Somatostatin modulators and uses thereof

Abstract

Described herein are compounds that are somatostatin modulators, methods of making such compounds, pharmaceutical compositions and medicaments comprising such compounds, and methods of using such compounds in the treatment of conditions, diseases, or disorders that would benefit from modulation of somatostatin activity.

What is claimed is: 
     
         1 . A compound of Formula (I), or a pharmaceutically acceptable salt, or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 2  is hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl; 
         R 3  is hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl; 
         or R 2  and R 3  are taken together with the N atom to which they are attached to form a substituted or unsubstituted 4-membered, substituted or unsubstituted 5-membered or substituted or unsubstituted 6-membered N-containing heterocyclic ring; 
         R 5  is hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl; 
         R 6  is substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, —CN, —OR 15 , —CO 2 R 15 , —C(═O)N(R 15 ) 2 , —C(═O)N(R 15 )OR 15 , —N(R 15 ) 2 , —NR 15 C(═O)R 15 , or —C(R 15 )═N—OR 15 ; 
         R 7  is —CN; 
         each R 8  and R 9  is independently hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, —CN, —OH, or substituted or unsubstituted C 1 -C 4 alkoxy; 
         X 1  is N or C—R 10 ; 
         R 10  is hydrogen, F, Cl, Br, —CN, —N(R 15 ) 2 , substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 4 fluoroalkoxy, substituted or unsubstituted C 1 -C 4 heteroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl; 
         R 12  is hydrogen, or substituted or unsubstituted C 1 -C 6 alkyl; 
         R 13  is hydrogen, —N(R 16 ) 2 , —CN, —CO 2 R 14 , —C(═O)N(R 15 ) 2 , —OR 16 , substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl; 
         or R 12  and R 13  are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring; 
         or R 12  and R 16  are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring; 
         each R 14  is independently selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; 
         each R 15  is independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; 
         or two R 15  on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle; 
         each R 16  is independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; 
         or two R 16  on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle. 
       
     
     
         2 . The compound of  claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of Formula (Ia), or a pharmaceutically acceptable salt, or solvate thereof: 
       
         
           
           
               
               
           
         
       
     
     
         3 . The compound of  claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 2  is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or C 3 -C 6 cycloalkyl;   R 3  is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or C 3 -C 6 cycloalkyl;   or R 2  and R 3  are taken together with the N atom to which they are attached to form a substituted or unsubstituted 5-membered or substituted or unsubstituted 6-membered N-containing heterocyclic ring; and   R 5  is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl.   
     
     
         4 . The compound of  claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 2  is hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , or —CH 2 CH 2 OCF 3 ;   R 3  is hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH 2 CF 3 , —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , or —CH 2 CH 2 OCF 3 ;   or R 2  and R 3  are taken together with the N atom to which they are attached to form substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, or substituted or unsubstituted piperazinyl; and   R 5  is hydrogen, —CH 3 , —CH 2 CH 3 , or —CH 2 CH 2 CH 3 .   
     
     
         5 . The compound of  claim 4 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 2  is hydrogen or —CH 3 ;   R 3  is hydrogen or —CH 3 ; and   R 5  is hydrogen.   
     
     
         6 . The compound of  claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 6  is substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl, —CN, or —OR 15 ; and   each R 8  and R 9  is independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or C 1 -C 4 alkoxy.   
     
     
         7 . The compound of  claim 6 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 6  is —CH 3 , —CH 2 CH 3 , —CF 3 , —CH═CH 2 , —C≡CH, —CN, —OH, —OCH 3 , —OCH 2 CH 3 , or —OCF 3 ; and   each R 8  and R 9  is independently hydrogen, F, Cl, Br, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )(CH 2 CH 3 ), —C(CH 3 ) 3 , —CH 2 F, —CHF 2 , —CH 2 CF 3 , —OCH 3 , or —OCH 2 CH 3 .   
     
     
         8 . The compound of  claim 7 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 6  is —CH 3 , —CN, —CF 3 , —OCH 3 , or —OCF 3 ; and   each R 8  and R 9  is independently F, Cl, —CH 3 , or —OCH 3 .   
     
