Subtype-selective NMDA receptor ligands and the use thereof

Abstract

The invention relates to subtype-selective NMDA receptor ligands and the use thereof for treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia and surgery, as well as treating neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, Huntington's disease and Down's syndrome, treating or preventing the adverse consequences of the overstimulation of the excitatory amino acids, treating anxiety, psychosis, convulsions, aminoglycoside antibiotics-induced hearing loss, migraine headache, chronic pain, Parkinson's disease, glaucoma, CMV retinitis, urinary incontinence, opioid tolerance or withdrawal, and inducing anesthesia, as well as for enhancing cognition.

What is claimed is:  
     
         1 . A compound having the Formula (I):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 R 1 -R 4  are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, cyanamido, N(CN) 2 , guanidino, amidino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;  
 E is (CR a R b ) r —G s —(CR c R d ) t , wherein R a , R b , R c  and R d  are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2  or O 2 C), carbonyl (CO), or NR e , wherein R e  is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1;  
 R 5  is hydrogen, hydroxy, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;  
 p is 0, 1, 2 or 3;  
 Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y 1 , ═—Y 1 , optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, carbonylamido, hydrazino, oximo, amidino, ureido, or guanidino; and  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.  
 
     
     
         2 . A compound having the Formula (II):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 R 1 -R 4  are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, cyanamido, N(CN) 2 , guanidino, amidino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;  
 R 5  is hydrogen, lower alkyl, acyl or aryl;  
 E is (CR a R b ) r —G s —(CR c R d ) t , wherein R a , R b , R c  and R d  are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2  or O 2 C), carbonyl (CO), or NR e , wherein R e  is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1;  
 R 6  is hydrogen, hydroxy, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;  
 p is 0, 1, 2 or 3;  
 Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y 1 , ═—Y 1 , optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, carbonylamido, hydrazino, oximo, amidino, ureido, or guanidino; and  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.  
 
     
     
         3 . A compound having the Formula (IIa):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 R 1 -R 4  are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, cyanamido, N(CN) 2 , guanidino, amidino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;  
 R 5  is hydrogen, lower alkyl, acyl or aryl;  
 E is (CR a R b ) r —G s —(CR c R d ) t , wherein R a , R b , R c  and R d  are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2  or O 2 C), carbonyl (CO), or NR e , wherein R e  is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1;  
 R 6  is hydrogen, hydroxy, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;  
 p is 0, 1, 2 or 3;  
 Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y 1 , ═—Y 1 , optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, carbonylamido, hydrazino, oximo, amidino, ureido, or guanidino; and  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.  
 
     
     
         4 . A compound having the Formula (III):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 W is an adamantyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;  
 X is a bond, (CH 2 ) m , carbonyl, oxygen, or NR;  
 E is (CR a R b ) r —G s —(CR c R d ) t , wherein R a , R b , R c  and R d  are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2  or O 2 C), carbonyl (CO), or NR e , wherein R e  is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1;  
 Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R; optionally substituted cycloalkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;  
 R is hydrogen, alkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl;  
 R 1  is hydrogen, hydroxy, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;  
 m is 0, 1, 2, or 3; and  
 p is 0, 1, 2, 3 or 4.  
 with the proviso, that when W is adamantyl or when p is other than zero, or when the piperidine ring is substituted in the 3-position with W—X, then Y may also be optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y 1 , ═—Y 1 , optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino; wherein 
 Y 1  is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.  
 
 
     
     
         5 . A compound having Formula IIIa:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 W is an adamantyl group or an optionally substituted aryl group;  
 Y is CH 3 , CN, CO 2 R, carboxamido, an optionally substituted cycloalkyl group or an optionally substituted heterocycloalkyl group;  
 R is alkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;  
 n is 0, 1, 2, 3, 4, 5, or 6; and  
 m is 0, 1, 2, 3;  
 with the proviso, that when W is adamantyl, then Y may also be optionally substituted aryl, optionally substituted aryloxy, SAr, COAr, hydroxy, ≡—Y 1 , ═—Y 1 , a heterocyclic group, a heteroaryl group, a cycloalkyl group, an amino group, an amido group, a ureido group, or a guanidino group; wherein 
 Y 1  is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group.  
 
