y 3 , and Y 4 are N, wherein one of Y 1 and Y 2 is N and the other is CH or CR 6 ;
W 1 and W 2 are each independently selected from aryl, heterocyclyl, or heteroaryl, which are each optionally substituted with one or more R 10 ;
L 1 is C 1 -C 6 alkylene or C 2 -C 6 alkenylene, optionally substituted with one or more R 7 ;
L 2 is C 1 -C 6 alkylene or C 2 -C 6 alkenylene, optionally substituted with one or more R 8 ;
R 2 is NH, or NR 11 ;
R 6 is hydrogen, halogen, —CN, —NO 2 , —SC 1 -C 6 alkyl, —COR g , —C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, C 1 -C 6 haloalkyl, C 1 -C 6 alkoxy, or —C 1 -C 6 haloalkoxy,
R 7 is halogen, —OH, —NR a R b , —CN, —C 1 -C 6 alkyl, —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-CN, —CH(OH)CH 2 CN, —C 1 -C 3 alkylene-(C 1 -C 6 alkoxy), —C 1 -C 3 alkylene-(C 1 -C 6 haloalkoxy), —C 1 -C 3 alkylene-OCO(optionally substituted heterocyclyl), —C 1 -C 3 alkylene-OCOR 9 , —C 1 -C 3 alkylene-OCOOR g , —C 1 -C 3 alkylene-NR a R b , —C 1 -C 3 alkylene-NR a COR 9 , —C 1 -C 3 alkylene-NR a CO (optionally substituted heterocyclyl), —C 1 -C 3 alkylene-NR a COOR g , —C 1 -C 3 alkylene-NR a CONR a R b , —C 1 -C 3 alkylene-CONR a R b , —C 1 -C 3 alkylene-CONR c R d , —CONR a R b , —CONR c R d , —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-OH, —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-CN, —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-O—(C 1 -C 4 alkyl), —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-O—(C 1 -C 4 haloalkyl), —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-S—(C 1 -C 3 alkyl), —C 1 -C 3 alkylene-S(C 1 -C 6 alkyl), —C 1 -C 3 alkylene-SO(C 1 -C 6 alkyl), —C 1 -C 3 alkylene-SO 2 (C 1 -C 6 alkyl), —C 1 -C 3 alkylene-SO 2 R 12 , or hetercyclyl optionally substituted with R 10 ;
R 8 is —OH, —CN, —NO 2 , —COR g , oxo, —C 1 -C 6 alkyl, C 1 -C 6 alkylene-OH, —C 1 -C 6 haloalkyl, or —C 3 -C 6 cycloalkyl;
R a and R b are each independently H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —CHO, —COOH, —CO(C 1 -C 3 alkyl), —CO(C 1 -C 3 haloalkyl), —CO(C 3 -C 8 cycloalkyl), —CO(C 2 -C 4 alkenyl), —CO(C 1 -C 6 alkylene)-OH, —CO(C 1 -C 6 alkylene)-(C 1 -C 6 alkoxy), —CONR e R f , —CO(C 1 -C 3 alkylene)-NR e R f , —CO(C 1 -C 3 alkylene)-NR e SR f , —CO(C 1 -C 3 alkylene)-NR e SOR g , —CO(C 1 -C 3 alkylene)-NR e SO 2 R f , —CO(C 2 -C 3 alkenyl), —CO(C 1 -C 3 haloalkyl), —CO(CH 2 ) n (cycloalkyl), —CO(CH 2 ) n (optionally substituted aryl), —CO(CH 2 ) n (optionally substituted heterocyclyl), or —CO(CH 2 ) n (optionally substituted heteroaryl);
R c and R d together with the nitrogen atom to which it is attached to form an optionally substituted ring, which can be monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring can contain up to 3 heteroatoms selected from N, O, or S;
R e and R f are each independently H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, or —C 1 -C 6 alkylene-OH;
R g is H, —C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —C 1 -C 6 haloalkyl, phenyl, or benzyl;
R 9 is —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-CN, —C 1 -C 3 alkylene-(C 1 -C 3 alkoxy), —C 1 -C 3 alkylene-NR a R b , —C1-C4 alkyl or —C1-C4 fluoroalkyl;
R 10 is halogen, —CN, oxo, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, —S—S—(C 1 -C 6 alkyl), or optionally substituted phenyl;
R 11 is —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-(C 1 -C 3 alkoxy), or —COO(C 1 -C 6 alkyl);
alternatively, R 11 and R 7 together form a 5- to 7-membered ring, which is optionally substituted with R 10 ;
R 12 is —OH, —C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, phenyl, benzyl, —NR a R b , —CONR a R b , or —NR a COR g ; and
n is 0, 1, or 2.