     
         9 . The compound of  claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 12  is hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , or —CH(CH 3 ) 2 ;   R 13  is hydrogen, —N(R 16 ) 2 , —CN, —CO 2 R 14 , —C(═O)N(R 15 ) 2 , —OR 16 , or substituted or unsubstituted C 1 -C 6 heteroalkyl;   or R 12  and R 13  are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring;   or R 12  and R 16  are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring; and   each R 16  is independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl.   
     
     
         10 . The compound of  claim 9 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 12  is hydrogen;   R 13  is hydrogen.   
     
     
         11 . The compound of  claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, that has the following structure of Formula (Ic), or a pharmaceutically acceptable salt, or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 2  is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl; 
         R 3  is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl; 
         or R 2  and R 3  are taken together with the N atom to which they are attached to form a substituted or unsubstituted 5-membered or substituted or unsubstituted 6-membered N-containing heterocyclic ring; 
         R 5  is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl; 
         R 6  is substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, —CN, —OR 15 , —CO 2 R 15 , —C(═O)N(R 15 ) 2 , —C(═O)N(R 15 )OR 15 , —N(R 15 ) 2 , —NR 15 C(═O)R 15 , or —C(R 15 )═N—OR 15 ; 
         each R 8  and R 9  is independently hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, —CN, —OH, or substituted or unsubstituted C 1 -C 4 alkoxy; and 
         each R 15  is independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; 
         or two R 15  on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle. 
       
     
     
         12 . The compound of  claim 11 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 2  is hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , or —CH 2 CH 2 OCF 3 ;   R 3  is hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , or —CH 2 CH 2 OCF 3 ;   or R 2  and R 3  are taken together with the N atom to which they are attached to form substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted morpholinyl, substituted or unsubstituted thiomorpholinyl, or substituted or unsubstituted piperazinyl; and   R 5  is hydrogen, —CH 3 , —CH 2 CH 3 , or —CH 2 CH 2 CH 3 .   
     
     
         13 . The compound of  claim 11 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 2  is hydrogen or —CH 3 ;   R 3  is hydrogen or —CH 3 ; and   R 5  is hydrogen;   R 6  is substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl, —CN, or —OR 15 ; and   each R 8  and R 9  is independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or C 1 -C 4 alkoxy.   
     
     
         14 . The compound of  claim 13 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 6  is —CH 3 , —CN, —CF 3 , —OCH 3 , or —OCF 3 ; and   each R 8  and R 9  is independently F, Cl, —CH 3 , or —OCH 3 .   
     
     
         15 . A compound of Formula (II), or a pharmaceutically acceptable salt, or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is —CN, —CO 2 R 15 , —C(═O)N(R 15 ) 2 , —S(═O) 2 R 15 , or —S(═O) 2 N(R 15 ) 2 ; 
         R 5  is hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl; 
         each R 6  and R 7  is independently halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, —CN, —OR 15 , —CO 2 R 15 , —C(═O)N(R 15 ) 2 , —C(═O)N(R 15 )OR 15 , —N(R 15 ) 2 , —NR 15 C(═O)R 15 , or —C(R 15 )═N—OR 15 ; 
         each R 8  and R 9  is independently hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, —CN, —OH, or substituted or unsubstituted C 1 -C 4 alkoxy; 
         X 1  is N or C—R 10 ; 
         R 10  is hydrogen, F, Cl, Br, —CN, —N(R 15 ) 2 , substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 4 fluoroalkoxy, substituted or unsubstituted C 1 -C 4 heteroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl; 
         R 12  is hydrogen, or substituted or unsubstituted C 1 -C 6 alkyl; 
         R 13  is hydrogen, —N(R 16 ) 2 , —CN, —CO 2 R 14 , —C(═O)N(R 15 ) 2 , —OR 16 , substituted or unsubstituted C 1 -C 6  alkyl, substituted or unsubstituted C 1 -C 6 fluoroalkyl, or substituted or unsubstituted C 1 -C 6 heteroalkyl; 
         or R 12  and R 13  are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring; 
         or R 12  and R 16  are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring; 
         each R 14  is independently selected from substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; 
         each R 15  is independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; 
         or two R 15  on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle; 
         each R 16  is independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; 
         or two R 16  on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle. 
       
