Aryl substituted indoles and the use thereof

Abstract

The invention relates to aryl and heteroaryl substituted compounds of Formula (I), and pharmaceutically acceptable salts, prodrugs, or solvates thereof, wherein G, R 1 , and Z 1 -Z 5 are defined as set forth in the specification. The invention is also directed to the use of compounds of Formula (I) to treat a disorder responsive to the blockade of sodium channels. Compounds of the present invention are especially useful for treating pain.

1 - 91 . (canceled) 
     
     
         92 . A method for treating a condition in a mammal, wherein the condition is stroke, neuronal damage resulting from head trauma, epilepsy, seizures, general epilepsy with febrile seizures, severe myoclonic epilepsy in infancy, neuronal loss following global and focal ischemia, migraine, familial primary erythromelalgia, paroxysmal extreme pain disorder, cerebellar atrophy, ataxia, distonia, tremor, mental retardation, autism, a neurodegenerative disorder, manic depression, tinnitus, myotonia, a movement disorder, or cardiac arrhythmia,
 said method comprising administering to the mammal identified as in need thereof an effective amount of a compound of Formula I:   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
 Z 1  is CR 2  or N, Z 2  is CR 3  or N, Z 3  is CR 4  or N, Z 4  is CR 5  or N, and Z 5  is CR 6  or N, provided that Z 2 , Z 3 , Z 4 , and Z 5  are not all N at the same time; 
 G is G 1 , G 2 , or G 3 , wherein 
 G 1  is 
 
       
         
           
           
               
               
           
         
         G 2  is 
       
       
         
           
           
               
               
           
         
         G 3  is 
       
       
         
           
           
               
               
           
         
         m is 0, 1, 2, or 3; 
         p is 0, 1, 2, or 3; 
         r is 0 or 1; 
         s is 1 or 2; provided that when r is 1, then s is 1; 
         R 7  is selected from the group consisting of 
         a) —C(═O)NR 1i R 11 , wherein R 10  and R 11  are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl; 
         b) —C(═O)OR 12 , wherein R 12  is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl; 
         c) —(CH 2 ) n OR 13 , wherein n is 1-5 and R 13  is hydrogen; and 
         d) hydrogen; 
         R 8  and R 9  are each independently selected from the group consisting of hydrogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, and optionally substituted arylcarbonyl; or 
         NR 8 R 9  is —NO 2 ; or 
         R 9  is hydrogen, R 7  is —(CH 2 ) n OR 13 , R 8  and R 13  together form a bridge —C(═O)— to form a heterocyclic ring, n is 1-5, and m is 1, 2 or 3; 
         R 7a  is selected from the group consisting of 
         a) —(CH 2 ) q OH, wherein q is 1, 2, 3, 4, or 5; 
         b) —C(═O)OR 12a , wherein R 12a  is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl; and 
         c) hydrogen; 
         R 8a  is hydrogen or a bond; provided that when R 7a  is hydrogen, then R 8a  is hydrogen; 
         R 7b  and R 8b  are are each independently selected from the group consisting of hydrogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, and optionally substituted arylcarbonyl; 
         R 9b  is hydrogen, alkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkyl, cyanoalkyl, or hydroxyalkyl; 
         one of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  is A, wherein 
         A is 
       
       
         
           
           
               
               
           
         
       
       wherein
 A 1  is aryl or heteroaryl, any of which is optionally substituted; 
 X is —O—, —S—, —SO—, —SO 2 —, —CH 2 —, —NR 27 —, —N(R 28 )SO 2 —, or —SO 2 N(R 29 )—, wherein 
 R 27 , R 28 , and R 29  are each independently hydrogen or alkyl; and 
 R 14  and R 15  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl; 
 R 1 , when not A, is hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonylalkyl, (alkylaminocarbonyl)alkyl, or (dialkylaminocarbonyl)alkyl; and 
 R 2 , R 3 , R 4 , R 5 , and R 6 , when not A, are each independently selected from the group consisting of hydrogen; optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; halogen; hydroxy; cyano; amino; alkylamino; dialkylamino; alkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylamino; alkylcarbonyloxy; carboxy; aminosulfonyl; alkylsulfonylamino; and alkoxycarbonyl. 
 