 
     
     
         6 . A compound having the Formula IIIb:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 W is an adamantyl group or an optionally substituted aryl group;  
 Y is CH 3 , CN, CO 2 R, carboxamido, an optionally substituted cycloalkyl group or an optionally substituted heterocycloalkyl group;  
 R is alkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;  
 n is 0, 1, 2, 3, 4, 5, or 6; and  
 m is 0, 1, 2, or 3;  
 with the proviso, that when W is adamantyl, then Y may also be optionally substituted aryl, optionally substituted aryloxy, SAr, COAr, hydroxy, ≡—Y 1 , ═—Y 1 , a heterocyclic group, a heteroaryl group, a cycloalkyl group, an amino group, an amido group, a ureido group, or a guanidino group; wherein 
 Y 1  is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group.  
 
 
     
     
         7 . A compound having the Formula IIIc:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 W is an adamantyl group or an optionally substituted aryl group;  
 Y is CH 3 , CN, CO 2 R, carboxamido, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, optionally substituted aryl, optionally substituted aryloxy, SAr, COAr, hydroxy, ≡—Y 1 , ═—Y 1 , a heterocyclic group, a heteroaryl group, an amino group, an amido group, a ureidoalkyl group, a guanidinoalkyl group, or O—N═CR 1 R 2 , where R 1  and R 2  are independently aryl or lower alkyl;  
 R is alkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;  
 n is 0, 1, 2, 3, 4, 5, or 6; and  
 m is 0, 1, 2, or 3;  
 with the proviso, that when W is adamantyl, then Y may also be optionally substituted aryl, optionally substituted aryloxy, SAr, COAr, hydroxy, ≡—Y 1 , ═—Y 1 , a heterocyclic group, a heteroaryl group, a cycloalkyl group, an amino group, an amido group, a ureido group, or a guanidino group; wherein 
 Y 1  is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group.  
 
 
     
     
         8 . A compound having the Formula IIId:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 W is an adamantyl group or an optionally substituted aryl group;  
 X is a bond, (CH 2 ) m , oxygen, or NR;  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;  
 R 1  is hydrogen, hydroxy, halo, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;  
 n is 0, 1, 2, 3, 4, 5, or 6; and  
 m is 0, 1, 2, or 3;  
 with the proviso that when W is an adamantyl group, then Y may further be an optionally substituted aralkyl group, or an optionally substituted aryl group.  
 
     
     
         9 . A compound having the Formula IIIe:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 W is an adamantyl group or an optionally substituted aryl group;  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;  
 R 1  is hydrogen, hydroxy, halo, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;  
 n is 0, 1, 2, 3, 4, 5, or 6; and  
 m is 0, 1, 2, or 3;  
 with the proviso that when W is an adamantyl group, then Y may further be an optionally substituted aralkyl group, or an optionally substituted aryl group.  
 
     
     
         10 . A compound having the Formula IIIf:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 W is an adamantyl group or an optionally substituted aryl group;  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;  
 R 1  is hydrogen, hydroxy, halo, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;  
 n is 0, 1, 2, 3, 4, 5, or 6; and  
 m is 0, 1, 2, or 3;  
 with the proviso that when W is an adamantyl group, then Y 1  may further be an optionally substituted aralkyl group, or an optionally substituted aryl group.  
 
     
     
         11 . A compound having the Formula IIIg:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 W is an adamantyl group or an optionally substituted aryl group;  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;  
 R 1  is hydrogen, hydroxy, halo, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;  
 n is 0, 1, 2, 3, 4, 5, or 6; and  
 m is 0, 1, 2, or 3;  
 with the proviso that when W is an adamantyl group, then Y may further be an optionally substituted aralkyl group, or an optionally substituted aryl group.  
 
     
     
         12 . A compound having the Formula IIIh:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 W is an adamantyl group or an optionally substituted aryl group;  
 Y is optionally substituted aryl, optionally substituted aryloxy, SAr, COAr, hydroxy, ≡—Y 1 , ═—Y 1 , a heterocyclic group, a heteroaryl group, a cycloalkyl group, an amino group, an amido group, a ureido group, or a guanidino group;  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;  
 Z is (CH 2 ) m , oxygen, sulfur, or NR;  
 m is 0, 1, 2, or 3; and  
 n is 1, 2, 3, 4, 5, or 6.  
 
