Opioid receptor modulators and products and methods related thereto

Abstract

Compounds are provided having the structure of Formula (I): or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein A, B, L, R 3 , R 4 , R 5 , R 6 , R 8 , m and n are as defined herein. Such compounds modulate the opioid receptor, particulate the mu-opioid receptor (MOR) and/or the kappa-opioid receptor (KOR), and/or the delta-opioid receptor (DOR). Products containing such compounds, as well as methods for their use and preparation, are also provided.

1 . A compound having the structure of Formula (I): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
 ring A is carbocycle or heterocycle; 
 ring B is carbocycle or heterocycle; 
 L is a bond, —(CR 7   2 ) q -Q-(CR 7   2 ) r —, or ring C; 
 Q is —C(R a ) 2 —, —NR a —, or —O—; 
 ring C is a C 3 -C 7  cycloalkyl or 3-7 membered heterocycloalkyl, substituted with 0-5 R 7 ; 
 each R a  is H or (C 1 -C 6 )alkyl; 
 R 1  and R 2  are each, independently, H, or (C 1 -C 6 )alkyl or C 3 -C 7  cycloalkyl substituted with 0-5 halo; 
 R 3  and R 4  are each, independently, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, carbocycle, or carbocyclealkyl; 
 or R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle; 
 R 5 , R 6 , and R 7  are each, independently, —C(O)NR 1 R 2 , —NR 1 C(O)R 2 , —OC(O)R 1 , —C(O)OR 1 , —S(O) t NR 1 R 2 , —NR 1 S(O) t R 2 , —OH, —CN, halo, oxo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, or carbocycle; 
 or R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle; 
 R 8  is H or (C 1 -C 6 )alkyl; 
 m is 0-5; 
 n is 0-5; 
 q is 0-5; 
 r is 0-5; and 
 t is 0-2; 
 
       with the provisos that:
 when L is —(CR 7   2 ) q -Q-(CR 7   2 ) r —,
 m is not 0 and at least one R 5  is not —OH, halo, or alkoxy when ring B is an aromatic monocyclic carbocycle or heterocyle, or 
 at least one R 5  is not halo or alkoxy when ring B is an aromatic monocyclic carbocycle or heterocyle and m is 2-5, or 
 R 3  and R 4  are not both H and ring A is not thiophene when ring B is an aromatic polycyclic carbocycle or heterocyle; 
 
 when L is ring C,
 m is not 0 when ring B is phenyl or pyrrolyl and R 3  is H, (C 1 -C 6 )alkyl, or forms a 5-7 membered heterocycle together with one R 5 , or 
 R 5  is not halo when R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle, one R 6  is halo, and m is 1; and 
 
 when L is a bond,
 m is not 0 when ring B is phenyl or pyrrolyl and R 3  is H or (C 1 -C 6 )alkyl, or 
 m′ is not 0 when R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle, 
 R 5  is not halo or alkoxy when ring B is phenyl, R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle, and m′ is 1, or 
 R 5  is not —OH when ring B is a 7-membered carbocycle, R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle, and m′ is 1, or 
 m is not 0 when ring B is a monocyclic carbocycle or heterocyle and R 3  and R 4  are each, independently, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, carbocycle, or carbocyclealkyl or R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle, or 
 R 5  is not halo when ring B is phenyl and R 3  and R 4  are each H or R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle, or 
 n is not 0 when ring A is imidazolyl and ring B is phenyl. 
 