     
     
         93 . The method of  claim 92 , wherein said compound is
 2-amino-3-[7-(4-phenoxyphenyl)-1H-indol-3-yl]propan-1-ol,   2-amino-3-[2-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,   2-amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,   2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propan-1-ol,   2-amino-N-(2-hydroxyethyl)-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]-propionamide,   2-amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propan-1-ol,   2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,   2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,   2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid,   2-methanesulfonylamino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]-propionamide,   2-tert-butoxycarbonylamino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid,   2-amino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,   2-tert-butoxycarbonylamino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,   2-nitro-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,   5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,   5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,   5-{4-[3-((2-oxooxazolidin-4-yl)methyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,   4-{[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]methyl}oxazolidin-2-one,   2-amino-3-[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]propan-1-ol,   2-(1-(4-phenoxyphenyl)-1H-indol-3-yl)ethanamine,   5-{4-[3-(1,2-dihydroxyethyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)-benzonitrile,   5-{4-[3-(2,3-dihydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,   5-{4-[3-(2-ethoxyoxalyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)-benzonitrile,   2-nitro-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,   2-amino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,   2-nitro-3-[2-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,   2-amino-3-[2-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,   2-nitro-3-[1-(4-phenoxyphenyl)-1H0indol-3-yl]propionic acid ethyl ester,   2-amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,   5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}benzonitrile,   (S)-5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,   (R)-5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,   (S)-5-{4-[3-((2-oxooxazolidin-4-yl)methyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,   (S)-4-{[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]methyl}oxazolidin-2-one,   (S)-2-amino-3-[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]propan-1-ol,   (S)-5-{4-[3-(2,3-dihydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,   (S)-5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}benzonitrile,   2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-oxoacetamide,   2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,   methyl 3-(2-amino-1-hydroxy-2-oxoethyl)-1-(4-(3-cyano-4-(trifluoromethyl)-phenoxy)phenyl)-1H-indole-3-carboxylate,   2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N-(2,3-dihydroxypropyl)-2-oxoacetamide,   2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N-(2,3-dihydroxypropyl)-2-hydroxyacetamide,   3,3′-(5-(4-(4-fluorophenoxy)phenyl)-1H-indole-1,3-diyl)bis(propane-1,2-diol),   4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,   4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,   3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,   3-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,   4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-N-methylbenzenesulfonamide,   4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-benzenesulfonamide,   2-(1-(4-(3-cyano-4-trifluoromethyl)phenoxy)phenyl)-5-(1,2-dihydroxyethyl)-1H-indol-3-yl)-2-oxoacetic acid,   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carbonitrile,   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-5-carbonitrile,   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-7-carbonitrile,   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carbonitrile,   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxamide,   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carboxamide,   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxylic acid,   5-(4-(4-(1,2-dihydroxyethyl)-3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)-2-(trifluoromethyl)benzonitrile,   (N)-(2-hydroxyethyl)-1-(4-phenoxyphenyl)-1H-indazole-3-carboxamide,   1-(4-phenoxyphenyl)-1H-indazole-3-carboxamide,   N-hydroxy-1-(4-phenoxyphenyl)-1H-indazole-3-carboxamide,   5-fluoro-1-(4-(4-trifluoromethyl)phenoxy)phenyl)-1H-indazole-3-carboxamide,   1-(4-(3-cyano-(4-trifluoromethyl)phenoxy)phenyl)-1H-indazole-3-carboxamide,   1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indazole-3-carboxamide,   1-(4-(4-cyanophenoxy)phenyl)-N-(2,3-dihydroxypropyl)-1H-indazole-3-carboxamide,   (1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methanol,   1-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-yl)ethane-1,2-diol,   3-(1-(4-(4-fluorophenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)propane-1,2-diol,   4-(4-(3-(2,3-dihydroxypropyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)phenoxy)benzonitrile,   2-(1-(2-diethylamino)ethyl-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)-2-oxoacetamide,   2-(1-(2-(diethylamino)ethyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,   3-(1-(2-diethylamino)ethyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,   2-(3-(2,3-dihydroxypropyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-1-yl)acetamide,   2-(1-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanamide,   2-(1-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,   2-hydroxy-2-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)acetamide,   2-amino-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propan-1-ol,   3-(5-(4-(4-fluorophenoxy)phenyl)-1-(2-hydroxyethyl)-1H-indol-3-yl)propane-1,2-diol,   (S)-2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N-(2,3-dihydroxypropyl)-2-oxoacetamide,   2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N—((S)-2,3-dihydroxypropyl)-2-hydroxyacetamide,   (2S,2′S)-3,3′-(5-(4-(4-fluorophenoxy)phenyl)-1H-indole-1,3-diyl)bis(propane-1,2-diol),   (S)-4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,   (R)-4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,   (S)-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,   (S)-3-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,   (S)-4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-N-methylbenzenesulfonamide,   (S)-4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-benzenesulfonamide,   (R)-2-(1-(4-(3-cyano-4-trifluoromethyl)phenoxy)phenyl)-5-(1,2-dihydroxyethyl)-1H-indol-3-yl)-2-oxoacetic acid,   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carbonitrile,   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-5-carbonitrile,   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-7-carbonitrile,   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carbonitrile,   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxamide,   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carboxamide,   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxylic acid,   5-(4-(4-(1,2-dihydroxyethyl)-3-((R)-2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)-2-(trifluoromethyl)benzonitrile,   5-(4-(4-(1,2-dihydroxyethyl)-3-((S)-2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)-2-(trifluoromethyl)benzonitrile,   (R)-1-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-yl)ethane-1,2-diol,   (S)-3-(1-(4-(4-fluorophenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)propane-1,2-diol,   (S)-4-(4-(3-(2,3-dihydroxypropyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)phenoxy)benzonitrile,   (S)-3-(1-(2-diethylamino)ethyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,   (S)-2-(3-(2,3-dihydroxypropyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-1-yl)acetamide,   (S)-2-amino-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propan-1-ol,   (S)-3-(5-(4-(4-fluorophenoxy)phenyl)-1-(2-hydroxyethyl)-1H-indol-3-yl)propane-1,2-diol,   (S)-2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,   (R)-2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,   or a pharmaceutically acceptable salt, prodrug or solvate thereof.   
     
