Vasopressin receptor antagonists and products and methods related thereto
Compounds are provided that antagonize vasopressin receptors, particularly the V1a receptor products containing such compounds, as well as to methods of their use and synthesis. Such compounds have the structure of Formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof: wherein Q 1 , Q 2 , Q 3 , R 2a , R 2b , R 3 and X are as defined herein.
1. A method for treating a neuropsychological disorder, comprising administering to a subject afflicted with a neuropsychological disorder an effective amount of a compound having the structure of Formula (I) or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof:
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O) t (CR x R y ) q —, —(CR x R y ) n N(R x )(CR x R y ) q —, or —(CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, halo, or R 6 ;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
Q 1 is N or CR 1a , Q 2 is N or CR 1b , and Q 3 is N or CR 1c , wherein at least one Q 1 , Q 2 , or Q 3 is not N;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 3 is —(CHR z ) m -Q-(R 4 ) p , —S(═O) 2 R 5 , or —C(═O)R 5 ;
R z is H or CH 3
Q is aryl or heteroaryl;
R 4 is, at each occurrence, independently H, —OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or —O-heterocyclyl;
R 6 is cycloalkyl, heterocyclyl, or —C(═O)R 7 ;
R 7 is H, lower alkyl, or lower haloalkyl;
n is 0, 1, or 2;
q is 0, 1, or 2;
t is 0, 1, or 2;
m is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
2. The method of claim 1 having the structure of Formula (II):
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O) t (CR x R y ) q —, —(CR x R y ) n N(R x )(CR x R y ) q —, or —(CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, halo, or R 6 ;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 3 is —(CHR z ) m -Q-(R 4 ) p , —S(═O) 2 R 5 , or —C(═O)R 5 ;
R z is H or CH 3
Q is aryl or heteroaryl;
R 4 is, at each occurrence, independently H, —OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or —O-heterocyclyl;
R 6 is cycloalkyl, heterocyclyl, or —C(═O) R 7 ;
R 7 is H, lower alkyl, or lower haloalkyl;
n is 0, 1, or 2;
q is 0, 1, or 2;
t is 0, 1, or 2;
m is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
3. The method of claim 2 having the structure of Formula (II-a):
wherein:
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 3 is —(CHR z ) m -Q-(R 4 ) p , —S(═O) 2 R 5 , or —C(═O)R 5 ;
R z is H or CH 3
Q is aryl or heteroaryl;
R 4 is, at each occurrence, independently H, —OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, cycloalkylalkyl, heterocyclyl, or —O-heterocyclyl;
m is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
4. The method of claim 3 , wherein R 3 is —(CHR z ) m -Q-(R 4 ) p , m and p are both 0, and Q is heteroaryl.
5. The method of claim 2 having the structure of Formula (II-b):
wherein:
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 3 is —(CHR z ) m -Q-(R 4 ) p , —S(═O) 2 R 5 , or —C(═O)R 5 ;
R z is H or CH 3
Q is aryl or heteroaryl;
R 4 is, at each occurrence, independently H, —OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or —O-heterocyclyl;
m is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
6. The method of claim 2 having the structure of Formula (II-c):
wherein:
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
R1a, R1b, and R1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R2a and R2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 3 is —(CHR z ) m -Q-(R 4 ) p , —S(═O) 2 R 5 , or —C(═O)R 5 ;
R z is H or CH 3
Q is aryl or heteroaryl;
R 4 is, at each occurrence, independently H, —OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or —O-heterocyclyl;
m is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
7. The method of claim 2 having the structure of Formula (II-d):
wherein:
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 3 is —(CHR z ) m -Q-(R 4 ) p , —S(═O) 2 R 5 , or —C(═O)R 5 ;
R z is H or CH 3
Q is aryl or heteroaryl;
R4 is, at each occurrence, independently H, —OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or —O-heterocyclyl;
m is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
8. The method of claim 2 having the structure of Formula (II-e):
wherein:
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 3 is —(CHR z ) m -Q-(R 4 ) p , —S(═O) 2 R 5 , or —C(═O)R 5 ;
R z is H or CH 3
Q is aryl or heteroaryl;
R 4 is, at each occurrence, independently H, —OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or —O-heterocyclyl;
m is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
9. The method of claim 2 having the structure of Formula (II-f):
wherein:
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 3 is —(CHR z ) m -Q-(R 4 ) p , —S(═O) 2 R 5 , or —C(═O)R 5 ;
R z is H or CH 3
Q is aryl or heteroaryl;
R4 is, at each occurrence, independently H, —OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or —O-heterocyclyl;