 
     
     
         2 . The compound of  claim 1  having the structure of formula (II): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
 ring A is carbocycle or heterocycle; 
 L is a bond, —(CR 7   2 ) q -Q-(CR 7   2 ) r —, or ring C; 
 Q is —C(R a ) 2 —, —NR a —, or —O—; 
 ring C is a C 3 -C 7  cycloalkyl or 3-7 membered heterocycloalkyl, substituted with 0-5 R 7 ; 
 each R a  is H or (C 1 -C 6 )alkyl; 
 R 1  and R 2  are each, independently, H, or (C 1 -C 6 )alkyl or C 3 -C 7  cycloalkyl substituted with 0-5 halo; 
 R 3  and R 4  are each, independently, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, carbocycle, or carbocyclealkyl; 
 or R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle; 
 R 5 , R 6 , and R 7  are each, independently, —C(O)NR 1 R 2 , —NR 1 C(O)R 2 , —OC(O)R 1 , —C(O)OR 1 , —S(O) t NR 1 R 2 , —NR 1 S(O) t R 2 , —OH, —CN, halo, oxo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, or carbocycle; 
 or R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle; 
 R 8  is H or (C 1 -C 6 )alkyl; 
 Q 1 , Q 2 , Q 3 , Q 4 , and Q 5  are each, independently, C or N; wherein 0, 1, or 2 of Q 1 , Q 2 , Q 3 , Q 4 , and Q 5  is N; 
 m is 0-5; 
 n is 0-5; 
 q is 0-5; 
 r is 0-5; and 
 t is 0-2; 
 
       with the provisos that:
 when L is —(CR 7   2 ) q -Q-(CR 7   2 ) r —,
 m is not 0 and at least one R 5  is not —OH, halo, or alkoxy, or 
 at least one R 5  is not halo when m is 2-5; or 
 
 when L is ring C,
 m is not 0 when Q 1 , Q 2 , Q 3 , Q 4 , and Q 5  are each, independently, C and R 3  is H, (C 1 -C 6 )alkyl, or forms a 5-7 membered heterocycle together with one R 5 , or 
 R 5  is not halo when R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle, one R 6  is halo, and m is 1; and 
 
 when L is a bond,
 m is not 0 when Q 1 , Q 2 , Q 3 , Q 4 , and Q 5  are each, independently, C and and R 3  is H or (C 1 -C 6 )alkyl, or 
 m′ is not 0 when R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle, 
 R 5  is not halo or alkoxy when Q 1 , Q 2 , Q 3 , Q 4 , and Q 5  are each, independently, C and, R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle, and m′ is 1, or 
 m is not 0 when R 3  and R 4  are each, independently, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, carbocycle, or carbocyclealkyl or R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle, or 
 R 5  is not halo when Q 1 , Q 2 , Q 3 , Q 4 , and Q 5  are each, independently, C and R 3  and R 4  are each H or R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle, or 
 n is not 0 when ring A is imidazolyl and Q 1 , Q 2 , Q 3 , Q 4 , and Q 5  are each, independently, C. 
 
 
     
     
         3 . The compound of  claim 1  or  2  having the structure of Formula (III): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
 ring A is carbocycle or heterocycle; 
 L is a bond, —(CR 7   2 ) q -Q-(CR 7   2 ) r —, or ring C; 
 Q is —C(R a ) 2 —, —NR a —, or —O—; 
 ring C is a C 3 -C 7  cycloalkyl or 3-7 membered heterocycloalkyl, substituted with 0-5 R 7 ; 
 each R a  is H or (C 1 -C 6 )alkyl; 
 R 1  and R 2  are each, independently, H, or (C 1 -C 6 )alkyl or C 3 -C 7  cycloalkyl substituted with 0-5 halo; 
 R 3  and R 4  are each, independently, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, carbocycle, or carbocyclealkyl; 
 or R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle; 
 R 5 , R 6 , and R 7  are each, independently, —C(O)NR 1 R 2 , —NR 1 C(O)R 2 , —OC(O)R 1 , —C(O)OR 1 , —S(O) t NR 1 R 2 , —NR 1 S(O) t R 2 , —OH, —CN, halo, oxo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, or carbocycle; 
 or R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle; 
 R 8  is H or (C 1 -C 6 )alkyl; 
 m is 0-5; 
 n is 0-5; 
 q is 0-5; 
 r is 0-5; and 
 t is 0-2; 
 
       with the provisos that:
 when L is —(CR 7   2 ) q -Q-(CR 7   2 ) r —,
 m is not 0 and at least one R 5  is not —OH, halo, or alkoxy, or 
 at least one R 5  is not halo when m is 2-5; or 
 