     
         94 . A method for providing local anesthesia in a subject, comprising administering to the subject identified as in need thereof an effective amount of a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, prodrug or solvate thereof, wherein:
 Z 1  is CR 2  or N, Z 2  is CR 3  or N, Z 3  is CR 4  or N, Z 4  is CR 5  or N, and Z 5  is CR 6  or N, provided that Z 2 , Z 3 , Z 4 , and Z 5  are not all N at the same time; 
 G is G 1 , G 2 , or G 3 , wherein 
 G 1  is 
 
       
         
           
           
               
               
           
         
         G 2  is 
       
       
         
           
           
               
               
           
         
       
       and
 G 3  is 
 
       
         
           
           
               
               
           
         
         m is 0, 1, 2, or 3; 
         p is 0, 1, 2, or 3; 
         r is 0 or 1; 
         s is 1 or 2; provided that when r is 1, then s is 1; 
         R 7  is selected from the group consisting of 
         a) —C(═O)NR 10 R 11 , wherein R 10  and R 11  are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl; 
         b) —C(═O)OR 12 , wherein R 12  is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl; 
         c) —(CH 2 ) n OR 13 , wherein n is 1-5 and R 13  is hydrogen; and 
         d) hydrogen; 
         R 8  and R 9  are each independently selected from the group consisting of hydrogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, and optionally substituted arylcarbonyl; or 
         NR 8 R 9  is —NO 2 ; or 
         R 9  is hydrogen, R 7  is —(CH 2 ) n OR 13 , R 8  and R 13  together form a bridge —C(═O)— to form a heterocyclic ring, n is 1-5, and m is 1, 2 or 3; 
         R 7a  is selected from the group consisting of 
         a) —(CH 2 ) q OH, wherein q is 1, 2, 3, 4, or 5; 
         b) —C(═O)OR 12a , wherein R 12a  is selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, and dialkylaminoalkyl; and 
         c) hydrogen; 
         R 8a  is hydrogen or a bond; provided that when R 7a  is hydrogen, then R 8a  is hydrogen; 
         R 7b  and R 8b  are are each independently selected from the group consisting of hydrogen, alkyl, alkylsulfonyl, alkylsulfinyl, alkylcarbonyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, haloalkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, hydroxy, haloalkylcarbonyl, and optionally substituted arylcarbonyl; 
         R 9b  is hydrogen, alkyl, haloalkyl, haloalkoxyalkyl, alkoxyalkyl, cyanoalkyl, or hydroxyalkyl; 
         one of R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  is A, wherein 
         A is 
       
       
         
           
           
               
               