     
     
         16 . The compound of  claim 15 , or a pharmaceutically acceptable salt, or solvate thereof, wherein the compound has the structure of Formula (IIa), or a pharmaceutically acceptable salt, or solvate thereof: 
       
         
           
           
               
               
           
         
       
     
     
         17 . The compound of  claim 16 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 1  is —CN, —CO 2 R 15 , or —C(═O)N(R 15 ) 2 ;   each R 15  is independently hydrogen or C 1 -C 4 alkyl; and   R 5  is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl;   R 6  is halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted monocyclic C 1 -C 5 heteroaryl, —CN, —OR 15 , —CO 2 R 15 , —C(═O)N(R 15 ) 2 , —C(═O)N(R 15 )OR 15 , —N(R 15 ) 2 , —NR 15 C(═O)R 15 , or —C(R 15 )═N—OR 15 ;   R 7  is halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, —CN, —OH, or —O-(substituted or unsubstituted C 1 -C 4 alkyl); and   each R 8  and R 9  is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or C 1 -C 4 alkoxy;   R 12  is hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , or —CH(CH 3 ) 2 ;   R 13  is hydrogen, —N(R 16 ) 2 , —CN, —CO 2 R 14 , —C(═O)N(R 15 ) 2 , —OR 16 , or substituted or unsubstituted C 1 -C 6 heteroalkyl;   or R 12  and R 13  are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring;   or R 12  and R 16  are taken together with the intervening atoms to which they are attached to form a substituted or unsubstituted N-containing heterocyclic ring;   each R 16  is independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl.   
     
     
         18 . The compound of  claim 17 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 6  is F, Cl, Br, —CH 3 , —CH 2 CH 3 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 CN, —CH 2 CO 2 H, —CH 2 CO 2 CH 3 , —CH 2 CO 2 CH 2 CH 3 , —CH 2 C(═O)NH 2 , —CH 2 C(═O)NHCH 3 , —CH 2 C(═O)N(CH 3 ) 2 , —CH 2 NH 2 , —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , —CH 2 F, —CHF 2 , —CF 3 , —CH═CH 2 , —C≡CH, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyl, pyrrolidinyl, tetrazolyl, —CN, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, —OCH 2 CN, —OCF 3 , —CO 2 H, —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(═O)NH 2 , —C(═O)NHCH 3 , —C(═O)N(CH 3 ) 2 , —C(═O)NHOCH 3 , —C(═O)N(CH 3 )OCH 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(═O)CH 3 , —NCH 3 C(═O)CH 3 , —NHC(═O)OCH 3 , —NCH 3 C(═O)OCH 3 , —CH═N—OH, or —CH═N—OCH 3 ;   R 7  is F, Cl, Br, —CH 3 , —CH 2 CH 3 , —CF 3 , —CH═CH 2 , —C≡CH, —CN, —OH, —OCH 3 , —OCH 2 CH 3 , or —OCF 3 ; and   each R 8  and R 9  is independently F, Cl, Br, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )(CH 2 CH 3 ), —C(CH 3 ) 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —OCH 3 , —OCH 2 CH 3 , or —CN.   
     
     
         19 . The compound of  claim 17 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 each R 6  and R 7  is independently substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl, —CN, or —OR 15 ; and   each R 8  and R 9  is independently halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or C 1 -C 4 alkoxy.   
     
     
         20 . The compound of  claim 17 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 each R 6  and R 7  is independently F, Cl, —CH 3 , —CF 3 , —CH═CH 2 , —C≡CH, —CN, —OH, —OCH 3 , or —OCF 3 ; and   each R 8  and R 9  is independently F, Cl, Br, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )(CH 2 CH 3 ), —C(CH 3 ) 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —OCH 3 , —OCH 2 CH 3 , or —CN.   
     