 when L is ring C,
 m is not 0 when R 3  is H, (C 1 -C 6 )alkyl, or forms a 5-7 membered heterocycle together with one R 5 , or 
 R 5  is not halo when R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle, one R 6  is halo, and m is 1; and 
 
 when L is a bond,
 m is not 0 when R 3  is H or (C 1 -C 6 )alkyl, or 
 m′ is not 0 when R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle, 
 R 5  is not halo or alkoxy when R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle, and m′ is 1, or 
 m is not 0 when R 3  and R 4  are each, independently, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, carbocycle, or carbocyclealkyl or R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle, or 
 R 5  is not halo when R 3  and R 4  are each H or R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle, or 
 n is not 0 when ring A is imidazolyl. 
 
 
     
     
         4 . The compound of any one of  claims 1 - 3 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5  is —C(O)NR 1 R 2  and having the structure of Formula (IV): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
 ring A is carbocycle or heterocycle; 
 L is a bond, —(CR 7   2 ) q -Q-(CR 7   2 ) r —, or ring C; 
 Q is —C(R a ) 2 —, —NR a —, or —O—; 
 ring C is a C 3 -C 7  cycloalkyl or 3-7 membered heterocycloalkyl, substituted with 0-5 R 7 ; 
 each R a  is H or (C 1 -C 6 )alkyl; 
 R 1  and R 2  are each, independently, H, or (C 1 -C 6 )alkyl or C 3 -C 7  cycloalkyl substituted with 0-5 halo; 
 R 3  and R 4  are each, independently, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, carbocycle, or carbocyclealkyl; 
 or R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle; 
 R 5 , R 6 , and R 7  are each, independently, —C(O)NR 1 R 2 , —NR 1 C(O)R 2 , —OC(O)R 1 , —C(O)OR 1 , —S(O) t NR 1 R 2 , —NR 1 S(O) t R 2 , —OH, —CN, halo, oxo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, or carbocycle; 
 or R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle; 
 R 8  is H or (C 1 -C 6 )alkyl; 
 m′ is 0-4; 
 n is 0-5; 
 q is 0-5; 
 r is 0-5; and 
 t is 0-2. 
 
     
     
         5 . The compound of claim any one of  claims 1 - 4  having the structure of Formula (V): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
 ring A is carbocycle or heterocycle; 
 L is a bond, —(CR 7   2 ) q -Q-(CR 7   2 ) r —, or ring C; 
 Q is —C(R a ) 2 —, —NR a —, or —O—; 
 ring C is a C 3 -C 7  cycloalkyl or 3-7 membered heterocycloalkyl, substituted with 0-5 R 7 ; 
 each R a  is H or (C 1 -C 6 )alkyl; 
 R 1  and R 2  are each, independently, H, or (C 1 -C 6 )alkyl or C 3 -C 7  cycloalkyl substituted with 0-5 halo; 
 R 3  and R 4  are each, independently, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, carbocycle, or carbocyclealkyl; 
 or R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle; 
 R 5 , R 6 , and R 7  are each, independently, —C(O)NR 1 R 2 , —NR 1 C(O)R 2 , —OC(O)R 1 , —C(O)OR 1 , —S(O) t NR 1 R 2 , —NR 1 S(O) t R 2 , —OH, —CN, halo, oxo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, or carbocycle; 
 or R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle; 
 R 8  is H or (C 1 -C 6 )alkyl; 
 m′ is 0-4; 
 n is 0-5; 
 q is 0-5; 
 r is 0-5; and 
 t is 0-2. 
 