           
         
       
       wherein
 A 1  is aryl or heteroaryl, any of which is optionally substituted; 
 X is —O—, —S—, —SO—, —SO 2 —, —CH 2 —, —NR 27 —, —N(R 28 )SO 2 —, or —SO 2 N(R 29 )—, wherein 
 R 27 , R 28 , and R 29  are each independently hydrogen or alkyl; and 
 R 14  and R 15  are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, acylamino, thiol, acyloxy, azido, mercaptoalkyl, alkoxy, carboxy, and aminocarbonyl; 
 R 1 , when not A, is hydrogen, alkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, aminocarbonylalkyl, (alkylaminocarbonyl)alkyl, or (dialkylaminocarbonyl)alkyl; and 
 R 2 , R 3 , R 4 , R 5 , and R 6 , when not A, are each independently selected from the group consisting of hydrogen; optionally substituted alkyl, optionally substituted alkenyl, or optionally substituted alkynyl; halogen; hydroxy; cyano; amino; alkylamino; dialkylamino; alkoxy; aminocarbonyl; alkylaminocarbonyl; dialkylaminocarbonyl; alkylcarbonylamino; alkylcarbonyloxy; carboxy; aminosulfonyl; alkylsulfonylamino; and alkoxycarbonyl. 
 
     
     
