Novel scaffolds for alpha-helix mimicry

Abstract

Functionalized pyridazine derivatives having a low molecular weight and pharmaceutical compositions thereof are useful as alpha-helix mimetics and for treating conditions and/or disorders mediated by alpha-helix-binding receptors and proteins.

1 . A compound having Formula I: 
     
       
         
         
             
             
         
       
     
     wherein the pyridazine heterocycle is optionally atropisomeric with respect to X and/or W and wherein:
 X is a radical selected from the group consisting of: 
 
     
       
         
         
             
             
         
       
     
     wherein A is either carbon or nitrogen, and Z is either hydrogen or (C 1-6 ) alkyl;
 W is a radical selected from the group consisting of: 
 
     
       
         
         
             
             
         
       
     
     wherein B is either carbon or nitrogen; and
 R 1  is selected from the group consisting of side chains of amino acids other than glycine; a substituted or unsubstituted aralkyl or heterocyclylalkyl group; and a C 1-10  alkyl group, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with —OR 4 , —C(O)R 4 , —COOR 4 , —S(O) q R 4 , —NR 4 R 5 , —C(Y)NR 4 R 5 , —N(R 4 )C(Y)OR 5 , —NR 6 C(Y)NR 4 R 5 , —NR 6 C(NR 7 )NR 4 R 5 , —C(NR 6 )NR 4 R 5 , —C(Y)NR 4 OR 5 , —S(O) 2 NR 4 R 5 , or —NR 4 —SO 2 —R 5 , wherein Y is O or S; 
 R 2  and R 3  are independently selected from the group consisting of side chains of amino acids other than glycine; a substituted or unsubstituted aralkyl or heterocyclylalkyl group; a C 1-10  alkyl group, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with —OR 4 , —C(O)R 4 , —COOR 4 , —S(O) q R 4 , —NR 4 R 5 , —C(Y)NR 4 R 5 , —N(R 4 )C(Y)OR 5 , —NR 6 C(Y)NR 4 R 5 , —NR 6 C(NR 7 )NR 4 R 5 , —C(NR 6 )NR 4 R 5 , —C(Y)NR 4 OR 5 , —S(O) 2 NR 4 R 5 , or —NR 4 —SO 2 —R 5 , wherein Y is O or S; —C(O)—NH—R 8 ; and —NH—C(O)—R 9 ; 
 R 4 , R 5 , R 6 , and R 7 , at each occurrence, are independently hydrogen or a substituted or unsubstituted C 1-8  alkyl, C 2-6  alkenyl, (C 0-6  alkylene)(C 6-10  aryl), or (C 0-6  alkylene)(C 3-9  heterocyclyl) group; or R 6  and R 7 , together with the N to which they are attached, form a substituted or unsubstituted heterocyclyl group; 
 R 8  and R 9 , at each occurrence, are independently a side chain of an amino acid other than glycine; a substituted or unsubstituted aralkyl or heterocyclylalkyl group; a C 1-10  alkyl group, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with —OR 4 , —C(O)R 4 , —COOR 4 , S(O) q R 4 , —NR 4 R 5 , —C(Y)NR 4 R 5 , —N(R 4 )C(Y)OR 5 , —NR 6 C(Y)NR 4 R 5 , —NR 6 C(NR 7 )NR 4 R 5 , —C(NR 6 )NR 4 R 5 , —C(Y)NR 4 OR 5 , —S(O) 2 NR 4 R 5 , or —NR 4 —SO 2 —R 5 , wherein Y is O or S; and 
 each q is independently 0-2; and 
 stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof. 
 
   
   
       2 . The compound according to  claim 1 , wherein R 1 , R 2 , and R 3  are independently a substituted or unsubstituted aralkyl or heterocyclylalkyl group; or a C 1-10  alkyl group, optionally substituted with —OR 4 , —C(O)R 4 , —COOR 4 , —S(O) q R 4 , —NR 4 R 5 , —C(Y)NR 4 R 5 , —N(R 4 )C(Y)OR 5 , —NR 6 C(Y)NR 4 R 5 , —NR 6 C(NR 7 )NR 4 R 5 , —C(NR 6 )NR 4 R 5 , —C(Y)NR 4 OR 5 , —S(O) 2 NR 4 R 5 , or —NR 4 —SO 2 —R 5 , and wherein Y is O or S. 
   
   
       3 . The compound according to  claim 2 , wherein R 1 , R 2 , and R 3  are independently substituted or unsubstituted aralkyl or heterocyclylalkyl group; or a C 1 - 10  alkyl group, optionally substituted with —OR 4  or —C(O)NR 4 R 5 . 
   
   
       4 . The compound according to  claim 2 , wherein R 1 , R 2 , and R 3  are independently —CH 3 , —CH 2 CH 3 , —(CH 2 ) 5 C(O)OH, —(CH 2 ) 3 NHC(NH)NH 2 , —CH 2 C(O)NH 2 , —CH 2 C(O)OH, benzyl, —(CH 2 ) 3 NHC(O)NH 2 , —CH 2 -cyclohexyl, —CH 2 SH, —(CH 2 ) 2 C(O)OH, —(CH 2 ) 2 C(O)NH 2 , —CH 2 -imidazolyl, —(CH 2 ) 2 OH, CH(OH)CH 3 , —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 )CH 3 , —(CH 2 ) 4 NH 2 , —(CH 2 ) 2 SCH 3 , —(CH 2 ) 3 CH 3 , —(CH 2 ) 2 CH 3 , —(CH 2 ) 3 NH 2 , —C(SH)(CH 3 )CH 3 , —CH 2 OH, —CH 2 -thienyl, —CH 2 -indole, —CH 2 -phenol, or —CH(CH 3 )(CH 3 ). 
   
   
       5 . The compound according to  claim 2 , wherein R 1 , R 2 , and R 3  are independently benzyl, methylnaphthyl, methylindolyl, or a C 1-10  alkyl group, optionally substituted with —OH or —C(O)NH 2 . 
   
   
       6 . The compound according to  claim 1 , wherein R 2  and R 3  are independently —C(O)—NH—R 8  or —NH—C(O)—R 9 . 
   
   
       7 . The compound according to  claim 6 , wherein R 1  is a substituted or unsubstituted aralkyl or heterocyclylalkyl group; or a C 1-10  alkyl group, optionally substituted with —OR 4 , —C(O)R 4 , —COOR 4 , —S(O) q R 4 , —NR 4 R 5 , —C(Y)NR 4 R 5 , —N(R 4 )C(Y)OR 5 , —NR 6 C(Y)NR 4 R 5 , —NR 6 C(NR 7 )NR 4 R 5 , —C(NR 6 )NR 4 R 5 , —C(Y)NR 4 OR 5 , —S(O) 2 NR 4 R 5 , or —NR 4 —SO 2 —R 5 , and wherein Y is O or S. 
   
   
       8 . The compound according to  claim 1 , wherein one of R 2  and R 3  is —C(O)—NH—R 8 , and the other of R 2  and R 3  is —NH—C(O)—R 9 . 
   
   
       9 . The compound according to  claim 1 , wherein R 8  and R 9  are independently —CH 3 , —CH 2 CH 3 , —(CH 2 ) 5 C(O)OH, —(CH 2 ) 3 NHC(NH)NH 2 , —CH 2 C(O)NH 2 , —CH 2 C(O)OH, benzyl, —(CH 2 ) 3 NHC(O)NH 2 , —CH 2 -cyclohexyl, —CH 2 SH, —(CH 2 ) 2 C(O)OH, —(CH 2 ) 2 C(O)NH 2 , —CH 2 -imidazolyl, —(CH 2 ) 2 OH, CH(OH)CH 3 , —CH(CH 3 )CH 2 CH 3 , —CH 2 CH(CH 3 )CH 3 , —(CH 2 ) 4 NH 2 , —(CH 2 ) 2 SCH 3 , —(CH 2 ) 3 CH 3 , —(CH 2 ) 2 CH 3 , —(CH 2 ) 3 NH 2 , —C(SH)(CH 3 )CH 3 , —CH 2 OH, —CH 2 -thienyl, —CH 2 -indolyl, —CH 2 -phenol, or —CH(CH 3 )(CH 3 ). 
   
   
       10 . The compound according to  claim 1  represented by the following structure: 
     
       
         
         
             
             
         
       
     
   
   
       11 . The compound according to  claim 1  represented by the following structure: 
     
       
         
         
             
             
         
       
     
   
   
       12 . The compound according to  claim 11  represented by the following structure: 
     
       
         
         
             
             
         
       
     
   
   
       13 . The compound according to  claim 1  represented by the following structure: 
     
       
         
         
             
             
         
       
     
   
   
       14 . A pharmaceutical composition comprising a therapeutically effective amount of a compound of  claim 1  and a pharmaceutically acceptable carrier. 
   
   
       15 . A method for binding a compound to an alpha-helix-binding receptor or protein, the method comprising contacting the alpha-helix-binding receptor or protein with a compound of  claim 1 . 
   
   
       16 . The method of  claim 15 , wherein the alpha-helix binding receptor is the galanin receptor. 
   
   
       17 . The method of  claim 15 , wherein the alpha-helix binding protein is the Bcl-x L  protein. 
   
   
       18 . A method for treating a biological condition mediated by an alpha-helix-binding receptor or protein, the method comprising administering to a subject in need thereof an effective amount of a compound of  claim 1 . 
   
   
       19 . The method of  claim 18 , wherein the biological condition is pain or cancer. 
   
   
       20 . The method of  claim 18 , wherein the alpha-helix-binding receptor is the galanin receptor. 
   
   
       21 . The method of  claim 18 , wherein the alpha-helix-binding receptor is the galanin receptor 1 and the biological condition is pain. 
   
   
       22 . The method of  claim 18 , wherein the alpha-helix-binding protein is the Bcl-x L  protein and the biological condition is cancer. 
   
   
       23 . The method of  claim 22 , wherein the cancer is pancreatic, ovarian, liver, skin, bladder, breast, prostate, colorectal and adrenal cancer, B-cell lymphoma, B-cell leukemia, chronic lymphocytic leukemia, multiple myeloma, malignant melanoma, or non-small cell lung carcinoma. 
   
   
       24 . A method of disrupting protein-protein interactions, the method comprising contacting an alpha-helix-binding protein with an effective amount of a compound of  claim 1 , thereby preventing or lessening the binding of the alpha-helix binding protein to an alpha-helical region of an alpha-helix containing protein. 
   
   
       25 . The method of  claim 24 , wherein the alpha-helix-binding protein is the galanin receptor. 
   
   
       26 . The method of  claim 24 , wherein the alpha-helix-binding protein is the Bcl-x L  protein. 
   
   
       27 . A method of preparing a compound of  claim 1 , the method comprising reacting a compound of Formula II 
     
       
         
         
             
             
         
       
       with a compound of Formula III 
     
     
       
         
         
             
             
         
       
     
     optionally in the presence of a solvent, to form a compound of  claim 1 , wherein X, W, and R 1  are as defined in  claim 1 . 
   
   
       28 . The method of  claim 27 , wherein the solvent is diethyl ether, pentane, toluene, chloroform, dioxane, carbon tetrachloride, nitrobenzene, dichloromethane, ethyl acetate, THF, benzene, acetonitrile, dimethyl ether, 1,2-dibromoethane, xylene, acetone, chlorobenzene, DMSO, methanol, mesitylene, or mixtures thereof. 
   
   
       29 . A method for preparing a compound of  claim 1 , the method comprising reacting a compound of Formula II 
     
       
         
         
             
             
         
       
       with a compound of Formula IV 
     
     
       
         
         
             
             
         
       
     
     optionally in the presence of a solvent, to form a compound of  claim 1 , wherein X, W, and R 1  are as defined in  claim 1  and R′ is a leaving group. 
   
   
       30 . The method of  claim 29 , wherein the leaving group is O-TMS, —SO-phenyl, morpholino, or pyrrolidino. 
   
   
       31 . The method of  claim 29 , wherein the solvent is diethyl ether, pentane, toluene, chloroform, dioxane, carbon tetrachloride, nitrobenzene, dichloromethane, ethyl acetate, THF, benzene, acetonitrile, dimethyl ether, 1,2-dibromoethane, xylene, acetone, chlorobenzene, DMSO, methanol, mesitylene, or mixtures thereof. 
   
   
       32 . A method for preparing a compound of  claim 1 , the method comprising reacting a compound of Formula II 
     
       
         
         
             
             
         
       
     
     with a compound of Formula V 
     
       
         
         
             
             
         
       
     
     optionally in the presence of a solvent, to form a compound of Formula Ib 
     
       
         
         
             
             
         
       
     
     wherein X and W are as defined in  claim 1 , and n is 1-3. 
   
   
       33 . The method of  claim 32 , wherein the solvent is diethyl ether, pentane, toluene, chloroform, dioxane, carbon tetrachloride, nitrobenzene, dichloromethane, ethyl acetate, THF, benzene, acetonitrile, dimethyl ether, 1,2-dibromoethane, xylene, acetone, chlorobenzene, DMSO, methanol, mesitylene, or mixtures thereof. 
   
   
       34 . A method of preparing a compound of  claim 1 , the method comprising reacting a compound of Formula II 
     
       
         
         
             
             
         
       
       with a compound of Formula VI 
     
     
       
         
         
             
             
         
       
     
     in the presence of a base and a solvent, to form a compound of  claim 1 , wherein X, W, and R 1  are as defined in  claim 1 . 
   
   
       35 . The method of  claim 34 , wherein the base is KOH, NaOH, LiOH, KOtBu, NaOMe, NaOEt, or NaH. 
   
   
       36 . The method of  claim 34 , wherein the solvent is dioxane, THF or ether. 
   
   
       37 . A method of preparing a compound of  claim 1  wherein one of R 2  and R 3  is —C(O)—NH—R 8  and the other is —NH—C(O)—R 9 , the method comprising converting one of R x  or R w  of Formula VII to —NH—C(O)—R 9  and converting the other of R x  or R w  of Formula VII to —C(O)—NH—R 8 ; wherein Formula VII has the structure: 
     
       
         
         
             
             
         
       
     
     wherein:
 X′ is a radical selected from the group consisting of: 
 
     
       
         
         
             
             
         
       
     
     wherein A is either carbon or nitrogen, and Z is either hydrogen or (C 1-6 ) alkyl;
 W′ is a radical selected from the group consisting of: 
 
     
       
         
         
             
             
         
       
     
     wherein B is either carbon or nitrogen;
 R 1  is selected from the group consisting of side chains of amino acids other than glycine; a substituted or unsubstituted aralkyl or heterocyclylalkyl group; and a C 1-10  alkyl group, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with —OR 4 , —C(O)R 4 , —COOR 4 , —S(O) q R 4 , —NR 4 R 5 , —C(Y)NR 4 R 5 , —N(R 4 )C(Y)OR 5 , —NR 6 C(Y)NR 4 R 5 , —NR 6 C(NR 7 )NR 4 R 5 , —C(NR 6 )NR 4 R 5 , —C(Y)NR 4 OR 5 , —S(O) 2 NR 4 R 5 , or —NR 4 —SO 2 —R 5 , wherein Y is O or S; 
 one of R x  and R w  is —NO 2  and the other is —COOR″; and 
 R″ is independently hydrogen or a substituted or unsubstituted C 1-8  alkyl, C 2-6  alkenyl, or (C 0-6  alkylene)(C 6-10  aryl); and 
 stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof; 
 such that only —NO 2  is converted to —NH—C(O)—R 9 , and only —COOR″ is converted to —C(O)—NH—R 8 R x . 
 
   
   
       38 . The method of  claim 37  wherein one of R x  and R w  is NO 2  and is converted to —NH—C(O)—R 9  by hydrogenolysis in the presence of hydrogen and a transition metal catalyst, followed by acylation with R 9 C(O)L wherein L is a leaving group for acylation. 
   
   
       39 . The method of  claim 38  wherein the transition metal catalyst is palladium on carbon. 
   
   
       40 . The method of  claim 38  wherein L is —F, —Cl, —Br, —N 3 , N-oxysuccinimide, 1-oxybenzotriazole, 1-oxy-7-azabenzotriazole, N-imidazolyl, or —OCH 3 . 
   
   
       41 . The method of  claim 37  wherein R″ is hydrogen, benzyl, allyl, trimethylsilylethyl, 2,2,2-trichloroethyl, or an unsubstituted C 1-6  alkyl group. 
   
   
       42 . The method of  claim 37  wherein R″ is methyl or ethyl and —COOR″ is hydrolyzed to —COOH in the presence of a base, activated for amidation and reacted with R 8 NH 2 . 
   
   
       43 . The method of  claim 42  wherein the base is LiOH, NaOH, or KOH. 
   
   
       44 . The method of  claim 42  wherein the —COOH group is activated with a coupling agent or by conversion to an acyl halide, acyl azide, or an active ester. 
   
   
       45 . The method of  claim 42  wherein the coupling agent is HATU or EDCI. 
   
   
       46 . A compound having Formula II: 
     
       
         
         
             
             
         
       
     
     wherein:
 X is a radical selected from the group consisting of: 
 
     
       
         
         
             
             
         
       
     
     wherein A is either carbon or nitrogen, and Z is either hydrogen or (C 1-6 ) alkyl;
 W is a radical selected from the group consisting of: 
 
     
       
         
         
             
             
         
       
     
     wherein B is either carbon or nitrogen; and
 R 2  and R 3  are independently selected from the group consisting of —COOR 4 ; —NO 2 ; —NH 2 ; —NR 4 R 5 ; —N(R 4 )C(Y)OR 5 ; —N(R 4 )C(Y)OR 5 ; side chains of amino acids other than glycine; a substituted or unsubstituted aralkyl or heterocyclylalkyl group; a C 1-10  alkyl group, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with —OR 4 , —C(O)R 4 , —COOR 4 , S(O) q R 4 , —NR 4 R 5 , —C(Y)NR 4 R 5 , —N(R 4 )C(Y)OR 5 , —NR 6 C(Y)NR 4 R 5 , —NR 6 C(NR 7 )NR 4 R 5 , —C(NR 6 )NR 4 R 5 , —C(Y)NR 4 OR 5 , —S(O) 2 NR 4 R 5 , or —NR 4 —SO 2 —R 5 , wherein Y is O or S; —C(O)—NH—R 8 ; and —NH—C(O)—R 9 ; 
 R 4 , R 5 , R 6 , and R 7 , at each occurrence, are independently hydrogen or a substituted or unsubstituted C 1-8  alkyl, C 2-6  alkenyl, (C 0-6  alkylene)(C 6-10  aryl), or (C 0-6  alkylene)(C 1-9  heterocyclyl) group; or R 6  and R 7 , together with the N to which they are attached, form a substituted or unsubstituted heterocyclyl group; 
 R 8  and R 9 , at each occurrence, are independently a side chain of an amino acid other than glycine; a substituted or unsubstituted aralkyl or heterocyclylalkyl group; a C 1-10  alkyl group, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with —OR 4 , —C(O)R 4 , —COOR 4 , S(O) q R 4 , —NR 4 R 5 , —C(Y)NR 4 R 5 , —N(R 4 )C(Y)OR 5 , —NR 6 C(Y)NR 4 R 5 , —NR 6 C(NR 7 )NR 4 R 5 , —C(NR 6 )NR 4 R 5 , —C(Y)NR 4 OR 5 , —S(O) 2 NR 4 R 5 , or —NR 4 —SO 2 —R 5 , wherein Y is O or S; and 
 each q is independently 0-2; and 
 stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof. 
 
   
   
       47 . A compound having Formula VIII or IX: 
     
       
         
         
             
             
         
       
     
     wherein:
 X is a radical selected from the group consisting of: 
 
     
       
         
         
             
             
         
       
     
     wherein A is either carbon or nitrogen, and Z is either hydrogen or (C 1-6 ) alkyl;
 W is a radical selected from the group consisting of: 
 
     
       
         
         
             
             
         
       
     
     wherein B is either carbon or nitrogen; and
 R 2  and R 3  are independently selected from the group consisting of —COOR 4 ; —NO 2 ; —NH 2 ; —NR 4 R 5 ; —N(R 4 )C(Y)OR 5 ; —N(R 4 )C(Y)OR 5 ; side chains of amino acids other than glycine; a substituted or unsubstituted aralkyl or heterocyclylalkyl group; a C 1-10  alkyl group, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with —OR 4 , —C(O)R 4 , —COOR 4 , —S(O) q R 4 , —NR 4 R 5 , —C(Y)NR 4 R 5 , —N(R 4 )C(Y)OR 5 , —NR 6 C(Y)NR 4 R 5 , —NR 6 C(NR 7 )NR 4 R 5 , —C(NR 6 )NR 4 R 5 , —C(Y)NR 4 OR 5 , —S(O) 2 NR 4 R 5 , or —NR 4 —SO 2 —R 5 , wherein Y is O or S; —C(O)—NH—R 8 ; and —NH—C(O)—R 9 ; 
 R 4 , R 5 , R 6 , and R 7 , at each occurrence, are independently hydrogen or a substituted or unsubstituted C 1-8  alkyl, C 2-6  alkenyl, (C 0-6  alkylene)(C 6-10  aryl), or (C 0-6  alkylene)(C 1-9  heterocyclyl) group; or R 6  and R 7 , together with the N to which they are attached, form a substituted or unsubstituted heterocyclyl group; 
 R 8  and R 9 , at each occurrence, are independently a side chain of an amino acid other than glycine; a substituted or unsubstituted aralkyl or heterocyclylalkyl group; a C 1-10  alkyl group, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with —OR 4 , —C(O)R 4 , —COOR 4 , S(O) q R 4 , —NR 4 R 5 , —C(Y)NR 4 R 5 , —N(R 4 )C(Y)OR 5 , —NR 6 C(Y)NR 4 R 5 , —NR 6 C(NR 7 )NR 4 R 5 , —C(NR 6 )NR 4 R 5 , —C(Y)NR 4 OR 5 , —S(O) 2 NR 4 R 5 , or —NR 4 —SO 2 —R 5 , wherein Y is O or S; and 
 each q is independently 0-2; and 
 stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof. 
 
   
   
       48 . A compound having the Formula XA or XB: 
     
       
         
         
             
             
         
       
     
     wherein:
 X is a radical selected from the group consisting of: 
 
     
       
         
         
             
             
         
       
     
     wherein A is either carbon or nitrogen, and Z is either hydrogen or (C 1-6 ) alkyl;
 W is a radical selected from the group consisting of: 
 
     
       
         
         
             
             
         
       
     
     wherein B is either carbon or nitrogen; and
 R 1  is selected from the group consisting of side chains of amino acids other than glycine; a substituted or unsubstituted aralkyl or heterocyclylalkyl group; and a C 1-10  alkyl group, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with —OR 4 , —C(O)R 4 , —COOR 4 , —S(O) q R 4 , —NR 4 R 5 , —C(Y)NR 4 R 5 , —N(R 4 )C(Y)OR 5 , —NR 6 C(Y)NR 4 R 5 , —NR 6 C(NR 7 )NR 4 R 5 , —C(NR 6 )NR 4 R 5 , —C(Y)NR 4 OR 5 , —S(O) 2 NR 4 R 5 , or —NR 4 —SO 2 —R 5 , wherein Y is O or S; 
 R 2  and R 3  are independently selected from the group consisting of side chains of amino acids other than glycine; a substituted or unsubstituted aralkyl or heterocyclylalkyl group; a C 1-10  alkyl group, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with —OR 4 , —C(O)R 4 , —COOR 4 , —S(O) q R 4 , —NR 4 R 5 , —C(Y)NR 4 R 5 , —N(R 4 )C(Y)OR 5 , —NR 6 C(Y)NR 4 , R 5 , —NR 6 C(NR 7 )NR 4 R 5 , —C(NR 6 )NR 4 R 5 , —C(Y)NR 4 OR 5 , —S(O) 2 NR 4 R 5 , or —NR 4 —SO 2 —R 5 , wherein Y is O or S; —C(O)—NH—R 8 ; and —NH—C(O)—R 9 ; 
 R 4 , R 5 , R 6 , and R 7 , at each occurrence, are independently hydrogen or a substituted or unsubstituted C 1-8  alkyl, C 2-6  alkenyl, (C 0-6  alkylene)(C 6-10  aryl), or (C 0-6  alkylene)(C 1-9  heterocyclyl) group; or R 6  and R 7 , together with the N to which they are attached, form a substituted or unsubstituted heterocyclyl group; 
 R 8  and R 9 , at each occurrence, are independently a side chain of an amino acid other than glycine; a substituted or unsubstituted aralkyl or heterocyclylalkyl group; a C 1-10  alkyl group, optionally comprising one or more unsaturated bonds within the alkyl chain, and optionally substituted with —OR 4 , —C(O)R 4 , —COOR 4 , —S(O) q R 4 , —NR 4 R 5 , —C(Y)NR 4 R 5 , —N(R 4 )C(Y)OR 5 , —NR 6 C(Y)NR 4 R 5 , —NR 6 C(NR 7 )NR 4 R 5 , —C(NR 6 )NR 4 R 5 , —C(Y)NR 4 OR 5 , —S(O) 2 NR 4 R 5 , or —NR 4 —SO 2 —R 5 , wherein Y is O or S; 
 R 10  is OH, unsubstituted C 1-6  alkoxy, benzyloxy, NHNH 2 , or a leaving group; 
 each q is independently 0-2; and 
 stereoisomers thereof, tautomers thereof, solvates thereof, prodrugs thereof, and pharmaceutically acceptable salts thereof. 
 
   
   
       49 . The compound according to  claim 48  wherein R 10  is a leaving group selected from the group consisting of —N 3 , N-hydroxysuccinimidyl, p-nitrophenolate, pentafluorophenolate, —OC(O)OR 11 , or N-oxybenzotriazole, wherein R 11  is unsubstituted C 1-6  alkyl.