     
     
         6 . The compound of claim any one of  claims 1 - 4  having the structure of Formula (VI): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
 ring A is carbocycle or heterocycle; 
 L is a bond, —(CR 7   2 ) q -Q-(CR 7   2 ) r —, or ring C; 
 Q is —C(R a ) 2 —, —NR a —, or —O—; 
 ring C is a C 3 -C 7  cycloalkyl or 3-7 membered heterocycloalkyl, substituted with 0-5 R 7 ; 
 each R a  is H or (C 1 -C 6 )alkyl; 
 R 1  and R 2  are each, independently, H, or (C 1 -C 6 )alkyl or C 3 -C 7  cycloalkyl substituted with 0-5 halo; 
 R 3  and R 4  are each, independently, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, carbocycle, or carbocyclealkyl; 
 or R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle; 
 R 5 , R 6 , and R 7  are each, independently, —C(O)NR 1 R 2 , —NR 1 C(O)R 2 , —OC(O)R 1 , —C(O)OR 1 , —S(O) t NR 1 R 2 , —NR 1 S(O) t R 2 , —OH, —CN, halo, oxo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, or carbocycle; 
 or R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle; 
 R 8  is H or (C 1 -C 6 )alkyl; 
 m′ is 0-4; 
 n is 0-5; 
 q is 0-5; 
 r is 0-5; and 
 t is 0-2. 
 
     
     
         7 . The compound of  claim 2 , wherein Q 1 , Q 2 , Q 3 , and Q 4  are each C, and Q 5  is N and having the structure of Formula (VII): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
 ring A is carbocycle or heterocycle; 
 L is a bond, —(CR 7   2 ) q -Q-(CR 7   2 ) r —, or ring C; 
 Q is —C(R a ) 2 —, —NR a —, or —O—; 
 ring C is a C 3 -C 7  cycloalkyl or 3-7 membered heterocycloalkyl, substituted with 0-5 R 7 ; 
 each R a  is H or (C 1 -C 6 )alkyl; 
 R 1  and R 2  are each, independently, H, or (C 1 -C 6 )alkyl or C 3 -C 7  cycloalkyl substituted with 0-5 halo; 
 R 3  and R 4  are each, independently, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, carbocycle, or carbocyclealkyl; 
 or R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle; 
 R 5 , R 6 , and R 7  are each, independently, —C(O)NR 1 R 2 , —NR 1 C(O)R 2 , —OC(O)R 1 , —C(O)OR 1 , —S(O) t NR 1 R 2 , —NR 1 S(O) t R 2 , —OH, —CN, halo, oxo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, or carbocycle; 
 or R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle; 
 R 8  is H or (C 1 -C 6 )alkyl; 
 m is 0-5; 
 n is 0-5; 
 q is 0-5; 
 r is 0-5; and 
 t is 0-2; 
 
       with the provisos that:
 when L is —(CR 7   2 ) q -Q-(CR 7   2 ) r —, 
 m is not 0 and at least one R 5  is not —OH, halo, or alkoxy, or 
 at least one R 5  is not halo when m is 2-5; and 
 when L is ring C,
 R 5  is not halo when R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle, one R 6  is halo, and m is 1; and 
 
 when L is a bond,
 m′ is not 0 when R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle, or 
 m is not 0 when ring B is a monocyclic carbocycle or heterocyle and R 3  and R 4  are each, independently, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, carbocycle, or carbocyclealkyl or R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle. 
 
 
     
     
         8 . The compound of  claim 7  having the structure of Formula (VIII): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
 ring A is carbocycle or heterocycle; 
 L is a bond, —(CR 7   2 ) q -Q-(CR 7   2 ) r —, or ring C; 
 Q is —C(R a ) 2 —, —NR a —, or —O—; 
 ring C is a C 3 -C 7  cycloalkyl or 3-7 membered heterocycloalkyl, substituted with 0-5 R 7 ; 
 each R a  is H or (C 1 -C 6 )alkyl; 
 R 1  and R 2  are each, independently, H, or (C 1 -C 6 )alkyl or C 3 -C 7  cycloalkyl substituted with 0-5 halo; 
 R 3  and R 4  are each, independently, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, carbocycle, or carbocyclealkyl; 
 or R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle; 
 R 5 , R 6 , and R 7  are each, independently, —C(O)NR 1 R 2 , —NR 1 C(O)R 2 , —OC(O)R 1 , —C(O)OR 1 , —S(O) t NR 1 R 2 , —NR 1 S(O) t R 2 , —OH, —CN, halo, oxo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, or carbocycle; 
 or R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle; 
 R 8  is H or (C 1 -C 6 )alkyl; 
 m′ is 0-4; 
 n is 0-5; 
 q is 0-5; 
 r is 0-5; and 
 t is 0-2. 
 