2. The method of claim 1 , wherein R 2 is NH.
3. The method of claim 1 , wherein Y 3 and Y 4 , are each independently CH or CR 6 .
4. The method of claim 1 , wherein R 6 is halogen, methyl, —CH 2 F, —CHF 2 , or —CF 3 .
5. The method of claim 1 , wherein R 10 is halogen, methyl, —CH 2 F, —CHF 2 , or —CF 3 .
6. The method of claim 1 , wherein L 2 is C 1 alkylene or C 4 alkenylene, optionally substituted with one R 8 .
7. The method of claim 1 , wherein L 2 is C 1 alkylene, optionally substituted with one R 8 .
8. The method of claim 1 , wherein R 8 is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, —CH 2 F, —CHF 2 , or —CF 3 .
9. The method of claim 1 , wherein L 1 is C 2 alkylene optionally substituted with one R 7 .
10. The method of claim 1 , wherein -L 1 -W 1 is —CHR 7 CH 2 —W 1 .
11. The method of claim 1 , wherein W 1 is phenyl optionally substituted with R 10 .
12. The method of claim 1 , wherein W 2 is phenyl optionally substituted with R 10 .
13. The method of claim 1 , wherein R 7 is —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-CN, —C 1 -C 3 alkylene-(C 1 -C 6 alkoxy), —C 1 -C 3 alkylene-NR a R b , —C 1 -C 3 alkylene-OCO(optionally substituted heterocyclyl), —C 1 -C 3 alkylene-OCOR 9 , —C 1 -C 3 alkylene-NR a COR 9 , —C 1 -C 3 alkylene-NR a CO(optionally substituted heterocyclyl), —C 1 -C 3 alkylene-NR a CONR a R b , —CONR c R d , —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-OH, —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-CN, —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), —C 1 -C 3 alkylene-S(C 1 -C 6 alkyl), —C 1 -C 3 alkylene-SO(C 1 -C 6 alkyl), or —C 1 -C 3 alkylene-SO 2 (C 1 -C 6 alkyl).
14. The method of claim 1 , wherein R 7 is —CH 2 OH, —CH 2 NH 2 , —CH(CH 3 )OH, —CH 2 CN, —CH 2 (C 1 -C 3 alkoxy), —CH 2 OCO(optionally substituted heterocyclyl), —CH 2 OCOR 9 , —CH 2 NR a COR 9 , —CH 2 NR a CO(optionally substituted heterocyclyl), —CH 2 NR a CONR a R b , —CONR c R d , —CH 2 O—(C 1 -C 3 alkylene)-OH, —CH 2 O—(C 1 -C 3 alkylene)-CN, —CH 2 O—(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), —CH 2 S(C 1 -C 6 alkyl), —CH 2 SO(C 1 -C 6 alkyl), or —CH 2 SO 2 (C 1 -C 6 alkyl).
15. The method of claim 1 , wherein R 7 is —CH 2 OH, —CH 2 NH 2 , —CH(CH 3 )OH, —CH 2 CN, —CH 2 OCH 3 , —CH 2 OCO(optionally substituted azetidinyl), —CH 2 OCOCH 2 OH, —CH 2 NR a COCH 2 OH, —CH 2 NHCOCH 2 NHCH 3 , —CH 2 NR a CO(azyridinyl), —CH 2 NR a CONH 2 , —CONR c R d , —CH 2 O—(C 1 -C 3 alkylene)-OH, —CH 2 O—(C 1 -C 3 alkylene)-CN, —CH 2 O—(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), —CH 2 S(C 1 -C 3 alkyl), —CH 2 SO(C 1 -C 3 alkyl), or —CH 2 SO 2 (C 1 -C 3 alkyl).