m is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
10. The method of claim 2 having the structure of Formula (II-g):
wherein:
R 1a , R 1b , and R 1 c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 3 is —(CHR z ) m -Q-(R 4 ) p , —S(═O) 2 R 5 , or —C(═O) R 5 ;
R z is H or CH 3
Q is aryl or heteroaryl;
R 4 is, at each occurrence, independently H, —OH, —O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or —O-heterocyclyl;
m is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
11. The method of claim 2 having the structure of Formula (II-h):
wherein:
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 3 is —(CHR z ) m -Q-(R 4 ) p , —S(═O) 2 R 5 , or —C(═O) R 5 ;
R z is H or CH 3
Q is aryl or heteroaryl;
R 4 is, at each occurrence, independently H, —OH, —O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or —O-heterocyclyl;
m is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
12. The method of claim 2 having the structure of Formula (II-i):
wherein:
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 3 is —(CHR z ) m -Q-(R 4 ) p , —S(═O) 2 R 5 , or —C(═O)R 5 ;
R z is H or CH 3
Q is aryl or heteroaryl;
R 4 is, at each occurrence, independently H, —OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or —O-heterocyclyl;
m is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
13. The method of claim 2 having the structure of Formula (II-j):
wherein:
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 3 is —(CHR z ) m -Q-(R 4 ) p , —S(═O) 2 R 5 , or —C(═O) R 5 ;
R z is H or CH 3
Q is aryl or heteroaryl;
R 4 is, at each occurrence, independently H, —OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or —O-heterocyclyl;
m is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
14. The method of claim 2 having the structure of Formula (II-k):
wherein:
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 3 is —(CHR z ) m -Q-(R 4 ) p , —S(═O) 2 R 5 , or —C(═O)R 5 ;
R z is H or CH 3
Q is aryl or heteroaryl;
R 4 is, at each occurrence, independently H, OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or —O-heterocyclyl;
m is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
15. The method of claim 2 wherein R 3 is —(CHR z ) m -Q-(R 4 ) p and having the structure of Formula (III):
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O) t (CR x R y ) q —, —(CR x R y ) n N(R x )(CR x R y ) q —, or —(CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R z is H or CH 3
Q is aryl or heteroaryl;
R 4 is, at each occurrence, independently H, —OH, —O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
n is 0, 1, or 2;
q is 0, 1, or 2;
t is 0, 1, or 2;
m is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
16. The method of claim 15 wherein m is 1, Q is aryl or heteroaryl of structure
and having the structure of Formula (IV):
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O) t (CR x R y ) q —, —(CR x R y ) n N(R x )(CR x R y ) q —, or —(CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R z is H or CH 3
J 1 , J 2 , J 3 , and J 4 are each, independently, N, CH, or CR 4 ;
R 4 is, at each occurrence, independently H, OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
n is 0, 1, or 2;
q is 0, 1, or 2;
t is 0, 1, or 2;
p is 0, 1, or 2.
17. The method of claim 15 wherein m is 0, Q is aryl or heteroaryl of structure
and having the structure of Formula (V):
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O) t (CR x R y ) q —, —(CR x R y ) n N(R x )(CR x R y ) q —, or (CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
R y is, at each occurrence, independently H, OH, lower alkyl, lower alkoxy, or halo;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
J 1 , J 2 , J 3 , and J 4 are each, independently, N, CH, or CR 4 ;
R 4 is, at each occurrence, independently H, —OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
n is 0, 1, or 2;
q is 0, 1, or 2;
t is 0, 1, or 2;
p is 0, 1, or 2.
18. The method of claim 15 wherein m is 0, Q is heteroaryl of structure
and having the structure of Formula (VI):
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O) t (CR x R y ) q —, —(CR x R y ) n N(R x )(CR x R y ) q —, or —(CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 4 is, at each occurrence, independently H, —OH, —O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
n is 0, 1, or 2;
q is 0, 1, or 2;
t is 0, 1, or 2;
p is 0, 1, or 2.
19. The method of claim 15 wherein m is 0, Q is heteroaryl of structure
and having the structure of Formula (VII):
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O) t (CR x R y ) q —, —(CR x R y ) n N(R x )(CR x R y ) q —, or —(CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 4 is, at each occurrence, independently H, —OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
n is 0, 1, or 2;
q is 0, 1, or 2;
t is 0, 1, or 2;
p is 0, 1, or 2.