     
     
         9 . The compound of  claim 1  having the structure of Formula (IX): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
 ring A is carbocycle or heterocycle; 
 L is a bond, —(CR 7   2 ) q -Q-(CR 7   2 ) r —, or ring C; 
 Q is —C(R a ) 2 —, —NR a —, or —O—; 
 ring C is a C 3 -C 7  cycloalkyl or 3-7 membered heterocycloalkyl, substituted with 0-5 R 7 ; 
 each R a  is H or (C 1 -C 6 )alkyl; 
 R 1  and R 2  are each, independently, H, or (C 1 -C 6 )alkyl or C 3 -C 7  cycloalkyl substituted with 0-5 halo; 
 R 3  and R 4  are each, independently, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, carbocycle, or carbocyclealkyl; 
 or R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle; 
 R 5 , R 6 , and R 7  are each, independently, —C(O)NR 1 R 2 , —NR 1 C(O)R 2 , —OC(O)R 1 , —C(O)OR 1 , —S(O) t NR 1 R 2 , —NR 1 S(O) t R 2 , —OH, —CN, halo, oxo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, or carbocycle; 
 or R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle; 
 R 8  is H or (C 1 -C 6 )alkyl; 
 Q 1 , Q 4 , and Q 5  are each, independently, C or N; 
 Q 2  and Q 3  are each C; 
 ring D is a 5-6 membered carbocycle or heterocycle which forms, together with Q 2  and Q 3 , a fused bicyclic ring B; 
 m is 0-5; 
 n is 0-5; 
 q is 0-5; 
 r is 0-5; and 
 t is 0-2; 
 
       with the proviso that:
 when L is —(CR 7   2 ) q -Q-(CR 7   2 ) r —,
 R 3  and R 4  are not both H, and ring A is not thiophene. 
 
 
     
     
         10 . The compound of  claim 1  having the structure of Formula (X): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
 ring A is carbocycle or heterocycle; 
 L is a bond, —(CR 7   2 ) q -Q-(CR 7   2 ) r —, or ring C; 
 Q is —C(R a ) 2 —, —NR a —, or —O—; 
 ring C is a C 3 -C 7  cycloalkyl or 3-7 membered heterocycloalkyl, substituted with 0-5 R 7 ; 
 each R a  is H or (C 1 -C 6 )alkyl; 
 R 1  and R 2  are each, independently, H, or (C 1 -C 6 )alkyl or C 3 -C 7  cycloalkyl substituted with 0-5 halo; 
 R 3  and R 4  are each, independently, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, carbocycle, or carbocyclealkyl; 
 or R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle; 
 R 5 , R 6 , and R 7  are each, independently, —C(O)NR 1 R 2 , —NR 1 C(O)R 2 , —OC(O)R 1 , —C(O)OR 1 , —S(O) t NR 1 R 2 , —NR 1 S(O) t R 2 , —OH, —CN, halo, oxo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, or carbocycle; 
 or R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle; 
 R 8  is H or (C 1 -C 6 )alkyl; 
 Q 1 , Q 4 , and Q 5  are each, independently, C or N; 
 m is 0-5; 
 n is 0-5; 
 q is 0-5; 
 r is 0-5; and 
 t is 0-2. 
 