16. The method of claim 1 , wherein R 7 is —CH 2 OH, —CH 2 NH 2 , —CH(CH 3 )OH, —CH 2 CN, —CH 2 OCH 3 , —CH 2 OCOCH 2 OH, —CH 2 NHCOCH 2 OH, —CH 2 N(CH 3 )COCH 2 OH, —CH 2 NHCOCH 2 NHCH 3 , —CH 2 NHCONH 2 , —CH 2 OCH 2 OH, —CH 2 OCH 2 CH 2 OH, —CH 2 OCH 2 CN, —CH 2 OCH 2 CH 2 CN, —CH 2 OCH 2 OCH 3 , —CH 2 OCH 2 CH 2 OCH 3 , —CH 2 SCH 3 , —CH 2 SOCH 3 , or —CH 2 SO 2 CH 3 .
17. The method of claim 1 , wherein R 7 is —CONR c R d selected from
each of which is optionally substituted with halogen, —CN, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkylene-OH, or —C 1 -C 6 alkylene-NH 2 .
18. The method of claim 1 , wherein the compound has the structure of formula (I):
or a pharmaceutically acceptable salt thereof, wherein:
Y 1 and Y 2 are each independently N or CR 6 ;
Ar 1 and Ar 2 are each independently C5-C10 aryl or 5- to 10-membered heteroaryl comprising one, two, or three heteroatoms selected from N, O, and S, each of which are optionally substituted with one or more R 10 ;
R 1 is —OH, —C 1 -C 4 alkoxy, —C 1 -C 4 haloalkoxy, —NR a R b , —NR a COR 9 , —NR a CO(optionally substituted heterocyclyl), —CONR a R b , —CONR c R d , SO 2 R 12 , —O—(C 1 -C 3 alkylene)O—(C 1 -C 4 alkyl) or —O—(C 1 -C 3 alkylene)-O—(C 1 -C 4 haloalkyl);
R 2 is NH, or NR 11 ,
R 3 is H or methyl;
R 4 is H, —CN, —NO 2 , —COR g , —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, or —C 3 -C 4 cycloalkyl;
R 5 is H or methyl;
R 6 is H, halogen, —CN, —NO 2 , —SCH 3 , —COR g , —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —C 3 -C 4 cycloalkyl, —C 1 -C 4 alkoxy, or —C 1 -C 4 haloalkoxy;
R a and R b are each independently H, —C 1 -C 4 alkyl, —C 1 -C 4 haloalkyl, —CHO, —CO(C 1 -C 3 alkyl), —CO(C 1 -C 6 alkylene)-OH, —CONR e R f , —CO(C 1 -C 3 alkylene)-NR e R f , —CO(C 1 -C 3 alkylene)-NR e SR f , —CO(C 1 -C 3 alkylene)-NR e SOR g , —CO(C 1 -C 3 alkylene)-NR e SO 2 R f , —CO(C 2 -C 3 alkenyl), C 3 haloalkyl), —CO(CH 2 ) n (cycloalkyl), —CO(CH 2 )(optionally substituted aryl), —CO(CH 2 ) n (optionally substituted heterocyclyl), or —CO(CH 2 ) n (optionally substituted heteroaryl);
R c and R d together with the nitrogen atom to which it is attached to form an optionally substituted ring, which can be monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring can contain up to 3 heteroatoms selected from N, O, and S;
R e and R f are each independently H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, or —C 1 -C 6 alkylene-OH,
R g is H, —C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —C 1 -C 6 haloalkyl, phenyl, or benzyl;
R 9 is —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-CN, —C 1 -C 3 alkylene-(C 1 -C 3 alkoxy), or —C 1 -C 3 alkylene-NR a R b , —C 1 -C 4 alkyl or —C 1 -C 4 fluoroalkyl;
R 10 is halogen, —CN, oxo, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, —S—S—(C 1 -C 6 alkyl), or optionally substituted phenyl;
R 11 is —C 1 -C 4 alkyl, —C 1 -C 4 fluoroalkyl, —C 1 -C 4 alkoxy, or COO(C 1 -C 4 alkyl);
alternatively, R 11 and R 7 together form a 5- to 7-membered ring, which is optionally substituted with R 10 ;
R 12 is —OH, —C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, phenyl, benzyl, —NR a R b , —CONR a R b , or —NR a COR g ;
n is 0, 1, or 2; and
m is 0, 1, or 2.