20. The method of claim 15 wherein m is 0, Q is heteroaryl of structure
and having the structure of Formula (VIII):
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O) t (CR x R y ) q —, —(CR x R y ) n N(R x )(CR x R y ) q —, or —(CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 4 is, at each occurrence, independently H, OH, O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
n is 0, 1, or 2;
q is 0, 1, or 2;
t is 0, 1, or 2;
p is 0, 1, or 2.
21. The method of claim 15 wherein m is 0, Q is heteroaryl of structure
and having the structure of Formula (IX):
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O) t (CR x R y ) q —, —(CR x R y ) n N(R x )(CR x R y ) q —, or —(CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 4 is, at each occurrence, independently H, —OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
n is 0, 1, or 2;
q is 0, 1, or 2;
t is 0, 1, or 2;
p is 0, 1, or 2.
22. The method of claim 15 wherein m is 0, Q is aryl or heteroaryl of structure
and having the structure of Formula (X):
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O) t (CR x R y ) q —, —(CR x R y ) n N(R x )(CR x R y ) q —, or —(CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
J 1 , J 2 , J 3 , and J 4 are each, independently, N, O, CH, or CR 4 ;
R 4 is, at each occurrence, independently H, —OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
n is 0, 1, or 2;
q is 0, 1, or 2;
t is 0, 1, or 2;
p is 0, 1, or 2.
23. The method of claim 22 wherein Q is heteroaryl of structure
and having the structure of Formula (XI):
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O) t (CR x R y ) q —, —(CR x R y ) n N(R x )(CR x R y ) q —, or —(CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 4 is, at each occurrence, independently H, —OH, O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
n is 0, 1, or 2;
q is 0, 1, or 2;
t is 0, 1, or 2; and
p is 0, 1, or 2.
24. The method of claim 22 wherein Q is heteroaryl of structure
and having the structure of Formula (XII):
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O): (CR x R y ) q —, —(CR x R y ) n N(R x )(CR x R y ) q —, or —(CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 4 is, at each occurrence, independently H, —OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
n is 0, 1, or 2;
q is 0, 1, or 2;
t is 0, 1, or 2; and
p is 0, 1, or 2.
25. The method of claim 22 wherein Q is heteroaryl of structure
and having the structure of Formula (XIII):
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O): (CR x R y ) q —, —(CR x R y ) n N(R x )(CR x R y ) q —, or —(CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 4 is, at each occurrence, independently H, —OH, —O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
n is 0, 1, or 2;
q is 0, 1, or 2;
t is 0, 1, or 2; and
p is 0, 1, or 2.
26. The method of claim 22 wherein Q is heteroaryl of structure
and having the structure of Formula (XIV):
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O) t (CR x R y ) q —, —(CR x R y ) n N(R x )(CR x R y ) q —, or —(CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 4 is, at each occurrence, independently H, —OH, O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
n is 0, 1, or 2;
q is 0, 1, or 2;
t is 0, 1, or 2; and
p is 0, 1, or 2.
27. The method of claim 1 having the structure of Formula (XV):
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O) t (CR x R y ) q —, —(CR x R y ) n N(R x )(CR x R y ) q —, or —(CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or —O-heterocyclyl;
n is 0, 1, or 2;
q is 0, 1, or 2; and
t is 0, 1, or 2.
28. The method of claim 1 having the structure of Formula (XVI):
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O) t (CR x R y ) q —, (CR x R y ) n N(R x )(CR x R y ) q —, or —(CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, or halo;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or —O-heterocyclyl;
n is 0, 1, or 2;
q is 0, 1, or 2; and
t is 0, 1, or 2.
