Vasopressin receptor antagonists and products and methods related thereto

1. A compound having the structure of Formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, 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 compound 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 compound 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 compound 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 compound 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 compound 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;

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.

7. The compound 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 compound 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 compound 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 compound of claim 2 having the structure of Formula (II-g):

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.

11. The compound 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 compound 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 compound 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 compound 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 compound 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 compound of claim 15 wherein m is 1, Q is aryl or heteroaryl of structure

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 compound of claim 15 wherein m is 0, Q is aryl or heteroaryl of structure

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, 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.

18. The compound of claim 15 wherein m is 0, Q is heteroaryl of structure

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 compound of claim 15 wherein m is 0, Q is heteroaryl of structure

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 compound of claim 15 wherein m is 0, Q is heteroaryl of structure

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 compound of claim 15 wherein m is 0, Q is heteroaryl of structure

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 compound of claim 15 wherein m is 0, Q is aryl or heteroaryl of structure

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 compound of claim 22 wherein Q is heteroaryl of structure

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 compound of claim 22 wherein Q is heteroaryl of structure

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) 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.

25. The compound of claim 22 wherein Q is heteroaryl of structure

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) 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.

26. The compound of claim 22 wherein Q is heteroaryl of structure

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 compound 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 compound 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. A substantially enantiomerically pure compound having the structure of Formula (XVII-S), or a pharmaceutically acceptable hydrate, solvate, 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. A substantially enantiomerically pure compound having the structure of Formula (XVII-R), or a pharmaceutically acceptable hydrate, solvate, 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 1 c, 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. A substantially enantiomerically pure compound having the structure of Formula (XVIII-S), or a pharmaceutically acceptable hydrate, solvate, 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. A substantially enantiomerically pure compound having the structure of Formula (XVIII-R), or a pharmaceutically acceptable hydrate, solvate, 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 1 c, 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 compound of claim 1 , wherein R 1b is halogen.

34. The compound of claim 33 , wherein R 1b is Cl.

35. The compound of claim 1 , wherein R 1b is lower alkyl.

36. The compound of claim 35 , wherein R 1b is methyl, ethyl, or isopropyl.

37. The compound of claim 1 , wherein R 1b is lower haloalkyl.

38. The compound of claim 37 , wherein R 1b is —CF 3 .

39. The compound of claim 1 , wherein R 1b is lower alkoxy.

40. The compound of claim 39 , wherein R 1b is methoxy, ethoxy, isopropoxy, or t-butoxy.

41. The compound of claim 1 , wherein R 1b is cyano.

42. The compound of claim 1 , wherein at least one R x is hydrogen.

43. The compound of claim 1 , wherein at least one R x is lower alkyl.

44. The compound of claim 43 , wherein at least one R x is methyl, ethyl, or isopropyl.

45. The compound of claim 1 , wherein at least one R y is lower alkoxy.

46. The compound of claim 45 , wherein at least one R y is methoxy, ethoxy, isopropoxy, or t-butoxy.

47. The compound of claim 1 , wherein at least one R x is cycloalkyl.

48. The compound of claim 47 , wherein at least one R x is cyclopropyl or cyclobutyl.

49. The compound of claim 1 , wherein R 4 is halogen.

50. The compound of claim 49 , wherein R 4 is F or Cl.

51. The compound of claim 1 , wherein R 4 is lower alkyl.

52. The compound of claim 51 , wherein R 4 is methyl or ethyl.

53. The compound of claim 1 , wherein R 4 is lower alkoxy.

54. The compound of claim 53 , wherein R 4 is methoxy or ethoxy.

55. The compound of claim 1 , wherein R 4 is cyano.

56. The compound of claim 1 , wherein R 4 is hydroxy.

57. The compound of claim 1 , wherein R 5 is lower alkyl.

58. The compound of claim 57 , wherein R 5 is methyl, ethyl, or isopropyl.

59. The compound of claim 1 , wherein R 5 is lower alkoxy.

60. The compound of claim 59 , wherein R 5 is t-butoxy.

61. A compound having a structure listed in Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

62. A substantially enantiomerically pure form of a compound having a structure listed in Table 2, or pharmaceutically acceptable hydrate, solvate, isotope, or salt thereof.

63. A composition comprising a compound of claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

64. The compound of claim 61 , wherein the compound is Compound No. 1-3 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

65. The compound of claim 61 , wherein the compound is Compound No. 1-22 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

66. The compound of claim 61 , wherein the compound is Compound No. 1-30 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

67. The compound of claim 61 , wherein the compound is Compound No. 1-39 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

68. The compound of claim 61 , wherein the compound is Compound No. 1-51 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

69. The compound of claim 61 , wherein the compound is Compound No. 1-59 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

70. The compound of claim 61 , wherein the compound is Compound No. 1-65 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

71. The compound of claim 61 , wherein the compound is Compound No. 1-66 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

72. The compound of claim 61 , wherein the compound is Compound No. 1-67 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

73. The compound of claim 61 , wherein the compound is Compound No. 1-69 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

74. The compound of claim 61 , wherein the compound is Compound No. 1-70 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

75. The compound of claim 61 , wherein the compound is Compound No. 1-78 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

76. The compound of claim 61 , wherein the compound is Compound No. 1-83 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

77. The compound of claim 61 , wherein the compound is Compound No. 4-3 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

78. The compound of claim 61 , wherein the compound is Compound No. 8-12 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

79. The compound of claim 61 , wherein the compound is Compound No. 8-13 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

80. The compound of claim 61 , wherein the compound is Compound No. 9-1 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

81. The compound of claim 61 , wherein the compound is Compound No. 9-3 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

82. The compound of claim 61 , wherein the compound is Compound No. 9-4 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

83. The compound of claim 61 , wherein the compound is Compound No. 9-7 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

84. The compound of claim 61 , wherein the compound is Compound No. 12-1 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

85. The compound of claim 61 , wherein the compound is Compound No. 13-1 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

86. The compound of claim 61 , wherein the compound is Compound No. 13-2 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

87. The compound of claim 61 , wherein the compound is Compound No. 13-3 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

88. The compound of claim 61 , wherein the compound is Compound No. 14-1 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

89. The compound of claim 61 , wherein the compound is Compound No. 18-2 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

90. The compound of claim 61 , wherein the compound is Compound No. 18-3 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

91. The compound of claim 61 , wherein the compound is Compound No. 19-1 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

92. The compound of claim 61 , wherein the compound is Compound No. 19-2 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

93. The compound of claim 61 , wherein the compound is Compound No. 19-4 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

94. The compound of claim 61 , wherein the compound is Compound No. 20-3 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

95. The compound of claim 61 , wherein the compound is Compound No. 20-9 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

96. The compound of claim 61 , wherein the compound is Compound No. 20-10 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

97. The compound of claim 61 , wherein the compound is Compound No. 21-1 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

98. The compound of claim 61 , wherein the compound is Compound No. 21-2 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

99. The compound of claim 61 , wherein the compound is Compound No. 21-4 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

100. The compound of claim 61 , wherein the compound is Compound No. 21-5 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

101. The compound of claim 61 , wherein the compound is Compound No. 21-6 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

102. The compound of claim 61 , wherein the compound is Compound No. 21-8 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

103. The compound of claim 61 , wherein the compound is Compound No. 21-9 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.

104. The compound of claim 61 , wherein the compound is Compound No. 21-10 of Table 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.