19. The method of claim 18 , wherein Ar 1 is phenyl optionally substituted with one or more R 10 , and R 10 is halogen, —CN, —C 1 -C 4 alkyl, or —C 1 -C 4 fluoroalkyl.
20. The method of claim 18 , wherein:
R 1 is —OH, —C 1 -C 4 alkoxy, C 1 -C 4 haloalkoxy, —NR a R b , —NHCOR 9 , or —CONR a R b ; R a and R b are each independently H, —C 1 -C 4 alkyl or —C 1 -C 4 fluoroalkyl; and R 9 is —C 1 -C 4 alkyl or —C 1 -C 4 fluoroalkyl or R 1 is —OH, —OCH 3 , —NHCH 3 , —N(CH 3 ) 2 , —NHSO 2 R 12 , or —NHCOR 12 ; and R 12 is —CH 3 , —CH 2 CH 3 , isopropyl, —CF 3 , —OH, —OCH 3 , —OCH 2 CH 3 , cyclopropyl, phenyl, benzyl, —NR a R b , —CONR a R b , or —NR a COR g ;
R 2 is NH, or NCH 3 ;
R 3 is H;
R 4 is H or methyl; and
R 6 is H, halogen, —CH 3 , —CF 3 , —CN, —SCH 3 , t-butyl, —OCH 3 , or —OCF 3 .
21. The method of claim 1 , wherein the compound has the structure of formula (B):
or a pharmaceutically acceptable salt thereof, wherein
Y 1 and Y 2 are each independently N or CR 6 ;
W 1 and W 2 are each independently 5- to 10-membered aryl, heterocyclyl, or heteroaryl, which are each optionally substituted with one or more R 10 ;
R 2 is NH;
R 6 is hydrogen, halogen, —CN, —C 1 -C 3 alkyl, —C 3 -C 6 cycloalkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, or C 1 -C 3 haloalkoxy;
R 7 is halogen, —OH, —CN, —C 1 -C 6 alkyl, —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-CN, —CH(OH)CH 2 CN, —C 1 -C 3 alkylene-(C 1 -C 6 alkoxy), —C 1 -C 3 alkylene-(C 1 -C 6 haloalkoxy), —C 1 -C 3 alkylene-OCO(optionally substituted heterocyclyl), —C 1 -C 3 alkylene-OCOR 9 , —C 1 -C 3 alkylene-OCOOR g , —C 1 -C 3 alkylene-NR a R b , —C 1 -C 3 alkylene-NR a COR 9 , —C 1 -C 3 alkylene-NR a CO(optionally substituted heterocyclyl), —C 1 -C 3 alkylene-NR a COOR g , —C 1 -C 3 alkylene-NR a CONR a R b , —C 1 -C 3 alkylene-CONR a R b , —C 1 -C 3 alkylene-CONR c R d , —CONR a R b , —CONR c R d , —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-OH, —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-CN, —C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-O—(C 1 -C 4 alkyl), —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-O—(C 1 -C 4 haloalkyl), —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-S—(C 1 -C 3 alkyl), —C 1 -C 3 alkylene-S(C 1 -C 6 alkyl), —C 1 -C 3 alkylene-SO(C 1 -C 6 alkyl), or —C 1 -C 3 alkylene-SO 2 (C 1 -C 6 alkyl);
R 8 is —OH, —CN, oxo, —C 1 -C 6 alkyl, C 1 -C 6 alkylene-OH, —C 1 -C 6 haloalkyl, or —C 3 -C 6 , cycloalkyl;
R a and R b are each independently H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —CHO, —CO(C 1 -C 3 alkyl), —CO(C 1 -C 6 alkylene)-OH, —CONR e R f , —CO(C 1 -C 3 alkylene)-NR e R f , —CO(C 1 -C 3 alkylene)-NR e SR f , —CO(C 1 -C 3 alkylene)-NR e SOR g , —CO(C 1 -C 3 alkylene)-NR e SO 2 R f , —CO(C 2 -C 3 alkenyl), —CO(C 1 -C 3 haloalkyl), —CO(CH 2 ) n (cycloalkyl), —CO(CH 2 ) n (optionally substituted aryl), —CO(CH 2 ) n (optionally substituted heterocyclyl), or —CO(CH 2 ) n (optionally substituted heteroaryl);
R c and R d together with the nitrogen atom to which it is attached to form an optionally substituted ring, which can be monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring can contain up to 3 heteroatoms selected from N, O, and S;
R e and R f are each independently H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, or —C 1 -C 6 alkylene-OH;
