Dipeptide mimics, libraries combining two dipeptide mimics with a third group, and methods for production thereof

Abstract

Monovalent compounds having moieties comprising at least one amino acid side chain are bound to a core molecule, which also comprises a nucleophilic moiety bound to said core molecule. Monovalent compounds also comprise a macrocyclic ring, a nucleophilic moiety, and a spacer group. Monovalent compounds may be combined into bivalent and trivalent compounds, some of which may have a labeling tag. Methods of production of bivalent compounds and contemplated uses thereof are disclosed.

1 . A compound having the structure selected from the group consisting of: 
     
       
         
         
             
             
         
       
       wherein R 1  and R 2  are comprised by at least one moiety comprising an amino acid side chain, and wherein R 1  and R 2  comprise non-peptidic bonds; 
       wherein X1 comprises a core molecule selected from the group consisting of heteroarylenes, arylenes and heterocyclenes and a nucleophilic moiety bound to said core molecule; and 
       wherein K 1  and K 2  comprise at least one spacer atom between said core molecule and said at least one moiety comprising an amino acid side chain. 
     
   
   
       2 . The compound of  claim 1 , further comprising at least one 1,2,3-triazine moiety bound to said core molecule. 
   
   
       3 . The compound of  claim 1 , wherein R 1  and R 2  comprise at least one structural fragment selected from the group consisting of: 
     
       
         
         
             
             
         
       
       wherein R 1  and R 2  are independently selected. 
     
   
   
       4 . The compound of  claim 1 , wherein said nucleophilic moiety comprises a moiety selected from the group consisting of piperidine, piperazine, pyrrolidine, azetidine, and any derivative or analog thereof. 
   
   
       5 . The compound of  claim 1 , wherein said nucleophilic moiety is bound directly to X1. 
   
   
       6 . The compound of  claim 1 , wherein said nucleophilic moiety is bound to X1 through at least one spacer atom. 
   
   
       7 . The compound of  claim 1 , wherein said core molecule comprises a moiety selected from the group consisting of a phenyl ring, a 1,2,3-triazole ring, a diketopiperazine ring, a 1,3,4-oxadiazole ring, a pyridine ring, and any substituted derivative or analog thereof. 
   
   
       8 . The compound of  claim 1 , wherein said compound has the structure: 
     
       
         
         
             
             
         
       
       wherein Z1 comprises a nucleophilic moiety selected from the group consisting of piperidine, piperazine, pyrrolidine, azetidine, and any derivative or analog thereof. 
     
   
   
       9 . The compound of  claim 1 , wherein said compound has the structure: 
     
       
         
         
             
             
         
       
       wherein Z1 comprises a nucleophilic moiety selected from the group consisting of piperidine, piperazine, pyrrolidine, azetidine, and any derivative or analog thereof; 
       wherein Z2 comprises a moiety selected from the group consisting of —CH 2 —, —CH 2 CH 2 — and —CH 2 CH 2 O—; and 
       wherein n1 is an integer from 1-20. 
     
   
   
       10 . The compound of  claim 9 , wherein said compound has the structure: 
     
       
         
         
             
             
         
       
     
   
   
       11 . The compound of  claim 1 , wherein said compound has the structure: 
     
       
         
         
             
             
         
       
       wherein Z1 comprises a nucleophilic moiety selected from the group consisting of piperidine, piperazine, pyrollidine, azetidine, and any derivative or analog thereof; and 
       wherein Z3 and Z4 comprise moieties independently selected from the group consisting of CO 2 R 3 , CONR 4 R 5 , and CH 2 OH,
 wherein R 3  is selected from the group consisting of hydrogen and alkyl, and 
 wherein R 4  and R 5  are independently selected from the group consisting of hydrogen and alkyl. 
 
     
   
   
       12 . The compound of  claim 11 , wherein said compound has the structure: 
     
       
         
         
             
             
         
       
       wherein R 6  and R 7  are independently selected from the group consisting of hydrogen and alkyl. 
     
   
   
       13 . The compound of  claim 1 , wherein said compound has the structure: 
     
       
         
         
             
             
         
       
       wherein Z1 comprises a nucleophilic moiety selected from the group consisting of piperidine, piperazine, pyrrolidine, azetidine, and any derivative or analog thereof. 
     
   
   
       14 . The compound of  claim 1 , wherein said compound has the structure: 
     
       
         
         
             
             
         
       
       wherein Z1 comprises a nucleophilic moiety selected from the group consisting of piperidine, piperazine, pyrollidine, azetidine, and any derivative or analog thereof; 
       wherein Z2 comprises a moiety selected from the group consisting of —CH 2 —, —CH 2 CH 2 — and —CH 2 CH 2 O—; and 
       wherein n1 is an integer from 1-20. 
     