     
     
         13 . A compound having the Formula (IIIi):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 R 1 -R 5  are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;  
 n is 1, 2, 3, 4, 5, or 6;  
 Y is optionally substituted aryl, optionally substituted aryloxy, SAr, COAr, hydrogen, hydroxy, ≡—Y 1 , ═—Y 1 , a heterocyclic group, a heteroaryl group, a cycloalkyl group, an amino group, an amido group, a ureido group, or a guanidino group; and  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group.  
 
     
     
         14 . A compound having Formula (IIIj):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 R 1 -R 5  are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;  
 n is 1, 2, 3, 4, 5, or 6;  
 Y is optionally substituted aryl, optionally substituted aryloxy, SAr, COAr, hydrogen, hydroxy, ≡—Y 1 , ═—Y 1 , a heterocyclic group, a heteroaryl group, a cycloalkyl group, an amino group, an amido group, a ureido group, or a guanidino group; and  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group.  
 
     
     
         15 . A compound having the Formula (IIIk):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 R 1 -R 5  are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;  
 n is 1, 2, 3, 4, 5, or 6;  
 Y is optionally substituted aryl, optionally substituted aryloxy, SAr, COAr, hydrogen, hydroxy, ≡—Y 1 , ═—Y 1 , a heterocyclic group, a heteroaryl group, a cycloalkyl group, an amino group, an amido group, a ureido group, or a guanidino group; and  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group.  
 
     
     
         16 . A compound having the Formula (IIIl):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 W is optionally substituted aryl;  
 Y is optionally substituted aryl, optionally substituted aryloxy, an optionally substituted aryloxy group, SAr, COAr, hydrogen, hydroxy, ≡—Y 1 , ═—Y 1 , a heterocyclic group, a heteroaryl group, a cycloalkyl group, an amino group, an amido group, a ureido group, or a guanidino group;  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;  
 Q is hydrogen, alkyl, aryl, aralkyl, a heterocyclic group, a heterocyclic substituted alkyl group, an aryl group, or an aralkyl group;  
 X is a bond, (CH 2 ) m , oxygen, or sulfur;  
 m is 0, 1, 2, or 3;  
 n is 1, 2, 3, 4, 5, or 6; and  
 p is 0 or 1.  
 
     
     
         17 . A compound having the Formula (IIIm):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 W is optionally substituted aryl;  
 X is a bond, (CH 2 ) m , oxygen, sulfur, or NR;  
 R is alkyl, hydroxy, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;  
 R 1  is hydrogen, hydroxy, aryl, or aralkyl;  
 m is 0, 1, 2, or 3;  
 n is 1, 2, 3, 4, 5, or 6;  
   =single or double bond; and  
   =carbon ring or heterocyclic ring, with the proviso that said carbon ring is not part of a naphthyl group.  
 
     
     
         18 . A compound having the Formula (IIIn):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 W is an adamantyl group or an optionally substituted aryl group;  
 X is a bond, (CH 2 ) m ;  
 Y is CH 3 , CN, CO 2 R; an optionally substituted aryl group, an optionally substituted aryloxy group, SAr, COAr, hydroxy, ≡—Y 1 , ═—Y 1 , a heterocyclic group, a heteroaryl group, a cycloalkyl group, an amino group, an amido group, a ureido group, or a guanidino group;  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, an optionally substituted aralkyl group, an optionally substituted aryl group, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group  
 R is alkyl, hydroxy, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;  
 n is 0, 1, 2, 3, 4, 5, or 6; and  
 m is 0, 1, 2, or 3.  
 
     
     
         19 . A compound having the Formula (IIIo):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y 1 , ═—Y 1 , optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino;  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl; and  
 n is 0, 1, 2, 3, 4, 5 or 6.  
 
     
     
         20 . A compound having the Formula (IV):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 R 1 -R 5  are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;  
 E is (CR a R b ) r —G s —(CR c R d ) t , wherein R a , R b , R c  and R d  are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2  or O 2 C), carbonyl (CO), or NR e , wherein R e  is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1;  
 Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y 1 , ═—Y 1 , optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino; and  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.  
 
     
     
         21 . A compound having the Formula (V):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 R 1 -R 4  are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;  
 E is (CR a R b ) r —G s —(CR c R d ) t , wherein R a , R b , R c  and R d  are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2  or O 2 C), carbonyl (CO), or NR e , wherein R e  is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1;  
 Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y 1 , ═—Y 1 , optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino; and  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.  
 