R g is H, —C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —C 1 -C 6 haloalkyl, phenyl, or benzyl;
R 9 is —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-CN, —C 1 -C 3 alkylene-(C 1 -C 3 alkoxy), or —C 1 -C 3 alkylene-NR a R b ;
R 10 is halogen, —CN, oxo, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, —S—S—(C 1 -C 6 alkyl), or optionally substituted phenyl;
R 11 is —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-(C 1 -C 3 alkoxy), or —COO(C 1 -C 6 alkyl);
alternatively, R 11 and R 7 together form a 5- to 7-membered ring, which is optionally substituted with R 10 ; and
n is 0, 1, or 2.
22. The method of claim 1 , wherein the compound has the structure of formula (C):
or a pharmaceutically acceptable salt thereof, wherein
Y 1 and Y 2 are each independently N or CR 6 ;
W 1 and W 2 are each independently 5- to 10-membered aryl, heterocyclyl, or heteroaryl, which are each optionally substituted with one or more R 10 ;
R 2 is NH;
R 6 is hydrogen, halogen, —CN, —C 1 -C 3 alkyl, —C 3 -C 6 cycloalkyl, C 1 -C 3 haloalkyl, C 1 C 3 alkoxy, or C 1 C 3 haloalkoxy;
R 7 is; —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-CN, —C 1 -C 3 alkylene-(C 1 -C 6 alkoxy), —C 1 -C 3 alkylene-NR a R b , —C 1 -C 3 alkylene-OCO(optionally substituted heterocyclyl), —C 1 -C 3 alkylene-OCOR 9 , —C 1 -C 3 alkylene-NR a R 9 , —C 1 -C 3 alkylene-NR a CO(optionally substituted heterocyclyl), —C 1 -C 3 alkylene-NR a CONR b , —CONR c R d , —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-OH, —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-CN, —(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), —C 1 -C 3 alkylene-S(C 1 -C 6 alkyl), —C 1 -C 3 alkylene-SO(C 1 -C 6 alkyl), or —C 1 -C 3 alkylene-SO 2 (C 1 -C 6 alkyl);
R 8 is —OH, —CN, oxo, —C 1 -C 6 alkyl, C 1 -C 6 alkylene-OH, —C 1 -C 6 haloalkyl, or —C 3 -C 6 cycloalkyl;
R a and R b are each independently H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —CHO, —CO(C 1 -C 3 alkyl), —CO(C 1 -C 6 alkylene)-OH, —CONR e R f , —CO(C 1 -C 3 alkylene)-NR e R f , —CO(C 1 -C 3 alkylene)-NR e SR f , —CO(C 1 -C 3 alkylene)-NR e SOR g , —CO(C 1 -C 3 alkylene)-NR e SO 2 R f , —CO(C 2 -C 3 alkenyl), —CO(C 1 -C 3 haloalkyl), —CO(CH 2 ) n (cycloalkyl), —CO(CH 2 ) n (optionally substituted aryl), —CO(CH 2 ) n (optionally substituted heterocyclyl), or —CO(CH 2 ) n (optionally substituted heteroaryl);
R c and R d together with the nitrogen atom to which it is attached to form an optionally substituted ring, which can be monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring can contain up to 3 heteroatoms selected from N, O, and S;
R e and R f are each independently H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, or —C 1 -C 6 alkylene-OH;
R g is H, —C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —C 1 -C 6 haloalkyl, phenyl, or benzyl;
R 9 is —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-CN, —C 1 -C 3 alkylene-(C 1 -C 3 alkoxy), or —C 1 -C 3 alkylene-NR a R b ;
R 10 is halogen, —CN, oxo, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, —S—S—(C 1 -C 6 alkyl), or optionally substituted phenyl;
R 11 is —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-(C 1 -C 3 alkoxy), —COO(C 1 -C 6 alkyl); and
n is 0, 1, or 2.