     
         21 . The compound of  claim 20 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 12  is hydrogen; and   R 13  is hydrogen.   
     
     
         22 . The compound of  claim 15 , or a pharmaceutically acceptable salt, or solvate thereof, that has the following structure of Formula (IIc), or a pharmaceutically acceptable salt, or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is —CN, —CO 2 R, or —C(═O)N(R 15 ) 2 ; 
         R 5  is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl; 
         each R 6  and R 7  is independently halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, —CN, —OR 15 , —CO 2 R 15 , —C(═O)N(R 15 ) 2 , —C(═O)N(R 15 )OR 15 , —N(R 15 ) 2 , —NR 15 C(═O)R 15 , or —C(R 15 )═N—OR 15 ; 
         each R 8  and R 9  is independently hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, —CN, —OH, or substituted or unsubstituted C 1 -C 4 alkoxy; and 
         each R 15  is independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; 
         or two R 15  on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle. 
       
     
     
         23 . The compound of  claim 22 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 1  is —CN, —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(═O)NH 2 , —CONHCH 3 , or —C(═O)N(CH 3 ) 2 ;   each R 6  and R 7  is independently halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl, —CN, or —OR 15 ; and   each R 8  and R 9  is independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or C 1 -C 4 alkoxy.   
     
     
         24 . The compound of  claim 23 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 each R 6  and R 7  is independently F, Cl, —CH 3 , —CF 3 , —CN, —OCH 3 , or —OCF 3 ; and   each R 8  and R 9  is independently F, Cl, —CH 3  or —OCH 3 .   
     
     
         25 . A compound of Formula (III), or a pharmaceutically acceptable salt, or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is —NR 2 R 3 , —OR 2 , or R 4 ; 
         R 2  is hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl; 
         R 3  is hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl; 
         or R 2  and R 3  are taken together with the N atom to which they are attached to form a substituted or unsubstituted 4-membered, substituted or unsubstituted 5-membered or substituted or unsubstituted 6-membered N-containing heterocyclic ring; 
         R 4  is F, Cl, Br, —CN, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 4 alkoxy, —SC 1 -C 4 alkyl, —S(═O)C 1 -C 4 alkyl, —S(═O) 2 -C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 heteroalkyl, substituted or unsubstituted C 3 -C 6 cycloalkyl, —CO 2 R 15 , —C(═O)N(R 15 ) 2 ; 
         R 5  is hydrogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl; 
         each R 6  and R 7  is independently halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, —CN, —OR 15 , —CO 2 R 15 , —C(═O)N(R 15 ) 2 , —C(═O)N(R 15 )OR 15 , —N(R 15 ) 2 , —NR 15 C(═O)R 15 , or —C(R 15 )═N—OR 15 ; 
         each R 8  and R 9  is independently hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, —CN, —OH, or substituted or unsubstituted C 1 -C 4 alkoxy; 
         X 1  is N or C—R 10 ; 
         R 10  is hydrogen, F, Cl, Br, —CN, —N(R 15 ) 2 , substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 alkoxy, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 4 fluoroalkoxy, substituted or unsubstituted C 1 -C 4 heteroalkyl, or substituted or unsubstituted C 3 -C 6 cycloalkyl; 
         R 11  is hydrogen or substituted or unsubstituted C 1 -C 6 alkyl; and 
         each R 15  is independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; 
         or two R 15  on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle. 
       
     
     
         26 . The compound of  claim 25 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 1  is —NR 2 R 3 ;   R 2  is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 heteroalkyl, or C 3 -C 6 cycloalkyl;   R 3  is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, C 1 -C 4 heteroalkyl, or C 3 -C 6 cycloalkyl;   or R 2  and R 3  are taken together with the N atom to which they are attached to form a substituted or unsubstituted 4-membered, substituted or unsubstituted 5-membered or substituted or unsubstituted 6-membered N-containing heterocyclic ring.   
     
     
         27 . The compound of  claim 26 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 2  is hydrogen or —CH 3 ; and   R 3  is hydrogen.   
     