29. The method of claim 1 wherein the compound is a substantially enantiomerically pure compound having the structure of Formula (XVII-S), or a pharmaceutically acceptable isotope, or salt thereof:
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O) t (CR x R y ) q —, (CR x R y ) n N(R x )(CR x R y ) q —, or —(CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, halo, or R 6 ;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
Q 1 is N or CR 1a , Q 2 is N or CR 1b , and Q 3 is N or CR 1c , wherein at least one Q 1 , Q 2 , or Q 3 is not N;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 3 is —(CHR z ) m -Q-(R 4 ) p , —S(═O) 2 R 5 , or —C(═O)R 5 ;
R z is H or CH 3
Q is aryl or heteroaryl;
R 4 is, at each occurrence, independently H, —OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or —O-heterocyclyl;
R 6 is cycloalkyl, heterocyclyl, or —C(═O) R 7 ;
R 7 is H, lower alkyl, or lower haloalkyl;
n is 0, 1, or 2;
q is 0, 1, or 2;
t is 0, 1, or 2;
m is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
30. The method of claim 1 wherein the compound is a substantially enantiomerically pure compound having the structure of Formula (XVII-R), or a pharmaceutically acceptable isotope, or salt thereof:
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O) t (CR x R y ) q —, —(CR x R y ) n (R x )(CR x R y ) q —, or —(CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, halo, or R 6 ;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
Q 1 is N or CR 1a , Q 2 is N or CR 1b , and Q 3 is N or CR 1c , wherein at least one Q 1 , Q 2 , or Q 3 is not N;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 3 is —(CHR z ) m -Q-(R 4 ) p , —S(═O) 2 R 5 , or —C(═O)R 5 ;
R z is H or CH 3
Q is aryl or heteroaryl;
R 4 is, at each occurrence, independently H, —OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or —O-heterocyclyl;
R 6 is cycloalkyl, heterocyclyl, or —C(═O)R 7 ;
R 7 is H, lower alkyl, or lower haloalkyl;
n is 0, 1, or 2;
q is 0, 1, or 2;
t is 0, 1, or 2;
m is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
31. The method of claim 1 wherein the compound is a substantially enantiomerically pure compound having the structure of Formula (XVIII-S), or a pharmaceutically acceptable isotope, or salt thereof:
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O) t (CR x R y ) q —, —(CR x R y ) n N(R x )(CR x R y ) q —, or —(CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, halo, or R 6 ;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
Q 1 is N or CR 1a , Q 2 is N or CR 1b , and Q 3 is N or CR 1c , wherein at least one Q 1 , Q 2 , or Q 3 is not N;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 3 is —(CHR z ) m -Q-(R 4 ) p , —S(═O) 2 R 5 , or —C(═O) R 5 ;
R z is H or CH 3
Q is aryl or heteroaryl;
R 4 is, at each occurrence, independently H, —OH, —O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or —O-heterocyclyl;
R 6 is cycloalkyl, heterocyclyl, or —C(═O) R 7 ;
R 7 is H, lower alkyl, or lower haloalkyl;
n is 0, 1, or 2;
q is 0, 1, or 2;
t is 0, 1, or 2;
m is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
32. The method of claim 1 wherein the compound is a substantially enantiomerically pure compound having the structure of Formula (XVIII-R), or a pharmaceutically acceptable isotope, or salt thereof:
wherein:
X is —(CR x R y ) n O(CR x R y ) q —, —(CR x R y ) n S(O) t (CR x R y ) q —, (CR x R y ) n N(R x )(CR x R y ) q —, or (CR x R y ) n —,
R x is, at each occurrence, independently H, lower alkyl, lower haloalkyl, halo, or R 6 ;
R y is, at each occurrence, independently H, —OH, lower alkyl, lower alkoxy, or halo;
Q 1 is N or CR 1a , Q 2 is N or CR 1b , and Q 3 is N or CR 1c , wherein at least one Q 1 , Q 2 , or Q 3 is not N;
R 1a , R 1b , and R 1c are each, independently, H, lower alkyl, lower haloalkyl, lower alkoxy, cyano, or halo;
R 2a and R 2b are each, independently, H, lower alkyl, lower haloalkyl, or lower alkoxy;
R 3 is —(CHR z ) m -Q-(R 4 ) p , —S(═O) 2 R 5 , or —C(═O) R 5 ;
R z is H or CH 3
Q is aryl or heteroaryl;
R 4 is, at each occurrence, independently H, —OH, ═O, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, lower haloalkoxy, halo, or cyano;
R 5 is H, cycloalkyl, lower alkyl, lower haloalkyl, lower alkoxy, aryl, heteroaryl, cycloalkylalkyl, heterocyclyl, or —O-heterocyclyl;
R 6 is cycloalkyl, heterocyclyl, or —C(═O) R 7 ;
R 7 is H, lower alkyl, or lower haloalkyl;
n is 0, 1, or 2;
q is 0, 1, or 2;
t is 0, 1, or 2;
m is 0, 1, 2, 3, 4, 5, or 6; and
p is 0, 1, or 2.