23. The method of claim 1 , wherein the compound has the structure of formula (D):
or a pharmaceutically acceptable salt thereof, wherein
Y 1 and Y 2 are each independently N or CR 6 ;
W 1 and W 2 are each phenyl, which are each optionally substituted with one or more R 10 ;
R 2 is NH;
R 6 is hydrogen, halogen, —CN, —C 1 -C 3 alkyl, —C 3 -C 6 cycloalkyl, C 1 -C 3 haloalkyl, C 1 -C 3 alkoxy, or —C 1 -C 3 haloalkoxy;
R 7 is —CH 2 OH, —CH 2 NH 2 , —CH(CH 3 )OH, —CH 2 CN, —CH 2 (C 1 -C 3 alkoxy), —CH 2 OCO(optionally substituted heterocyclyl), —CH 2 OCOR 9 , —CH 2 NR a COR 9 , —CH 2 NR a CO(optionally substituted heterocyclyl), —CH 2 NR a CONR a R b , —CONR e R d , —CH 2 O—(C 1 -C 3 alkylene)-OH, —CH 2 O—(C 1 -C 3 alkylene)-CN, —CH 2 O—(C 1 -C 3 alkylene)-O—(C 1 -C 3 alkyl), —CH 2 S(C 1 -C 6 alkyl), —CH 2 SO(C 1 -C 6 alkyl), or —CH 2 SO 2 (C 1 -C 6 alkyl);
R 8 is —OH, —CN, oxo, —C 1 -C 6 alkyl, C 1 -C 6 alkylene-OH, —C 1 -C 6 haloalkyl, or —C 3 -C 6 cycloalkyl;
R a and R b are each independently —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —CHO, —CO(C 1 -C 3 alkyl), —CO(C 1 -C 6 alkylene)-OH, —CONR e R f , —CO(C 1 -C 3 alkylene)-NR e R f , —CO(C 1 -C 3 alkylene)-NR e SR f , —CO(C 1 -C 3 alkylene)-NR e SOR g , —CO(C 1 -C 3 alkylene)-NR e SO 2 R f , —CO(C 2 -C 3 alkenyl), —CO(C 1 -C 3 haloalkyl), —CO(CH 2 ) n (cycloalkyl), —CO(CH 2 ) n (optionally substituted aryl), —CO(CH 2 ) n (optionally substituted heterocyclyl), or —CO(CH 2 ) n (optionally substituted heteroaryl);
R c and R d together with the nitrogen atom to which it is attached to form an optionally substituted ring, which can be monocyclic, fused bicyclic, or spiral bicyclic, wherein the ring can contain up to 3 heteroatoms selected from N, O, and S;
R e and R f are each independently H, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, or —C 1 -C 6 alkylene-OH;
R g is H, —C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl, —C 1 -C 6 haloalkyl, phenyl, or benzyl;
R 9 is —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-CN, —C 1 -C 3 alkylene-(C 1 -C 3 alkoxy), or —C 1 -C 3 alkylene-NR a R b ;
R 10 is halogen, —CN, oxo, —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 6 haloalkoxy, —S—S—(C 1 -C 6 alkyl), or optionally substituted phenyl;
R 11 is —C 1 -C 6 alkyl, —C 1 -C 6 haloalkyl, —C 1 -C 6 alkoxy, —C 1 -C 3 alkylene-OH, —C 1 -C 3 alkylene-(C 1 -C 3 alkoxy), or —COO(C 1 -C 6 alkyl); and
n is 0, 1, or 2.
24. The method of claim 1 , for increasing resistance to diet-induced accumulation of body fat, in a subject in need thereof.
25. The method of claim 1 , for shortening recovery period from general anesthesia or jet lag, in a subject in need thereof.
26. The method of claim 1 , for treating narcolepsy, in a subject in need thereof.