     
     
         11 . The compound of  claim 1  having the structure of Formula (XI): 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:
 ring A is carbocycle or heterocycle; 
 L is a bond, —(CR 7   2 ) q -Q-(CR 7   2 ) r —, or ring C; 
 Q is —C(R a ) 2 —, —NR a —, or —O—; 
 ring C is a C 3 -C 7  cycloalkyl or 3-7 membered heterocycloalkyl, substituted with 0-5 R 7 ; 
 each R a  is H or (C 1 -C 6 )alkyl; 
 R 1  and R 2  are each, independently, H, or (C 1 -C 6 )alkyl or C 3 -C 7  cycloalkyl substituted with 0-5 halo; 
 R 3  and R 4  are each, independently, H, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, carbocycle, or carbocyclealkyl; 
 or R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle; 
 R 5 , R 6 , and R 7  are each, independently, —C(O)NR 1 R 2 , —NR 1 C(O)R 2 , —OC(O)R 1 , —C(O)OR 1 , —S(O) t NR 1 R 2 , —NR 1 S(O) t R 2 , —OH, —CN, halo, oxo, (C 1 -C 6 )alkyl, (C 1 -C 6 )haloalkyl, (C 1 -C 6 )alkoxy, or carbocycle; 
 or R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle; 
 R 8  is H or (C 1 -C 6 )alkyl; 
 Q 1 , Q 4 , and Q 5  are each, independently, C or N; 
 m is 0-5; 
 n is 0-5; 
 q is 0-5; 
 r is 0-5; and 
 t is 0-2. 
 
     
     
         12 . The compound of any one of  claims 1 - 11 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring A is an aromatic carbocycle. 
     
     
         13 . The compound of  claim 12 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring A is phenyl. 
     
     
         14 . The compound of any one of  claims 1 - 11 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring A is an aromatic heterocycle. 
     
     
         15 . The compound of  claim 14 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring A is pyrrolyl, furanyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinazolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 2,3-dihydro indolyl, benzoxazolone, or pyrazolopyridine. 
     
     
         16 . The compound of  claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring B is pyrrolyl, furanyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, thiophenyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, quinazolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, 2,3-dihydro indolyl, benzoxazolone, or pyrazolopyridine. 
     
     
         17 . The compound of any one of  claims 1 - 16 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L is —(CR 7   2 ) q -Q-(CR 7   2 ) r . 
     
     
         18 . The compound of  claim 17 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein q is 0. 
     
     
         19 . The compound of any one of  claims 1 - 18 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q is —O—. 
     
     
         20 . The compound of any one of  claims 1 - 18 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q is —C(R a ) 2 —. 
     
     
         21 . The compound of any one of  claims 1 - 18 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein Q is —NR a —. 
     
     
         22 . The compound of any one of  claims 1 - 16 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L is ring C. 
     
     
         23 . The compound of  claim 22 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring C is cyclopropyl. 
     
     
         24 . The compound of  claim 22 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein ring C is pyrrolidinyl. 
     
     
         25 . The compound of any one of  claims 1 - 16 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein L is a bond. 
     
     
         26 . The compound of any one of  claims 1 - 25 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 3  and R 4  are each, independently, H, (C 1 -C 6 )alkyl, carbocycle, or carbocyclealkyl. 
     
     
         27 . The compound of any one of  claims 1 - 26 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 3  and R 4  are each methyl or ethyl. 
     
     
         28 . The compound of any one of 1-26, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 3  and R 4  are each H. 
     
     
         29 . The compound of any one of  claims 1 - 26 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 3  is methyl and R 4  is cyclopropylmethyl. 
     
     
         30 . The compound of any one of  claims 1 - 25 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 3  and R 4 , together with the N to which they are connected, form a 4-7 membered heterocycle. 
     
     
         31 . The compound of  claim 30 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 3  and R 4 , together with the N to which they are connected, form pyrrolidinyl or mopholinyl. 
     
     
         32 . The compound of any one of  claims 1 - 25 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 3  and one R 5 , together with the atoms to which they are connected, form a 5-7 membered heterocycle. 
     
     
         33 . The compound of any one of  claims 1 - 32 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5  is —OH. 
     
     
         34 . The compound of any one of  claims 1 - 32 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5  is —C(O)NR 1 R 2 . 
     
     
         35 . The compound of any one of  claims 1 - 32 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5  is halo. 
     