33. The method of claim 1 , wherein R 1b is halogen.
34. The method of claim 33 , wherein R 1b is Cl.
35. The method of claim 1 , wherein R 1b is lower alkyl.
36. The method of claim 35 , wherein R 1b is methyl, ethyl, or isopropyl.
37. The method of claim 1 , wherein R 1b is lower haloalkyl.
38. The method of claim 37 , wherein R 1b is —CF 3 .
39. The method of claim 1 , wherein R 1b is lower alkoxy.
40. The method of claim 39 , wherein R 1b is methoxy, ethoxy, isopropoxy, or t-butoxy.
41. The method of claim 1 , wherein R 1b is cyano.
42. The method of claim 1 , wherein R x is hydrogen.
43. The method of claim 1 , wherein R x is lower alkyl.
44. The method of claim 43 , wherein R x is methyl, ethyl, or isopropyl.
45. The method of claim 1 , wherein R x is lower alkoxy.
46. The method of claim 45 , wherein R x is methoxy, ethoxy, isopropoxy, or t-butoxy.
47. The method of claim 1 , wherein R x is cycloalkyl.
48. The method of claim 47 , wherein R x is cyclopropyl or cyclobutyl.
49. The method of claim 1 , wherein R 4 is halogen.
50. The method of claim 49 , wherein R 4 is F or Cl.
51. The method of claim 1 , wherein R 4 is lower alkyl.
52. The method of claim 51 , wherein R 4 is methyl or ethyl.
53. The method of claim 1 , wherein R 4 is lower alkoxy.
54. The method of claim 53 , wherein R 4 is methoxy or ethoxy.
55. The method of claim 1 , wherein R 4 is cyano.
56. The method of claim 1 , wherein R 4 is hydroxy.
57. The method of claim 1 , wherein R 5 is lower alkyl.
58. The method of claim 57 , wherein R 5 is methyl, ethyl, or isopropyl.
59. The method of claim 1 , wherein R 5 is lower alkoxy.
60. The method of claim 59 , wherein R 5 is t-butoxy.
61. The method of claim 1 , wherein the compound has a structure listed in Table 1, or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
62. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
63. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
64. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
65. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
66. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
67. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
68. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
69. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
70. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
71. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
72. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
73. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
74. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
75. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
76. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
77. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
78. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
79. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemateisotope, or salt thereof.
80. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
81. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
82. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
83. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
84. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
85. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
86. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
87. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
88. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
89. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
90. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
91. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
92. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
93. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
94. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
95. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
96. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
97. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
98. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
99. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
100. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
101. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
102. The method of claim 61 , wherein the compound has the following structure:
or a pharmaceutically acceptable stereoisomer, racemate, isotope, or salt thereof.
103. The method of claim 1 , wherein the compound is a substantially enantiomerically pure form of a compound having a structure listed in Table 2, or pharmaceutically acceptable isotope, or salt thereof.
104. The method of claim 1 , wherein the compound is in combination with a pharmaceutically acceptable carrier, diluent, or excipient.
105. The method of claim 1 , wherein the neuropsychological disorder is an autistic spectrum disorder.
106. The method of claim 1 , wherein the neuropsychological disorder is aggressive behavior.
107. The method of claim 106 , wherein the aggressive behavior is co-occurring with a cognitive disorder.
108. The method of claim 107 , wherein the cognitive disorder is Alzheimer's disease, Parkinson's disease, or Huntington's disease.
109. The method of claim 1 , wherein the neuropsychological disorder is agitation associated with dementia in Alzheimer's disease.
110. The method of claim 1 , wherein the neuropsychological disorder is intermittent explosive disorder.
111. The method of claim 1 , wherein the neuropsychological disorder is an anxiety disorder.
112. The method of claim 111 , wherein the anxiety disorder is generalized anxiety disorder, panic disorder, stress-related disorder, obsessive compulsive disorder, phobia, social anxiety disorder, separation anxiety disorder, or post-traumatic stress disorder.
113. The method of claim 112 , wherein the anxiety disorder is social anxiety disorder.
114. The method of claim 112 , wherein the anxiety disorder is phobia.
115. The method of claim 112 , wherein the anxiety disorder is stress-related disorder.
116. The method of claim 112 , wherein the anxiety disorder is post-traumatic stress disorder.
117. The method of claim 112 , wherein the anxiety disorder is obsessive compulsive disorder.
118. The method of claim 1 , wherein the neuropsychological disorder is a depressive disorder, a mood disorder, or an affective disorder.
119. The method of claim 118 , wherein the depressive disorder is major depression, drug-resistant depression, dysthymia, and bipolar disorder.
120. The method of claim 119 , wherein the depressive disorder is major depression.
121. The method of claim 118 , wherein the mood disorder is anhedonia.
122. The method of claim 1 , wherein the neuropsychological disorder is a schizophrenia spectrum disorder.
123. The method of claim 122 , wherein the schizophrenia spectrum disorder is schizophrenia, schizoaffective disorder, psychotic state, or memory disorder.