     
     
         22 . A compound having the Formula (VI):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 W is an adamantyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;  
 X is a bond, (CH 2 ) m , oxygen, or NR;  
 E is (CR a R b ) r —G s —(CR c R d ) t , wherein R a , R b , R c  and R d  are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2  or O 2 C), carbonyl (CO), or NR e , wherein R e  is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1;  
 Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y 1 , ═—Y 1 , optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino;  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl;  
 R is alkyl, hydroxy, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;  
 R 1  is hydrogen, hydroxy, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;  
 m is 0, 1, 2, or 3; and  
 p is 0, 1 or 2.  
 
     
     
         23 . A compound having the Formula (VII):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 W is an adamantyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;  
 X is a bond, (CH 2 ) m , oxygen, or NR;  
 E is (CR a R b ) r —G s —(CR c R d ) t , wherein R a , R b , R c  and R d  are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2  or O 2 C), carbonyl (CO), or NR e , wherein R e  is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1;  
 Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y 1 , ═—Y 1 , optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino;  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl;  
 R is alkyl, hydroxy, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;  
 R 1  is hydrogen, hydroxy, halo, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;  
 m is 0, 1, 2, or 3; and  
 p is 0, 1 or 2.  
 
     
     
         24 . A compound having the Formula (VIII):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 W is an adamantyl group, an optionally substituted aryl group, or an optionally substituted heteroaryl group;  
 X is a bond, (CH 2 ) m , oxygen, or NR;  
 E is (CR a R b ) r —G s —(CR c R d ) t , wherein R a , R b , R c  and R d  are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2  or O 2 C), carbonyl (CO), or NR e , wherein R e  is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1;  
 Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y 1 , ═—Y 1 , optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino;  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl;  
 R is alkyl, hydroxy, an aminoalkyl group, an amidoalkyl group, a ureidoalkyl group, or a guanidinoalkyl group;  
 R 1  is hydrogen, hydroxy, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;  
 m is 0, 1, 2, or 3; and  
 p is 0, 1 or 2.  
 
     
     
         25 . A compound having the Formula (IX):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 one of K and L is nitrogen and the other is CH;  
 E is (CR a R b ) r —G s —(CR c R d ) t , wherein R a , R b , R c  and R d  are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2  or O 2 C), carbonyl (CO), or NR e , wherein R e  is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1;  
 Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y 1 , ═—Y 1 , optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino; and  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.  
 
     
     
         26 . A compound having the Formula (X):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 E is (CR a R b ) r —G s —(CR c R d ) t , wherein R a , R b , R c  and R d  are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2  or O 2 C), carbonyl (CO), or NR e , wherein R e  is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1;  
 Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y 1 , ═—Y 1 , optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino; and  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.  
 
     
     
         27 . A compound having the Formula (XI):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 E is (CR a R b ) r —G s —(CR c R d ) t , wherein R a , R b , R c  and R d  are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2  or O 2 C), carbonyl (CO), or NR e , wherein R e  is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1;  
 Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y 1 , ═—Y 1 , optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino; and  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.  
 
     
     
         28 . A compound having the Formula (XII):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 A and B are one or more substituents which are independently hydrogen, halo, alkoxy, trifluoromethylthio, cyano, carboxy or hydroxy;  
 R 1  is alkyl, alkenyl, aralkyl, cycloalkyl-alkyl, dialkylaminoalkyl, or hydroxyalkyl;  
 E is (CR a R b ) r —G s —(CR c R d ) t , wherein R a , R b , R c  and R d  are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2  or O 2 C), carbonyl (CO), or NR e , wherein R e  is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1;  
 Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y 1 , ═—Y 1 , optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino; and  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.  
 