     
         28 . The compound of  claim 25 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 1  is —OR 2 ; and   R 2  is hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )(CH 2 CH 3 ), —C(CH 3 ) 3 , —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , —CH 2 CN, —CH 2 F, —CHF 2 , —CF 3 , or —CH 2 CF 3 .   
     
     
         29 . The compound of  claim 25 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 1  is R 4 ; and   R 4  is F, Cl, Br, —CN, C 1 -C 4 alkyl, —SC 1 -C 4 alkyl, —S(═O)C 1 -C 4 alkyl, —S(═O) 2 -C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, —CO 2 C 1 -C 4 alkyl, or —C(═O)N(R 15 ) 2 .   
     
     
         30 . The compound of  claim 25 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 1  is —NR 2 R 3 , —OR 2 , F, Cl, Br, —CN, C 1 -C 4 alkyl, or C 1 -C 4 fluoroalkyl;   R 5  is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl;   R 6  is halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted monocyclic C 1 -C 5 heteroaryl, —CN, —OR 15 , —CO 2 R 15 , —C(═O)N(R 15 ) 2 , —C(═O)N(R 15 )OR 15 , —N(R 15 ) 2 , —NR 15 C(═O)R 15 , or —C(R 15 )═N—OR 15 ;   R 7  is halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, —CN, —OH, or —O-(substituted or unsubstituted C 1 -C 4 alkyl); and   each R 8  and R 9  is independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or C 1 -C 4 alkoxy;   R 11  is hydrogen or C 1 -C 4 alkyl.   
     
     
         31 . The compound of  claim 30 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 6  is F, Cl, Br, —CH 3 , —CH 2 CH 3 , —CH 2 OH, —CH 2 CH 2 OH, —CH 2 CN, —CH 2 CO 2 H, —CH 2 CO 2 CH 3 , —CH 2 CO 2 CH 2 CH 3 , —CH 2 C(═O)NH 2 , —CH 2 C(═O)NHCH 3 , —CH 2 C(═O)N(CH 3 ) 2 , —CH 2 NH 2 , —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , —CH 2 F, —CHF 2 , —CF 3 , —CH═CH 2 , —C≡CH, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, oxetanyloxy, tetrahydrofuranyloxy, tetrahydropyranyloxy, azetidinyl, pyrrolidinyl, tetrazolyl, —CN, —OH, —OCH 3 , —OCH 2 CH 3 , —OCH 2 CH 2 OH, —OCH 2 CN, —OCF 3 , —CO 2 H, —CO 2 CH 3 , —CO 2 CH 2 CH 3 , —C(═O)NH 2 , —C(═O)NHCH 3 , —C(═O)N(CH 3 ) 2 , —C(═O)NHOCH 3 , —C(═O)N(CH 3 )OCH 3 , —NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —NHC(═O)CH 3 , —NCH 3 C(═O)CH 3 , —NHC(═O)OCH 3 , —NCH 3 C(═O)OCH 3 , —CH═N—OH, or —CH═N—OCH 3 ;   R 7  is F, Cl, Br, —CH 3 , —CH 2 CH 3 , —CF 3 , —CH═CH 2 , —C≡CH, —CN, —OH, —OCH 3 , —OCH 2 CH 3 , or —OCF 3 ; and   each R 8  and R 9  is independently hydrogen, F, Cl, Br, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )(CH 2 CH 3 ), —C(CH 3 ) 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —OCH 3 , or —OCH 2 CH 3 .   
     
     
         32 . The compound of  claim 31 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 each R 6  and R 7  is independently F, Cl, Br, —CH 3 , —CF 3 , —CN, —OH, —OCH 3 , or —OCF 3 ; and   each R 8  and R 9  is independently hydrogen, F, Cl, Br, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 CH 2 CH 2 CH 3 , —CH 2 CH(CH 3 ) 2 , —CH(CH 3 )(CH 2 CH 3 ), —C(CH 3 ) 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —OCH 3 , or —OCH 2 CH 3 .   
     
     
         33 . The compound of  claim 31 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 each R 6  and R 7  is independently F, Cl, —CN, or —OCH 3 ; and   each R 8  and R 9  is independently hydrogen, F, Cl, —CH 3 , or —OCH 3 ;   R 11  is hydrogen.   
     