         95 . The method of  claim 94 , wherein said compound is
 2-amino-3-[7-(4-phenoxyphenyl)-1H-indol-3-yl]propan-1-ol,   2-amino-3-[2-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,   2-amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,   2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propan-1-ol,   2-amino-N-(2-hydroxyethyl)-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]-propionamide,   2-amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propan-1-ol,   2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,   2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,   2-amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid,   2-methanesulfonylamino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]-propionamide,   2-tert-butoxycarbonylamino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid,   2-amino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionamide,   2-tert-butoxycarbonylamino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,   2-nitro-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,   5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,   5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,   5-{4-[3-((2-oxooxazolidin-4-yl)methyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,   4-{[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]methyl}oxazolidin-2-one,   2-amino-3-[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]propan-1-ol,   2-(1-(4-phenoxyphenyl)-1H-indol-3-yl)ethanamine,   5-{4-[3-(1,2-dihydroxyethyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)-benzonitrile,   5-{4-[3-(2,3-dihydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,   5-{4-[3-(2-ethoxyoxalyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)-benzonitrile,   2-nitro-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,   2-amino-3-[6-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,   2-nitro-3-[2-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,   2-amino-3-[2-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,   2-nitro-3-[1-(4-phenoxyphenyl)-1H0indol-3-yl]propionic acid ethyl ester,   2-amino-3-[1-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid ethyl ester,   5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}benzonitrile,   (S)-5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,   (R)-5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,   (S)-5-{4-[3-((2-oxooxazolidin-4-yl)methyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,   (S)-4-{[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]methyl}oxazolidin-2-one,   (S)-2-amino-3-[3-(2-dimethylaminoethyl)-1-(4-phenoxyphenyl)-1H-indol-5-yl]propan-1-ol,   (S)-5-{4-[3-(2,3-dihydroxypropyl)-1H-indol-1-yl]phenoxy}-2-(trifluoromethyl)benzonitrile,   (S)-5-{4-[3-(2-amino-3-hydroxypropyl)-1H-indol-1-yl]phenoxy}benzonitrile,   2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-oxoacetamide,   2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,   methyl 3-(2-amino-1-hydroxy-2-oxoethyl)-1-(4-(3-cyano-4-(trifluoromethyl)-phenoxy)phenyl)-1H-indole-3-carboxylate,   2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N-(2,3-dihydroxypropyl)-2-oxoacetamide,   2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N-(2,3-dihydroxypropyl)-2-hydroxyacetamide,   3,3′-(5-(4-(4-fluorophenoxy)phenyl)-1H-indole-1,3-diyl)bis(propane-1,2-diol),   4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,   4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,   3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,   3-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,   4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-N-methylbenzenesulfonamide,   4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-benzenesulfonamide,   2-(1-(4-(3-cyano-4-trifluoromethyl)phenoxy)phenyl)-5-(1,2-dihydroxyethyl)-1H-indol-3-yl)-2-oxoacetic acid,   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carbonitrile,   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-5-carbonitrile,   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-7-carbonitrile,   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carbonitrile,   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxamide,   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carboxamide,   3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxylic acid,   5-(4-(4-(1,2-dihydroxyethyl)-3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)-2-(trifluoromethyl)benzonitrile,   (N)-(2-hydroxyethyl)-1-(4-phenoxyphenyl)-1H-indazole-3-carboxamide,   1-(4-phenoxyphenyl)-1H-indazole-3-carboxamide,   N-hydroxy-1-(4-phenoxyphenyl)-1H-indazole-3-carboxamide,   5-fluoro-1-(4-(4-trifluoromethyl)phenoxy)phenyl)-1H-indazole-3-carboxamide,   1-(4-(3-cyano-(4-trifluoromethyl)phenoxy)phenyl)-1H-indazole-3-carboxamide,   1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indazole-3-carboxamide,   1-(4-(4-cyanophenoxy)phenyl)-N-(2,3-dihydroxypropyl)-1H-indazole-3-carboxamide,   (1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)methanol,   1-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-yl)ethane-1,2-diol,   3-(1-(4-(4-fluorophenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)propane-1,2-diol,   4-(4-(3-(2,3-dihydroxypropyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)phenoxy)benzonitrile,   2-(1-(2-diethylamino)ethyl-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)-2-oxoacetamide,   2-(1-(2-(diethylamino)ethyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,   3-(1-(2-diethylamino)ethyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,   2-(3-(2,3-dihydroxypropyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-1-yl)acetamide,   2-(1-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-3,3,3-trifluoro-2-hydroxypropanamide,   2-(1-(4-(4-cyano-3-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,   2-hydroxy-2-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)acetamide,   2-amino-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propan-1-ol,   3-(5-(4-(4-fluorophenoxy)phenyl)-1-(2-hydroxyethyl)-1H-indol-3-yl)propane-1,2-diol,   (S)-2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N-(2,3-dihydroxypropyl)-2-oxoacetamide,   2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-N—((S)-2,3-dihydroxypropyl)-2-hydroxyacetamide,   (2S,2′S)-3,3′-(5-(4-(4-fluorophenoxy)phenyl)-1H-indole-1,3-diyl)bis(propane-1,2-diol),   (S)-4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,   (R)-4-(4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)benzonitrile,   (S)-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,   (S)-3-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,   (S)-4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-N-methylbenzenesulfonamide,   (S)-4-(3-(2,3-dihydroxypropyl)-1H-indol-1-yl)-N-(4-fluorophenyl)-benzenesulfonamide,   (R)-2-(1-(4-(3-cyano-4-trifluoromethyl)phenoxy)phenyl)-5-(1,2-dihydroxyethyl)-1H-indol-3-yl)-2-oxoacetic acid,   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carbonitrile,   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-5-carbonitrile,   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-7-carbonitrile,   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carbonitrile,   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxamide,   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-6-carboxamide,   (S)-3-(2,3-dihydroxypropyl)-1-(4-(4-fluorophenoxy)phenyl)-1H-indole-4-carboxylic acid,   5-(4-(4-(1,2-dihydroxyethyl)-3-((R)-2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)-2-(trifluoromethyl)benzonitrile,   5-(4-(4-(1,2-dihydroxyethyl)-3-((S)-2,3-dihydroxypropyl)-1H-indol-1-yl)phenoxy)-2-(trifluoromethyl)benzonitrile,   (R)-1-(1-(4-(4-(trifluoromethyl)phenoxy)phenyl)-1H-pyrazolo[3,4-c]pyridine-3-yl)ethane-1,2-diol,   (S)-3-(1-(4-(4-fluorophenoxy)phenyl)-1H-pyrrolo[2,3-c]pyridin-3-yl)propane-1,2-diol,   (S)-4-(4-(3-(2,3-dihydroxypropyl)-1H-pyrrolo[3,2-b]pyridin-1-yl)phenoxy)benzonitrile,   (S)-3-(1-(2-diethylamino)ethyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-3-yl)propane-1,2-diol,   (S)-2-(3-(2,3-dihydroxypropyl)-5-(4-(4-fluorophenoxy)phenyl)-1H-indol-1-yl)acetamide,   (S)-2-amino-3-(1-(4-((5-(trifluoromethyl)pyridin-2-yl)oxy)phenyl)-1H-indol-3-yl)propan-1-ol,   (S)-3-(5-(4-(4-fluorophenoxy)phenyl)-1-(2-hydroxyethyl)-1H-indol-3-yl)propane-1,2-diol,   (S)-2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,   (R)-2-(1-(4-(3-cyano-4-(trifluoromethyl)phenoxy)phenyl)-1H-indol-3-yl)-2-hydroxyacetamide,   or a pharmaceutically acceptable salt, prodrug or solvate thereof.