     
     
         29 . A compound having the Formula (XIII):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 R is hydrogen, C 2 -C 6  acyl, C 1 -C 6  alkyl, aryl, C 1 -C 6  alkoxycarbonyl, C 7 -C 10  aralkyl, C 2 -C 6  alkenyl, C 3 -C 15  dialkylaminoalkyl, C 1 -C 6  hydroxyalkyl, C 2 -C 6  alkynyl, C 3 -C 15  trialkylsilyl, C 4 -C 10  alkylcycloalkyl, or C 3 -C 6  cycloalkyl;  
 A and B are independently selected from the group consisting of a halogen such as chloro, fluoro, bromo, iodo, trifluoromethyl, azido, C 1 -C 6  alkoxy, C 2 -C 6  dialkoxymethyl, C 1 -C 6  alkyl, cyano, C 3 -C 15  dialkylaminoalkyl, carboxy, carboxamido, C 1 -C 6  haloalkyl, C 1 -C 6  haloalkylthio, allyl, aralkyl, C 3 -C 6  cycloalkyl, aroyl, aralkoxy, C 2 -C 6  acyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, C 5 -C 6  heterocycloalkyl, C 1 -C 6  alkylthio, C 1 -C 6  alkylsulfonyl, C 1 -C 6  haloalkylsulfonyl, C 1 -C 6  alkylsulfinyl, C 1 -C 6  haloalkylsulfinyl, arylthio, C 1 -C 6  haloalkoxy, amino, C 1 -C 6  alkylamino, C 2 -C 15  dialkylamino, hydroxy, carbamoyl, C 1 -C 6  N-alkylcarbamoyl, C 2 -C 15  N,N-dialkylcarbamoyl, nitro and C 2 -C 15  dialkylsulfamoyl;  
 Z represents a group selected from  
                     wherein R 1  is hydrogen, C 1 -C 6  alkyl, C 2 -C 6  alkenyl, aralkyl, C 4 -C 15  dialkylaminoalkyl, heterocycloalkyl, C 2 -C 6  acyl, aroyl, or aralkanoyl, and R 3  is C 1 -C 6  alkyl, C 2 -C 6  alkenyl, phenyl, aralkyl or C 3 -C 15  dialkylaminoalkyl; and    
 f and g are independently integers selected from 0 (A or B is hydrogen, respectively), 1, 2, 3, or 4;  
 E is (CR a R b ) r —G s —(CR c R d ) t , wherein R a , R b , R c  and R d  are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2  or O 2 C), carbonyl (CO), or NR e , wherein R e  is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1;  
 Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y 1 , ═—Y 1 , optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino; and  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.  
 
     
     
         30 . A compound having the Formula (XIV):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 R 1  is carboxy or an alkylester or amide thereof; alkyl carboxy or an alkyl ester or amide thereof; hydroxy or hydroxymethyl group;  
 p is 0, 1 or 2;  
 the dotted line represents a single or double bond;  
 E is (CR a R b ) r —G s —(CR c R d ) t , wherein R a , R b , R c  and R d  are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2  or O 2 C), carbonyl (CO), or NR e , wherein R e  is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1;  
 Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y 1 , ═—Y 1 , optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino; and  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.  
 
     
     
         31 . A compound having the Formula (XV):  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 R 1 -R 4  are independently hydrogen, halo, haloalkyl, aryl, fused aryl, a heterocyclic group, a heteroaryl group, alkyl, alkenyl, alkynyl, arylalkyl, arylalkenyl, arylalkynyl, hydroxyalkyl, nitro, amino, cyano, cyanamido, N(CN) 2 , guanidino, amidino, acylamido, hydroxy, thiol, acyloxy, azido, alkoxy, carboxy, carbonylamido, or alkylthiol;  
 E is (CR a R b ) r —G s —(CR c R d ) t , wherein R a , R b , R c  and R d  are independently selected from the group consisting of hydrogen, alkyl, aryl, hydroxy or carboxy; G is oxygen, sulfur, sulfone, sulfoxide, carboxy (CO 2  or O 2 C), carbonyl (CO), or NR e , wherein R e  is hydrogen, alkyl or aryl; r and t are independently 0, 1, 2, 3, 4, or 5; and s is 0 or 1;  
 R 6  is hydrogen, hydroxy, alkylcarboxy, optionally substituted aryl, optionally substituted aralkyl, optionally substituted aryloxyalkyl, optionally substituted benzyloxyalkyl, a heterocyclic group, a heterocyclic substituted alkyl group, heteroaryl, or a heteroaryl substituted alkyl group;  
 p is 0, 1, 2, or 3;  
 Y is hydrogen, hydroxy, CH 3 , CN, CO 2 R, sulfate, optionally substituted aryl, optionally substituted aryloxy, optionally substituted arylthioxy, optionally substituted aroyl, ≡—Y 1 , ═—Y 1  (which may be cis or trans, throughout) carbonylamido, hydrazino, oximo, amidino, optionally substituted heterocyclic group, optionally substituted heterocycloxy, optionally substituted heteroaryl, optionally substituted heteroaryloxy, optionally substituted cycloalkyl group, optionally substituted cycloalkoxy group, amino, amido, ureido, or guanidino; and  
 Y 1  is hydrogen, alkyl, hydroxyalkyl, optionally substituted aralkyl, an optionally substituted aryl, optionally substituted cycloalkyl, aminoalkyl, amidoalkyl, ureidoalkyl, or guanidinoalkyl.  
 
     
     
         32 . A compound of the Formula XVI:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 Ar 1  is optionally substituted aryl or optionally substituted heteroaryl;  
 X is O, NR 1  or (CH 2 ) n  wherein n is 0, 1, 2, 3 or 4 and R 1  is hydrogen or a lower alkyl group having 1 to 6 carbon atoms;  
 U is hydroxy or hydrogen;  
 Y is (CH 2 ) m  wherein m is 1, 2 or 3;  
 Z is (CHR 2 ) z  wherein z is 0, 1, 2, 3, or 4 and R 2  is hydroxy, hydrogen or a lower alkyl group having 1 to 6 carbon atoms; and  
 A and B are each hydrogen or together are (CH 2 ) w  wherein w is 0, 1, 2, 3 or 4.  
 
     
     
         33 . A compound of the Formula XVII:  
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof; wherein 
 Ar 1  is optionally substituted aryl or optionally substituted heteroaryl;  
 X is O, NR, or (CH 2 ) n  wherein n is 0, 1, 2, 3, or 4 and R 1  is hydrogen or a lower alkyl group having 1 to 6 carbon atoms;  
 U is hydroxy or hydrogen;  
 Z is (CHR 2 ) z  wherein z is 0, 1, 2, 3 or 4 and R 2  is hydroxy, hydrogen or a lower alkyl group having 1 to 6 carbon atoms;  
 Q is —CH═CH═ or —C≡C—;  
 R 3  is hydrogen, hydroxy or hydroxy substituted lower alkyl having 1 to 6 carbon atoms; and  
 Y is hydrogen, hydroxy, optionally substituted aryl or optionally substituted heteroaryl.  
 
     
     
         34 . A quaternary ammonium salt of the compounds of any one of claims  1 - 33 , obtained by reacting the compound with a lower alkyl halide or methyl sulfate.  
     
     
         35 . A pharmaceutical composition comprising the compound of any one of claims  1 - 33  and a pharmaceutically acceptable carrier.  
     
     
         36 . A pharmaceutical composition comprising the compound of  claim 34  and a pharmaceutically acceptable carrier.  
     
     
         37 . A method of treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia or surgery, or treating a neurodegenerative disease, or treating or preventing the adverse consequences of the overstimulation of the excitatory amino acids, or treating anxiety, psychosis, glaucoma, CMV retinitis, urinary incontinence, migraine headache, convulsions, aminoglycoside antibiotics-induced hearing loss, Parkinson's disease, chronic pain or inducing anesthesia, opioid tolerance or withdrawal, or enhancing cognition, comprising administering to an animal in need of such treatment an effective amount of a compound of any one of claims  1 - 33 .  
     
     
         38 . A method of treating or preventing neuronal loss associated with stroke, ischemia, CNS trauma, hypoglycemia or surgery, or treating a neurodegenerative disease, or treating or preventing the adverse consequences of the overstimulation of the excitatory amino acids, or treating anxiety, psychosis, glaucoma, CMV retinitis, urinary incontinence, migraine headache, convulsions, aminoglycoside antibiotics-induced hearing loss, Parkinson's disease, chronic pain or inducing anesthesia, opioid tolerance or withdrawal, or enhancing cognition, comprising administering to an animal in need of such treatment an effective amount of a compound of  claim 34 .  
     
     
         39 . The method of  claim 37 , wherein said compound is administered as part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.  
     
     
         40 . The method of  claim 38 , wherein said compound is administered as part of a pharmaceutical composition comprising a pharmaceutically acceptable carrier.