     
         36 . The compound of  claim 35 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5  is Cl or F. 
     
     
         37 . The compound of any one of  claims 1 - 32 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5  is (C 1 -C 6 )alkyl. 
     
     
         38 . The compound of  claim 37 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5  is methyl. 
     
     
         39 . The compound of any one of  claims 1 - 32 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5  is —OC(O)R 1 . 
     
     
         40 . The compound of any one of  claims 1 - 39 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 6  is carbocycle. 
     
     
         41 . The compound of  claim 40 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 6  is cycloalkyl. 
     
     
         42 . The compound of  claim 41 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 6  is cyclopropyl. 
     
     
         43 . The compound of  claim 1 - 39 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 6  is an aromatic carbocycle. 
     
     
         44 . The compound of  claim 43 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 6  is phenyl. 
     
     
         45 . The compound of any one of  claims 1 - 39 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 6  is halo. 
     
     
         46 . The compound of  claim 39 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 6  is Cl, F or Br. 
     
     
         47 . The compound of any one of  claims 1 - 39 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 6  is (C 1 -C 6 )alkyl. 
     
     
         48 . The compound of  claim 47 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the at least one R 6  is methyl. 
     
     
         49 . The compound of any one of  claims 1 - 39 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 6  is (C 1 -C 6 )alkoxy. 
     
     
         50 . The compound of  claim 49 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein the at least one R 6  is methoxy. 
     
     
         51 . The compound of any one of  claims 1 - 16  and  22 - 24 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 7  is (C 1 -C 6 )alkyl. 
     
     
         52 . The compound of  claim 51 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 7  is methyl, ethyl, isopropyl, or t-butyl. 
     
     
         53 . The compound of any one of  claims 1 - 16  and  22 - 24 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 7  is carbocycle. 
     
     
         54 . The compound of  claim 53 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 7  is cycloalkyl. 
     
     
         55 . The compound of  claim 54 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein at least one R 7  is cyclopropyl. 
     
     
         56 . The compound of any one of  claims 1 - 55 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 8  is H. 
     
     
         57 . The compound of any one of  claims 1 - 55 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 8  is methyl. 
     
     
         58 . The compound of  claim 1 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, having the structure of any one of the compounds listed in Table 1, Table 2, or Table 3. 
     
     
         59 . A pharmaceutical composition comprising a compound of any one of  claims 1 - 58 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         60 . A method of modulating an opioid receptor comprising contacting the opioid receptor with an effective amount of a compound of any one of  claims 1 - 58 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. 
     
     
         61 . The method of  claim 60 , wherein the compound is mu opioid receptor agonist. 
     
     
         62 . The method of  claim 60  or  61 , wherein the compound is a kappa opioid receptor antagonist. 
     
     
         63 . The method of any one of  claims 60 - 62 , wherein the method does not modulate arrestin function. 
     
     
         64 . A method of treating pain, comprising administering to a subject in need thereof an effective amount of a compound of any one of  claims 1 - 58 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. 
     
     
         65 . The method of  claim 64 , wherein the method does not increase the risk of respiratory depression or constipation in the subject. 
     
     
         66 . The method of  claim 64 , wherein the pain is acute pain. 
     
     
         67 . The method of  claim 64 , wherein the pain is chronic pain. 
     
     
         68 . The method of  claim 64 , wherein the pain is fibromyalgia, neuropathic pain, chronic low back pain, surgical pain, cancer pain, or severe pain. 
     
     
         69 . A method of treating opioid overdose, comprising administering to a subject in need thereof an effective amount of a compound of any one of  claims 1 - 58 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. 
     
     
         70 . A method of treating addiction, comprising administering to a subject in need thereof an effective amount of a compound of any one of  claims 1 - 58 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. 
     
     
         71 . The method of  claim 70 , wherein the addiction is opioid use disorder. 
     
     
         72 . The method of  claim 70 , wherein the method comprises maintenance of the opioid use disorder in a subject in need thereof. 
     