     
         34 . The compound of  claim 25 , or a pharmaceutically acceptable salt, or solvate thereof, that has the following structure of Formula (IIIa), or a pharmaceutically acceptable salt, or solvate thereof: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is —NR 2 R 3 , —OR 2 , F, Cl, Br, or —CN; 
         R 2  is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl; 
         R 3  is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl; 
         or R 2  and R 3  are taken together with the N atom to which they are attached to form substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperidinyl, substituted or unsubstituted thiomorpholinyl, or substituted or unsubstituted piperazinyl; 
         R 5  is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl; 
         each R 6  and R 7  is independently halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted monocyclic carbocycle, substituted or unsubstituted monocyclic heterocycle, —CN, —OR 15 , —CO 2 R 15 , —C(═O)N(R 15 ) 2 , —C(═O)N(R 15 )OR 15 , —N(R 15 ) 2 , —NR 15 C(═O)R 15 , or —C(R 15 )═N—OR 15 ; 
         each R 8  and R 9  is independently hydrogen, halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, —CN, —OH, or substituted or unsubstituted C 1 -C 4 alkoxy; 
         R 11  is hydrogen or substituted or unsubstituted C 1 -C 4 alkyl; and 
         each R 15  is independently selected from hydrogen, substituted or unsubstituted C 1 -C 6 alkyl, substituted or unsubstituted C 1 -C 6 heteroalkyl, substituted or unsubstituted C 3 -C 7 cycloalkyl, substituted or unsubstituted monocyclic C 2 -C 6 heterocycloalkyl, substituted or unsubstituted phenyl, and substituted or unsubstituted monocyclic heteroaryl; 
         or two R 15  on the same N atom are taken together with the N atom to which they are attached to form a substituted or unsubstituted N-containing heterocycle. 
       
     
     
         35 . The compound of  claim 34 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 1  is —NR 2 R 3 ;   R 2  is hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , or —CH 2 CH 2 OCF 3 ;   R 3  is hydrogen, —CH 3 , —CH 2 CH 3 , —CH 2 CH 2 CH 3 , —CH(CH 3 ) 2 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , or —CH 2 CH 2 OCF 3 ;   or R 2  and R 3  are taken together with the N atom to which they are attached to form substituted or unsubstituted piperidinyl, or substituted or unsubstituted piperazinyl; and   R 5  is hydrogen, —CH 3 , —CH 2 CH 3 , or —CH 2 CH 2 CH 3 ;   each R 6  and R 7  is independently halogen, substituted or unsubstituted C 1 -C 4 alkyl, substituted or unsubstituted C 1 -C 4 fluoroalkyl, substituted or unsubstituted C 2 -C 4 alkenyl, substituted or unsubstituted C 2 -C 4 alkynyl, —CN, or —OR 15 ; and   each R 8  and R 9  is independently hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 fluoroalkyl, or C 1 -C 4 alkoxy.   
     
     
         36 . The compound of  claim 35 , or a pharmaceutically acceptable salt, or solvate thereof, wherein:
 R 2  is hydrogen or —CH 3 ;   R 3  is hydrogen;   R 5  is hydrogen;   each R 6  and R 7  is independently F, Cl, —CH 3 , —CN, —OCH 3 , or —OCF 3 ; and   each R 8  and R 9  is independently hydrogen, F, Cl, —CH 3 , or —OCH 3 .   
     
     
         37 . A pharmaceutical composition comprising a compound of  claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, and at least one pharmaceutically acceptable excipient. 
     
     
         38 . A method of treating a disease or condition in a mammal comprising administering a compound of  claim 1 , or a pharmaceutically acceptable salt, or solvate thereof, to the mammal in need thereof; wherein the disease or condition is acromegaly, a neuroendocrine tumor, an ophthalmic disease or condition, neuropathy, nephropathy, a respiratory disease or condition, cancer, pain, a neurodegenerative disease or condition, an inflammatory disease or condition, a psychiatric disease or condition, or combinations thereof.