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 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;
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 -W 1 is —CHR 7 CH 2 —W 1 ;
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 O, 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 heterocyclyl 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 compound of claim 1 , wherein R 2 is NH.
3. The compound of claim 1 , wherein Y 3 and Y 4 , are each independently CR 6 .
4. The compound of claim 1 , wherein R 6 is halogen, methyl, —CH 2 F, —CHF 2 , or —CF 3 .
5. The compound of claim 1 , wherein R 10 is halogen, methyl, —CH 2 F, —CHF 2 , or —CF 3 .
6. The compound of claim 1 , wherein L 2 is C 1 alkylene or C 4 alkenylene, optionally substituted with one R 8 .
7. The compound of claim 1 , wherein L 2 is C 1 alkylene, optionally substituted with one R 8 .
8. The compound of claim 1 , wherein R 8 is methyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, —CH 2 F, —CHF 2 , or —CF 3 .
9. The compound of claim 1 , wherein one of Y 1 and Y 2 is N and the other is CR 6 .
10. The compound of claim 1 , wherein Y 1 , Y 2 , Y 3 and Y 4 , are each independently CR 6 .
11. The compound of claim 1 , wherein W 1 is phenyl optionally substituted with R 10 .
12. The compound of claim 1 , wherein W 2 is phenyl optionally substituted with R 10 .
13. The compound 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 compound 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 compound 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 compound 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 compound 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 compound 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 C 5 -C 10 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 O, 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;
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), —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 , —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);
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 compound 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 compound 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 , or —N(CH 3 ) 2 ; 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 O, 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 compound 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 O or 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, —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), 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;
and
n is 0, 1, or 2.
22. The compound 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 O or 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 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 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;
and
n is 0, 1, or 2.
23. The compound 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 selected O or 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 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);
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;
and
n is 0, 1, or 2.
24. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient, formulated in unit dosage form.