     
         73 . A method of treating a neuropsychiatric disorder, comprising administering to a subject in need thereof an effective amount of a compound of any one of  claims 1 - 58 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. 
     
     
         74 . The method of  claim 73 , wherein the neuropsychiatric disorder is characterized by compulsive behavior. 
     
     
         75 . The method of  claim 73 , wherein the neuropsychiatric disorder characterized by compulsive behavior is obsessive compulsive disorder, trichotillomania, or skin picking. 
     
     
         76 . The method of  claim 75 , wherein the compulsive behavior is associated with a neurodegenerative disorder. 
     
     
         77 . The method of  claim 76 , wherein the neurodegenerative disorder is Huntington's disease or Parkinson's disease. 
     
     
         78 . The method of  claim 73 , wherein the neuropsychiatric disorder is characterized by impulsive behavior. 
     
     
         79 . The method of  claim 78 , wherein the neuropsychiatric disorder characterized by impulsive behavior is addiction, pathological gambling, alcohol use disorder, nicotine addiction, sex addiction, Tourette syndrome, or kleptomania. 
     
     
         80 . The method of  claim 78 , wherein the impulsive behaviour is associated with a neurodegenerative disorder. 
     
     
         81 . The method of  claim 80 , wherein the neurodegenerative disorder is frontotemporal dementia or Alzheimer's disorder. 
     
     
         82 . The method of  claim 73 , wherein the neuropsychiatric disorder is characterized by depressive mood. 
     
     
         83 . The method of  claim 82 , wherein the neuropsychiatric disorder characterized by depressive mood is major depressive disorder, anxiety disorder, panic disorder, dysphoria, or anhedonia. 
     
     
         84 . The method of  claim 73 , wherein the neuropsychiatric disorder is an eating disorder. 
     
     
         85 . The method of  claim 84 , wherein the eating disorder is anorexia nervosa, bulimia nervosa, binge eating disorder, or obesity. 
     
     
         86 . A method of treating a sleep disorder, comprising administering to a subject in need thereof an effective amount of a compound of any one of  claims 1 - 58 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. 
     
     
         87 . The method of  claim 86 , wherein the sleep disorder is sleep disruption. 
     
     
         88 . The method of  claim 87 , wherein the sleep disruption is associated with a neurodegenerative disorder. 
     
     
         89 . The method of  claim 88 , wherein the neurodegenerative disorder is supranuclear palsy. 
     
     
         90 . A method of treating a gastrointestinal disorder, comprising administering to a subject in need thereof an effective amount of a compound of any one of  claims 1 - 58 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. 
     
     
         91 . The method of  claim 90 , wherein the gastrointestinal disorder is constipation, diarrhea, irritable bowel syndrome, inflammatory bowel disease, or Crohn's disease. 
     
     
         92 . A method of treating a skin disorder, comprising administering to a subject in need thereof an effective amount of a compound of any one of  claims 1 - 58 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. 
     
     
         93 . The method of  claim 92 , wherein the skin disorder is itching or urticaria. 
     
     
         94 . A method of treating dyspnea, comprising administering to a subject in need thereof an effective amount of a compound of any one of  claims 1 - 58 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. 
     
     
         95 . The method of  claim 73 , wherein the neuropsychiatric disorder is Schizophrenia, psychosis, or bipolar disorder. 
     
     
         96 . A method of treating autism spectrum disorder, comprising administering to a subject in need thereof an effective amount of a compound of any one of  claims 1 - 58 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. 
     
     
         97 . A method of treating Prader-Willi Syndrome, comprising administering to a subject in need thereof an effective amount of a compound of any one of  claims 1 - 58 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. 
     
     
         98 . A method of treating headache, comprising administering to a subject in need thereof an effective amount of a compound of any one of  claims 1 - 58 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof. 
     
     
         99 . The method of  claim 98 , wherein the headache is migraine. 
     
     
         100 . A method of treating temporomandibular joint dysfunction, comprising administering to a subject in need thereof an effective amount of a compound of any one of  claims 1 - 58 , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof.