Low molecular weight peptidomimetic growth hormone secretagogues

Abstract

The present invention comprises growth hormone releasing peptides/peptidomimetics (GHRP) capable of causing release of growth hormone from the pituitary. Compositions containing the GHRP's of this invention are used to promote growth in mammals either alone or in combination with other growth promoting compounds, especially IGF-1. In a method of this invention GHRP's in combination with IGF-1 are used to treat Type II diabetes. An exemplary compound of this invention is provided below.

What is claimed is:  
     
         1 . A compound represented by structural Formula (I)  
       
         
           
           
               
               
           
         
       
       where 
 A is selected from the group  
                     
 B is selected from the group  
                     
 B may optionally be selected from the group 
 a covalent bond, and  
 C 1 -C 3 alkyl,  
 
 when L 2  is —N(R C )—Q,.  
 C is selected from the group 
 hydrogen,  
                     
 
 D is selected from the group  
                     
 E is selected from the group  
                     
 Ar 1  and Ar 2  are each independently selected from 
 indoyl substituted with (R 4 ) n ,  
                     
 
 Ar 1  and Ar 2  are each independently selected from 
 hydrogen, and  
 C 1 -C 6 alkyl;  
 
 when R B  or R C  are L 1 —Ar 1  or L 2 —Ar 2 ;  
 Ar 3  is selected from the group  
                     
 Ar 3  is selected from 
 hydrogen, and  
 C 1 -C 6 alkyl;  
 
 when R D  is L 3 —Ar 3 ;  
 Ar 1  together with a, Ar 2  together with b and Ar 3  together with c, each pair together with the carbon to which they are attached may independently form a 5 or 6 member carbocyclic ring; a, b and c are independently selected from 
 hydrogen, and  
 C 1 -C 6 alkyl;  
 
 n and o are independently 1, 2 or 3;  
 L 1  is selected from 
 —CH 2 —O—,  
 —CH 2 —CH 2 —O— 
 —CH 2 —,  
 —CH 2 —CH 2 —, and  
 —CH 2 —CH 2 —CH 2 —;  
 
 L 2  and L 3  are independently selected from 
 a covalent bond,  
 —O—,  
 —O—CH 2 —,  
 —N(R C )—Q, and  
 L 1 ;  
 
 Q is selected from the group 
 —L 2 —,  
 —S(═O) 2 —L 2 —,  
 —C(═O)—,  
 —C(═O)—O—,  
 —CH(X)—, and  
 —CH(X)—CH 2 —;  
 
 R A  is selected from the group 
 C 0 -C 3 alkyl-heterocycle where the heterocycle comprises a mono-, bi-, or tricycle containing 5-12 ring atoms, one or two of which are heteroatoms selected from O, S, and N, provided at least one heteroatom is N, where any N atom is optionally substituted with R 1 ,  
 C 0 -C 6 alkyl substituted with one or two substituents selected from the group 
 NR 2 R 3 ,  
 imidazolinyl,  
 pyridinyl,  
 dihydropyridinyl, and  
 piperidinyl;  
 
 
 R B , R C  and R D  are selected from the group 
 R A ,  
 L 1 —Ar 1 ,  
 L 2 —Ar 2 ,  
 hydrogen,  
 C 1 -C 6 alkyl, and  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R A  and R B  together with the N to which they are bonded may form a 5- or 6-member heterocycle, optionally containing one additional hetero atom selected from O, S, and N where any N is optionally substituted with R 1 , any carbon is optionally substituted with R 6  and where the heterocycle is optionally fused to a phenyl ring, optionally substituted with R 4 ;  
 R 1  is selected from 
 hydrogen,  
 C 1 -C 6 alkyl,  
 C(═O)—C 1 -C 6 alkyl,  
 C(═O)—NR 2 R 3 ,  
 C(═NR 2 )—NR 2 R 3 ,  
 C(═O)O-C 1 -C 6 alkyl,  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl, and  
 C 2 -C 6 alkyl substituted with 1-3 hydroxyl groups;  
 
 R 2  and R 3  are independently selected from 
 R 1 , and  
 piperidinyl;  
 
 R 2  and R 3  together with the N to which they are bonded may form a 5- or 6-member heterocycle, optionally containing one additional hetero atom selected from O, S, and N where any N is optionally substituted with R 1 , any carbon is optionally substituted with R 6  and where the heterocycle is optionally fused to a phenyl ring, optionally substituted with R 4 ;  
 R 4  and R 5  are independently selected from the group 
 hydrogen,  
 halo(F, Cl, Br, and I),  
 cyano,  
 amino,  
 amido,  
 nitro,  
 hydroxy,  
 C 1 -C 6 alkyl optionally substituted with 1-3 R 6 ,  
 C 2 -C 6 alkynyl optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 alkyloxy optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 acylamino optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 alkylcarbonyl optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 alkyloxycarbonyl optionally substituted with 1-3 R 6 ,  
 N-(C 1 -C 6 alkyl),N-(C 1 -C 6 acyl)amino optionally substituted with 1-3 R 6 ,  
 N-(C 1 -C 6 alkyl)carboxamido optionally substituted with 1-3 R 6 ,  
 N,N-di(C 0 -C 6 alkyl)amino optionally substituted with 1-3 R 6 ,  
 N,N-di(C 1 -C 6 alkyl)carboxamido optionally substituted with 1-3 R 6 ,  
 C 1 -C 4 perfluoroalkyl, and  
 C 1 -C 3 perfluoroalkoxy;  
 
 R 6  is selected from the group 
 COOR 2 ,  
 O(C═O)R 2 ,  
 CONR 2 R 3 ,  
 cyano,  
 NR 2 R 3 ,  
 NR 2 COR 3 ,  
 azido,  
 nitro, and  
 hydroxy;  
 
 R 7  is selected from the group 
 R 6 ,  
 C 6 -C 10 aryl optionally substituted with 
 halo(F, Cl, Br, and I),  
 cyano,  
 amino,  
 amido,  
 nitro,  
 hydroxy,  
 C 1 -C 4 perfluoroalkyl, and  
 C 1 C 3 perfluoroalkoxy;  
 
 
 X is selected from the group 
 hydrogen,  
 C 1 -C 6 alkyl optionally substituted with 1-3 R 6 , and  
 C 1 -C 6 acyl optionally substituted with a group selected from 
 L 2 —Ar 2 ,  
 R A , and  
 R 6 ;  
 
 
 Y is selected from the group 
 —(C═O)—R A ,  
 C 1 -C 6 alkyl substituted with 1-2 R 7 ,  
 C 2 -C 6 alkynyl optionally substituted with 1-2R 7 ,  
 C 2 -C 6 alkyenyl optionally substituted with 1-2 R 7 , and  
 C 1 -C 6 alkyloxy optionally substituted with 1-2 R 7 ,  
 
 Y and R D  together with the N to which they are bonded may form a 5- or 6-member heterocycle, optionally containing one additional hetero atom selected from O, S, and N where any N is optionally substituted with R 1 , any carbon is optionally substituted with R 7  and where the heterocycle is optionally fused to a phenyl ring;  
 Z is selected from the group 
 C 1 -C 6 alkyl substituted with 1-2 R 7 ,  
 C 2 -C 6 alkynyl optionally substituted with 1-2R 7 ,  
 C 2 -C 6 alkyenyl optionally substituted with 1-2 R 7 ,  
 C 1 -C 6 alkyloxy optionally substituted with 1-2 R 7   1  and piperidinyl; and  
 
 pharmaceutically acceptable salts thereof.  
 
     
     
         2 . The compound of  claim 1  represented by Formula II  
       
         
           
           
               
               
           
         
       
       where 
 Ar 1  and Ar 2  are each independently selected from 
 indoyl,  
                     
 
 n and o are independently 1, 2 or 3;  
 L 1  is selected from 
 —CH 2 —O—,  
 —CH 2 —CH 2 —O— 
 —CH 2 —,  
 CH 2 —CH 2 —, and  
 —CH 2 —CH 2 —CH 2 —,  
 
 L 2  is selected from 
 a covalent bond,  
 —O—,  
 —O—CH 2 —, and  
 L 1 ;  
 
 R A  is selected from the group 
 C 0 -C 3 alkyl-heterocycle,  
 O—C 0 -C 3 alkyl-heterocycle, and  
 NR 2 -C 2 -C 6 alkyl-heterocycle, 
 where the heterocycle comprises a mono-, bi-, or tricycle containing 5-12 ring atoms, one or two of which are heteroatoms selected from O, S, and N, provided at least one heteroatom is N, where any N atom is optionally substituted with R 1 ,  
 
 C 0 -C 6 alkyl substituted with one or two substituents,  
 O—C 2 -C 6 alkyl substituted with one or two substituents, and  
 NR 2 —C 2 -C 6 alkyl substituted with one or two substituents where the substituents are selected from the group 
 NR 2 R 3 ,  
 imidazolinyl,  
 pyridinyl,  
 dihydropyridinyl, and  
 piperidinyl;  
 
 
 R B  and R C  are selected from the group 
 hydrogen,  
 C 1 -C 6 alkyl optionally substituted with a group selected from 
 NR 2 R 3 , and  
 phenyl-C 1 -C 3 —NR 2 R 3 , and  
 
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 1  is selected from 
 hydrogen,  
 C 1 -C 6 alkyl,  
 C(═O)—C 1 -C 6 alkyl,  
 C(═O)—NR 2 R 3 ,  
 C(═NR 2 )—NR 2 R 3 ,  
 C(═O)O—C 1 -C 6 -alkyl,  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl, and  
 C 1 -C 6 alkyl substituted with 1-3 hydroxyl groups;  
 
 R 2  and R 3  are independently selected from 
 C 1 -C 6 alkyl-NH 2 ,  
 C 1 -C 6 alkyl-heterocycle,  
 C 1 -C 6 alkyl-NH—C 1 -C 6 alkyl,  
 C 1 -C 6 alkyl-N-(di-C 1 -C 6 alkyl),  
 R 1 , and  
 piperidinyl;  
 
 R 2  and R 3  together with the N to which they are bonded may form a 5- or 6-member heterocycle, optionally containing one additional hetero atom selected from O, S, and N where any N is optionally substituted with R 1 , any carbon is optionally substituted with R 6 , and where the heterocycle is optionally fused to a phenyl ring, optionally substituted with R 4 ;  
 R 4  and R 5  are independently selected from the group 
 hydrogen,  
 halo(F, Cl, Br, and I),  
 cyano,  
 amino,  
 amido,  
 nitro,  
 hydroxy,  
 C 1 -C 6 alkyl optionally substituted with 1-3 R 6 ,  
 C 2 -C 6 alkynyl optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 -alkyloxy optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 acylamino optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 alkylcarbonyl optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 alkyloxycarbonyl optionally substituted with 1-3 R 6 ,  
 N-(C 1 -C 6 alkyl),N-(C 1 -C 6 acyl)amino optionally substituted with 1-3 R 6 ,  
 N-(C 1 -C 6 alkyl)carboxamido optionally substituted with 1-3 R 6 ,  
 N,N-di(C 0 -C 6 alkyl)amino optionally substituted with 1-3 R 6 ,  
 N,N-di(C 1 -C 6 alkyl)carboxamido optionally substituted with 1-3 R 6 ,  
 C 1 C 4 perfluoroalkyl, and  
 C 1 -C 3 perfluoroalkoxy;  
 
 R 6  is selected from the group 
 COOR 2 ,  
 CONR 2 R 3 ,  
 cyano,  
 NR 2 R 3 ,  
 NR 2 COR 3 ,  
 azido,  
 nitro, and  
 hydroxy;  
 
 X is selected from the group 
 hydrogen,  
 oxo (═O),  
 COOR 2 ,  
 CONR 2 R 3 ,  
 C 0 -C 6 alkyl-O—C 1 -C 6 alkyl optionally substituted with 1-2 R 6 , and  
 C 1 -C 6 alkyl optionally substituted with 1-2 R 6 ; and  
 
 pharmaceutically acceptable salts thereof.  
 
     
     
         3 . The compound of  claim 1  represented by Formula IIa-IIg  
       
         
           
           
               
               
           
         
       
       where 
 Ar 1  and Ar 2  are each independently selected from 
 indoyl,  
                     
 
 n and o are independently 1, 2 or 3;  
 p is 0, 1, or 2;  
 L 2  is selected from 
 a covalent bond,  
 —O—,  
 —O—CH 2 —,  
 —CH 2 —O—,  
 —CH 2 —CH 2 —O— 
 —CH 2 —,  
 —CH 2 —CH 2 —, and  
 —CH 2 —CH 2 —CH 2 —;  
 
 R B  and R C  are selected from the group 
 hydrogen,  
 C 1 -C 6 alkyl optionally substituted with a group selected from 
 NR 2 R 3 , and  
 phenyl-C 1 -C 3 -NR 2 R 3 , and  
 
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 1  is selected from 
 hydrogen,  
 C 1 -C 6 alkyl,  
 C(═O)—C 1 -C 6 alkyl,  
 C(═O)—NR 2 R 3 ,  
 C(═NR 2 )—NR 2 R 3 ,  
 C(═O)O—C 1 -C 6 alkyl, and  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 2  and R 3  are independently selected from 
 hydrogen,  
 C 1 -C 6 alkyl,  
 piperidinyl, and  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 2  and R 3  together with the nitrogen to which they are attached may form a optionally mono- or di-substituted ring selected from 
 piperidinyl,  
 pyrroylidinyl,  
 pyrryl,  
 imidazolyl,  
 piperazinyl, and  
 morpholinyl  
 
 where the substituents are selected from C 1 -C 3 alkyl;  
 R 4  and R 5  are independently selected from the group 
 hydrogen,  
 halo(F, Cl, Br, and I),  
 cyano,  
 amino,  
 amido,  
 nitro,  
 hydroxy,  
 C 1 -C 6 alkyl optionally substituted with 1-3 R 6 ,  
 C 2 -C 6 alkynyl optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 alkyloxy optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 acylamino optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 -alkylcarbonyl optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 alkyloxycarbonyl optionally substituted with 1-3 R 6 ,  
 N-(C 1 -C 6 alkyl),N-(C 1 -C 6 acyl)amino optionally substituted with 1-3 R 6 ,  
 N-(C 1 -C 6 alkyl)carboxamido optionally substituted with 1-3 R 6 ,  
 N,N-di(C 0 -C 6 alkyl)amino optionally substituted with 1-3 R 6 ,  
 N,N-di(C 1 -C 6 alkyl)carboxamido optionally substituted with 1-3 R 6 ,  
 C 1 -C 4 perfluoroalkyl, and  
 C 1 -C 3 perfluoroalkoxy;  
 
 R 6  is selected from the group 
 COOR 2 ,  
 CONR 2 R 3 ,  
 cyano,  
 NR 2 R 3 ,  
 NR 2 COR 3 ,  
 azido,  
 nitro, and  
 hydroxy;  
 
 Q is selected from the group 
 —L 2 —,  
 —S(═O) 2 —L 2 —,  
 —C(═O)—,  
 —C(═O)—O—,  
 —CH(X)—, and  
 —CH(X)—CH 2 —;  
 
 X is selected from the group 
 hydrogen,  
 oxo (═O),  
 COOR 2 ,  
 CONR 2 R 3 ,  
 C 0 -C 6 alkyl-O—C 1 -C 6 -alkyl optionally substituted with 1-2 R 6 , and  
 C 1 -C 6 alkyl optionally substituted with 1-2 R 6 ; and  
 
 pharmaceutically acceptable salts thereof.  
 
     
     
         4 . The compound of  claim 3  represented by structural Formula (IIa)  
       
         
           
           
               
               
           
         
       
       where 
 Ar 1  and Ar 2  are each independently selected from 
 indoyl, and  
                     
 
 R B  and R C  are selected from the group 
 hydrogen, and  
 methyl;  
 
 R 1  is selected from 
 hydrogen,  
 C 1 -C 6 alkyl,  
 C(═O)—C 1 -C 6 alkyl,  
 C(═O)—NR 2 R 3 ,  
 C(═NR 2 )—NR 2 R 3 ,  
 C(═O)O—C 1 -C 6 alkyl, and  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 2  and R 3  are independently selected from 
 hydrogen,  
 C 1 -C 6 alkyl,  
 piperidinyl, and  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 2  and R 3  together with the nitrogen to which they are attached may form 
 piperidinyl,  
 pyrroylidinyl,  
 piperazinyl, and  
 morpholinyl;  
 
 R 6  is selected from the group 
 COOR 2 ,  
 CONR 2 R 3 ,  
 cyano,  
 NR 2 R 3 ,  
 NR 2 COR 3 ,  
 azido,  
 nitro, and  
 hydroxy;  
 
 X is selected from the group 
 hydrogen,  
 oxo (═O),  
 COOR 2 ,  
 CONR 2 R 3 ,  
 C 0 -C 6 alkyl-O—C 1 -C 6 alkyl optionally substituted with 1-2 R 6 , and  
 C 1 -C 6 alkyl optionally substituted with 1-2 R 6 ; and  
 
 pharmaceutically acceptable salts thereof.  
 
     
     
         5 . The compound of  claim 2  selected from the group  
       
         
           
           
               
               
           
         
         pharmaceutically acceptable salts thereof.  
       
     
     
         6 . The compound of  claim 1  represented by structural Formula (III)  
       
         
           
           
               
               
           
         
       
       where 
 Ar 1  and Ar 2  are each independently selected from 
 indoyl,  
                     
 
 n and o are independently 1, 2 or 3;  
 L 1  and L 2  are independently selected from 
 —CH 2 —O—,  
 CH 2 —CH 2 —O— 
 —CH 2 —,  
 —CH 2 —CH 2 —, and  
 —CH 2 —CH 2 —CH 2 —;  
 
 R A  is selected from the group 
 C 0 -C 3 alkyl-heterocycle where the heterocycle comprises a mono-, bi-, or tricycle containing 5-12 ring atoms, one or two of which are heteroatoms selected from O, S, and N, provided at least one heteroatom is N, where any N atom is optionally substituted with R 1 ,  
 C 0 -C 6 alkyl substituted with one or two substituents selected from the group 
 NR 2 R 3 , and  
 imidazolinyl,  
 pyridinyl,  
 dihydropyridinyl, and  
 pipedinyl;  
 
 
 R B , R C  and R D  are selected from the group 
 hydrogen,  
 C 1 -C 6 alkyl optionally substituted with a group selected from 
 NR 2 R 3 , and  
 phenyl-C 1 -C 3 —NR 2 R 3 , and  
 
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 1  is selected from 
 hydrogen,  
 C 1 -C 6 alkyl,  
 C(═O)—C 1 -C 6 alkyl,  
 C(═O)—NR 2 R 3 ,  
 C(═NR 2 )—NR 2 R 3 ,  
 C(═O)O—C 1 -C 6 alkyl, and  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 2  and R 3  are independently selected from 
 hydrogen,  
 C 1 -C 6 alkyl,  
 piperidinyl, and  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 2  and R 3  together with the N to which they are bonded may form a 5- or 6-member heterocycle, optionally containing one additional hetero atom selected from O, S, and N where any N is optionally substituted with R 1 , any carbon is optionally substituted with R 6  and where the heterocycle is optionally fused to a phenyl ring, optionally substituted with R 4 ;  
 R 4  and R 5  are independently selected from the group 
 hydrogen,  
 halo(F, Cl, Br, and I),  
 cyano,  
 amino,  
 amido,  
 nitro,  
 hydroxy,  
 C 1 -C 6 alkyl optionally substituted with 1-3 R 6 ,  
 C 2 -C 6 alkynyl optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 alkyloxy optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 acylamino optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 alkylcarbonyl optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 alkyloxycarbonyl optionally substituted with 1-3 R 6 ,  
 N-(C 1 -C 6 alkyl),N-(C 1 -C 6 acyl)amino optionally substituted with 1-3 R 6 ,  
 N-(C 1 -C 6 alkyl)carboxamido optionally substituted with 1-3 R 6 ,  
 N,N-di(C 0 -C 6 alkyl)amino optionally substituted with 1-3 R 6 ,  
 N,N-di(C 1 -C 6 alkyl)carboxamido optionally substituted with 1-3 R 6 ,  
 C 1 -C 4 perfluoroalkyl, and  
 C 1 -C 3 perfluoroalkoxy;  
 
 R 6  is selected from the group 
 COOR 2 ,  
 CONR 2 R 3 ,  
 cyano,  
 NR 2 R 3 ,  
 NR 2 COR 3 ,  
 azido,  
 nitro, and  
 hydroxy;  
 
 R 7  is selected from the group 
 R 6 , and  
 C 6 -C 10 aryl optionally substituted with 
 halo(F, Cl, Br, and I),  
 cyano,  
 amino,  
 amido,  
 nitro,  
 hydroxy,  
 C 1 -C 4 perfluoroalkyl, and  
 C 1 -C 3 perfluoroalkoxy;  
 
 
 Y is selected from the group 
 C 1 -C 6 alkyl substituted with 1-2 R 7 ,  
 C 2 -C 6 alkynyl optionally substituted with 1-2R 7 ,  
 C 2 -C 6 alkyenyl optionally substituted with 1-2 R 7 , and  
 C 1 -C 6 alkyloxy optionally substituted with 1-2 R 7 , and  
 
 pharmaceutically acceptable salts thereof.  
 
     
     
         7 . The compound of  claim 6  selected from the group  
       
         
           
           
               
               
           
         
         pharmaceutically acceptable salts thereof.  
       
     
     
         8 . The compound of  claim 1  represented by structural Formula IIIa-IIIi  
       
         
           
           
               
               
           
         
       
       where 
 Ar 1  and Ar 2  are each independently selected from 
 indoyl,  
                     
 
 n and o are independently 1, 2 or 3;  
 R B , R C  and R D  are selected from the group 
 hydrogen,  
 C 1 -C 6 alkyl optionally substituted with a group selected from 
 NR 2 R 3 , and  
 phenyl-C 1 -C 3 —NR 2 R 3 , and  
 
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 1  is selected from 
 hydrogen,  
 C 1 -C 6 alkyl,  
 C(═O)C—C 1 -C 6 alkyl ,  
 C(═O)—NR 2 R 3 ,  
 C(NR 2 )—NR 2 R 3 ,  
 C(═O)O—C 1 -C 6 alkyl, and  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 2  and R 3  are selected from 
 hydrogen,  
 C 1 -C 6 alkyl,  
 piperidinyl, and  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 2  and R 3  together with the N to which they are bonded may form a 5- or 6-member heterocycle, optionally containing one additional hetero atom selected from O, S, and N where any N is optionally substituted with R 1 , any carbon is optionally substituted with R 7  and where the heterocycle is optionally fused to a phenyl ring, optionally substituted with R 4 ;  
 R 4  and R 5  are independently selected from the group 
 hydrogen,  
 halo(F, Cl, Br, and I),  
 cyano,  
 amino,  
 amido,  
 nitro,  
 hydroxy,  
 C 1 -C 4 perfluoroalkyl, and  
 C 1 -C 3 perfluoroalkoxy;  
 
 R 7  is selected from the group 
 COOR 2 ,  
 CONR 2 R 3 ,  
 cyano,  
 NR 2 R 3 ,  
 NR 2 COR 3 ,  
 azido,  
 nitro,  
 hydroxy,  
 C 6 -C 10 aryl optionally substituted with 
 halo(F, Cl, Br, and I),  
 cyano,  
 amino,  
 amido,  
 nitro,  
 hydroxy,  
 C 1 -C 4 perfluoroalkyl, and  
 C 1 -C 3 perfluoroalkoxy;  
 
 
 Y is selected from the group 
 C 1 -C 6 alkyl substituted with 1-2 R 7 ,  
 C 2 -C 6 alkynyl optionally substituted with 1-2R 7 ,  
 C 2 -C 6 alkyenyl optionally substituted with 1-2 R 7 ,  
 C 1 -C 6 alkyloxy optionally substituted with 1-2 R 7 , and piperidinyl; and  
 
 pharmaceutically acceptable salts thereof.  
 
     
     
         9 . The compound of  claim 8  represented by structural Formula (IIIa)  
       
         
           
           
               
               
           
         
       
       where 
 Ar 1  and Ar 2  are each independently selected from 
 indoyl, and  
                     
 
 R B , R C  and R D  are selected from the group 
 hydrogen,  
 C 1 -C 6 alkyl,  
 C 6 -C 10 aryl-C 1 -C 6 alkyl, and  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 1  is selected from 
 hydrogen,  
 C 1 -C 6 alkyl,  
 C(═O)OC 1 -C 6 alkyl, and  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 2  and R 3  are selected from 
 hydrogen,  
 C 1 -C 6 alkyl,  
 piperidinyl, and  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 2  and R 3  together with the nitrogen to which they are attached may form an optionally mono- or di-substituted ring selected from 
 piperidinyl,  
 pyrroylidinyl,  
 pyrryl,  
 imidazolyl,  
 piperazinyl, and  
 morpholinyl  
 
 where the substituents are selected from C 1 -C 3 alkyl;  
 R 7  is selected from the group 
 COOR 2 ,  
 CONR 2 R 3 ,  
 cyano,  
 NR 2 R 3 ,  
 NR 2 COR 3 ,  
 azido,  
 nitro,  
 hydroxy, and  
 C 6 -C 10 aryl optionally substituted with 
 halo(F, Cl, Br, and I),  
 cyano,  
 amino,  
 amido,  
 nitro,  
 hydroxy,  
 C 1 -C 4 perfluoroalkyl, and  
 C 1 -C 3 perfluoroalkoxy;  
 
 
 Y is selected from the group 
 C 1 -C 6 alkyl substituted with 1-2 R 7 ,  
 C 2 C 6 alkynyl optionally substituted with 1-2R 7 ,  
 C 2 -C 6 alkyenyl optionally substituted with 1-2 R 7 ,  
 C 1 -C 6 alkyloxy optionally substituted with 1-2 R 7 , and  
 piperidinyl;  
 
 Y and R D  together with the N to which they are bonded may form a 5 or 6-member heterocycle, optionally containing one additional hetero atom selected from O, S, and N where any N is optionally substituted with R 1 , any carbon is optionally substituted with R 7  and where the heterocycle is optionally fused to a phenyl ring; and  
 pharmaceutically acceptable salts thereof.  
 
     
     
         10 . The compound of  claim 9  selected from the group  
       
         
           
           
               
               
           
         
         pharmaceutically acceptable salts thereof.  
       
     
     
         11 . The compound of  claim 1  represented by structural Formula (IV)  
       
         
           
           
               
               
           
         
       
       where 
 Ar 1  and Ar 2  are each independently selected from 
 indoyl,  
                     
 
 Ar 3  is selected from the group  
                     
 n and o are independently 1, 2 or 3;  
 R A  is selected from the group 
 C 0 -C 3 alkyl-heterocycle where the heterocycle comprises a mono-, bi-, or tricycle containing 5-12 ring atoms, one or two of which are heteroatoms selected from O, S, and N, provided at least one heteroatom is N, where any N atom is optionally substituted with R 1 ,  
 
 C 0 -C 6 alkyl substituted with one or two substituents selected from the group 
 NR 2 R 3 ,  
 imidazolinyl,  
 pyridinyl,  
 dihydropyridinyl, and  
 piperidinyl;  
 
 R B , R C , R D , and R E  are selected from the group 
 hydrogen,  
 C 1 -C 6 alkyl optionally substituted with a group selected from NR 2 R 3 , and  
 phenyl-C 1 -C 3 —NR 2 R 3 , and  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 1  is selected from 
 hydrogen,  
 C 1 -C 6 alkyl,  
 C(═O)—C 1 -C 6 alkyl,  
 C(═O)—NR 2 R 3 ,  
 C(═NR 2 )—NR 2 R 3 ,  
 C(═O)O—C 1 -C 6 alkyl, and  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 2  and R 3  are independently selected from 
 hydrogen,  
 C 1 -C 6 alkyl,  
 piperidinyl, and  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 2  and R 3  together with the N to which they are bonded may form a 5- or 6-member heterocycle, optionally containing one additional hetero atom selected from O, S, and N where any N is optionally substituted with R 1 , any carbon is optionally substituted with R 6  and where the heterocycle is optionally fused to a phenyl ring, optionally substituted with R 4 ;  
 R 4  and R 5  are independently selected from the group 
 hydrogen,  
 halo(F, Cl, Br, and I),  
 cyano,  
 amino,  
 amido,  
 nitro,  
 hydroxy,  
 C 1 -C 6 alkyl optionally substituted with 1-3 R 6 ,  
 C 2 -C 6 alkynyl optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 alkyloxy optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 -acylamino optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 alkylcarbonyl optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 alkyloxycarbonyl optionally substituted with 1-3 R 6 ,  
 N(C 1 -C 6 alkyl),N-(C 1 -C 6 -acyl)amino optionally substituted with 1-3R 6 ,  
 N-(C 1 -C 6 alkyl)carboxamido optionally substituted with 1-3 R 6 ,  
 N,N-di(C 0 -C 6 alkyl)amino optionally substituted with 1-3 R 6 ,  
 N,N-di(C 1 -C 6 alkyl)carboxamido optionally substituted with 1-3 R 6 ,  
 C 1 -C 4 perfluoroalkyl, and  
 C 1 -C 3 perfluoroalkoxy;  
 
 R 6  is selected from the group 
 COOR 2 ,  
 CONR 2 R 3 ,  
 O(C═O)R 2 ,  
 cyano,  
 NR 2 R 3 ,  
 NR 2 COR 3 ,  
 azido,  
 nitro, and  
 hydroxy;  
 
 R 7  is selected from the group 
 R 6 , and  
 C 6 -C 10 aryl optionally substituted with 
 halo(F, Cl, Br, and I),  
 cyano,  
 amino,  
 amido,  
 nitro,  
 hydroxy,  
 C 1 -C 4 perfluoroalkyl, and  
 C 1 -C 3 perfluoroalkoxy;  
 
 
 Z is selected from the group 
 C 1 -C 6 alkyl substituted with 1-2 R 7 ,  
 C 2 -C 6 alkynyl optionally substituted with 1-2R 7 ,  
 C 2 -C 6 alkyenyl optionally substituted with 1-2 R 7 , and  
 C 1 -C 6 alkyloxy optionally substituted with 1-2 R 7 ,  
 
 Z and R E  together with the N to which they are bonded may form a 5- or 6-member heterocycle, optionally containing one additional hetero atom selected from O, S, and N where any N is optionally substituted with R 1 , any carbon is optionally substituted with R 7  and where the heterocycle is optionally fused to a phenyl ring; and  
 pharmaceutically acceptable salts thereof.  
 
     
     
         12 . The compound of  claim 11  selected from the group  
       
         
           
           
               
               
           
         
         pharmaceutically acceptable salts thereof.  
       
     
     
         13 . The compound of  claim 11  represented by structural Formula (IVa)  
       
         
           
           
               
               
           
         
       
       where 
 R B , R C , R D  and R E  are selected from the group 
 hydrogen, and  
 C 1 -C 6 alkyl;  
 
 Ar 1  and Ar 2  are each independently selected from 
 indoyl, and  
                     
 
 Ar 3  is selected from the group  
                     
 R F  is selected from the group 
 OH,  
 C 1 -C 4 alkyloxy,  
 NR 5 R 6 , and  
 1 to 4 α-amino acid residues;  
 
 R 4  is selected from 
 hydrogen,  
 halo(F, Cl, Br, and I),  
 cyano,  
 amino,  
 amido,  
 nitro,  
 hydroxy,  
 C 1 -C 4 alkoxy,  
 C 1 -C 4 perfluoroalkyl, and  
 C 1 -C 3 perfluoroalkoxy;  
 
 R 5  and R 6  are independently selected from 
 hydrogen, and  
 C 1 -C 6 alkyl; and  
 
 pharmaceutically acceptable salts thereof.  
 
     
     
         14 . The compound of  claim 13  selected from the group  
       
         
           
           
               
               
           
         
         pharmaceutically acceptable salts thereof.  
       
     
     
         15 . The compound of  claim 1  represented by Formula V  
       
         
           
           
               
               
           
         
       
       where 
 Ar 1  and Ar 2  are each independently selected from 
 indoyl,  
                     
 
 n and o are are independently 1, 2 or 3;  
 L 1  is selected from 
 —CH 2 —O—,  
 —CH 2 —CH 2 —O— 
 —CH 2 —,  
 —CH 2 —CH 2 —, and  
 —CH 2 —CH 2 —CH 2 —;  
 
 L 2  is selected from 
 a covalent bond,  
 —O—,  
 —O—CH 2 —, and  
 L 1 ;  
 
 R A  is selected from the group 
 C 0 -C 3 alkyl-heterocycle where the heterocycle comprises a mono, bi-, or tricycle containing 5-12 ring atoms, one or two of which are heteroatoms selected from O, S, and N, provided at least one heteroatom is N, where any N atom is optionally substituted with R 1 ,  
 C 0 -C 6 alkyl substituted with one or two substituents selected from the group 
 NR 2 R 3 , and  
 imidazolinyl,  
 pyridinyl,  
 dihydropyridinyl, and  
 pipedinyl;  
 
 
 R B  and R C  are selected from the group 
 hydrogen,  
 C 1 -C 6 alkyl optionally substituted with a group selected from NR 2 R 3 , and  
 phenyl-C 1 -C 3 -NR 2 R 3 , and  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R A  and R B  together with the N to which they are bonded may form a 5- or 6-member heterocycle, optionally containing one additional hetero atom selected from O, S, and N where any N is optionally substituted with R 1 , any carbon is optionally substituted with R 6  and where the heterocycle is optionally fused to a phenyl ring, optionally substituted with R 4 ;  
 R 1  is selected from 
 hydrogen,  
 C 1 -C 6 alkyl,  
 C(═O)—C 1 -C 6 alkyl,  
 C(═O)—NR 2 R 3 ,  
 C(═NR 2 )—NR 2 R 3 ,  
 C(═O)O—C 1 -C 6 alkyl, and  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 2  and R 3  are independently selected from 
 R 1 ,  
 hydrogen,  
 C 1 -C 6 alkyl,  
 piperidinyl, and  
 halo(F, Cl, Br, I)C 1 -C 6 alkyl;  
 
 R 2  and R 3  together with the N to which they are bonded may form a 5- or 6-member heterocycle, optionally containing one additional hetero atom selected from O, S, and N where any N is optionally substituted with R 1 , any carbon is optionally substituted with R 6  and where the heterocycle is optionally fused to a phenyl ring, optionally substituted with R 4 ;  
 R 4  and R 5  are independently selected from the group 
 hydrogen,  
 halo(F, Cl, Br, and I),  
 cyano,  
 amino,  
 amido,  
 nitro,  
 hydroxy,  
 C 1 -C 6 -alkyl optionally substituted with 1-3 R 6 ,  
 C 2 -C 6 alkynyl optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 alkyloxy optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 acylamino optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 alkylcarbonyl optionally substituted with 1-3 R 6 ,  
 C 1 -C 6 alkyloxycarbonyl optionally substituted with 1-3 R 6 ,  
 N-(C 1 -C 6 alkyl),N-(C 1 -C 6 -acyl)amino optionally substituted with 1-3 R 6 ,  
 N-(C 1 -C 6 alkyl)carboxamido optionally substituted with 1-3 R 6 ,  
 N,N-di(CO-C 6 alkyl)amino optionally substituted with 1-3 R 6 ,  
 N,N-di(C 1 -C 6 alkyl)carboxamido optionally substituted with 1-3 R 6 ,  
 C 1 -C 4 perfluoroalkyl, and  
 C 1 -C 3 perfluoroalkoxy;  
 
 R 6  is selected from the group 
 COOR 2 ,  
 CONR 2 R 3 ,  
 cyano,  
 NR 2 R 3 ,  
 NR 2 COR 3 ,  
 azido,  
 nitro, and  
 hydroxy;  
 
 X is selected from the group 
 hydrogen,  
 COOR 2 ,  
 C 0 -C 6 alkyl-NR 2 R 3 ,  
 C 0 -C 6 alkyl-O—C 1 -C 6 alkyl optionally substituted with 1-2 R 6 , and  
 C 1 -C 6 alkyl optionally substituted with 1-2 R 6 ; and  
 
 pharmeceutically acceptable salts thereof.  
 
     
     
         16 . The compound of  claim 15  selected from the group  
       
         
           
           
               
               
           
         
         pharmaceutically acceptable salts thereof.  
       
     
     
         17 . A pharmaceutical composition comprising a pharmaceutically acceptable excipient and the compound of  claim 1 .  
     
     
         18 . A method for increasing the level of endogenous growth hormone in a mammal comprising administering to the mammal a pharmaceutically effective amount of the composition of  claim 17  to the mammal.  
     
     
         19 . The method of  claim 18  further comprising administering the composition in combination with a growth factor selected from the group; growth hormone (GH), growth hormone releasing hormone (GHRH), insulin like growth factor-1 (IGF-1), and insulin like growth factor-2 (IGF-2).  
     
     
         20 . A method for treating Type II diabetes in a mammal in need of such treatment comprising administering to the mammal a pharmaceutically effective amount of the composition of  claim 17  to the mammal.