   
   
       15 . The compound of  claim 14 , wherein said compound has the structure: 
     
       
         
         
             
             
         
       
     
   
   
       16 . The compound of  claim 1 , wherein said compound has the structure: 
     
       
         
         
             
             
         
       
       wherein Z1 comprises a nucleophilic moiety selected from the group consisting of piperidine, piperazine, pyrrolidine, azetidine, and any derivative or analog thereof, and 
       wherein R 8  and R 9  are each independently selected from the group consisting of hydrogen and alkyl. 
     
   
   
       17 . The compound of  claim 1 , wherein said compound has the structure: 
     
       
         
         
             
             
         
       
       wherein Z1 comprises a nucleophilic moiety selected from the group consisting of piperidine, piperazine, pyrrolidine, azetidine, and any derivative or analog thereof; and 
       wherein R 10  and R 11  are independently selected from the group consisting of hydrogen and alkyl. 
     
   
   
       18 . The compound of  claim 1 , wherein said compound has the structure: 
     
       
         
         
             
             
         
       
       wherein Z1 comprises a nucleophilic moiety selected from the group consisting of piperidine, piperazine, pyrrolidine, azetidine, and any derivative or analog thereof. 
     
   
   
       19 . The compound of  claim 1 , wherein the compound has the structure: 
     
       
         
         
             
             
         
       
       wherein Z1 comprises a nucleophilic moiety selected from the group consisting of piperidine, piperazine, pyrrolidine, azetidine, and any derivative or analog thereof. 
     
   
   
       20 . The compound of  claim 1 , wherein said compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
   
   
       21 . A compound having the structure: 
     
       
         
         
             
             
         
       
       wherein A1 comprises a macrocyclic ring comprising at least two amino acids, wherein said at least two amino acids are bound to each other in a ring comprising at least one peptide bond; 
       wherein Z1 comprises a nucleophilic moiety selected from the group consisting of piperidine, piperazine, pyrrolidine, azetidine, and any derivative or analog thereof; and 
       wherein S1 comprises a spacer group having at least one carbonyl moiety, wherein S1 does not comprise glycine. 
     
   
   
       22 . The compound of  claim 21 , wherein said compound is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       23 . A compound having the structure: 
     
       
         
         
             
             
         
       
       wherein B1 is a core molecule selected from the group consisting of heteroarylenes, arylenes, and heterocyclenes; and 
       wherein P1 and P2 comprise an organic moiety comprising removal of a hydrogen atom from the compounds of  claims 1  or  21 , and wherein P1 and P2 are independently selected. 
     
   
   
       24 . The compound of  claim 23  further comprising a labeling tag T1 bound to B1. 
   
   
       25 . The compound of  claim 23  further comprising a third organic moiety comprising removal of a hydrogen atom from the compounds of  claims 1  or  21  bound to B1, wherein said third organic moiety is selected independently of P1 and P2. 
   
   
       26 . A compound having the structure: 
     
       
         
         
             
             
         
       
       wherein P3 and P4 comprise an organic moiety comprising removal of a hydrogen atom from the nitrogen atom of the piperidine or piperazine ring of any of the compounds of  claims 20  or  22 , and wherein P3 and P4 are independently selected; and 
       wherein P5 comprises a moiety selected from the group consisting of an organic moiety comprising removal of a hydrogen atom from the nitrogen atom of the piperidine or piperazine ring of any of the compounds of  claims 20  or  22  and a labeling tag T1, wherein P5 is selected independently of P3 and P4. 
     
   
   
       27 . The compound of  claim 26 , wherein said compound has the structure: 
     
       
         
         
             
             
         
       
     
   
   
       28 . The compound of  claim 27 , wherein at least one of P3 and P4 further comprise a morpholinyl group, with the proviso that both P3 and P4 are not a morpholinyl group. 
   
   
       29 . The compound of  claims 24  or  26 , wherein T1 is selected from the group consisting of a fluorescein tag, a biotin tag, a polyether tag, and a 1,2,3-triazole-functionalized polyether tag. 
   
   
       30 . The compound of  claim 29 , wherein T1 is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       31 . The compound of  claim 28  comprising a combinatorial library, wherein compounds comprising the library are expressed in the shorthand form P3P4T1, and wherein:
 1) P3 is selected from the group consisting of a, A, b, B, C, C, d, D, e, E, f, F, g, G, h, H, i, I, j, J, k, K, l, L, m, M, n, N, o, O, p, q, Q, r, R, s, S, t, T, u, U, v, V, w, W, x, X, y, Y, z, Z, a′, A′, b′, B′, c′, C′, d′, D′, e′, E′, f′, F′, g′, G′, h′, H′, i′, I′, j′, J′, k′, K′, l′, L′, m′, M′, n′, N′, o′, O′, p′, P′, q′, Q′, r′, R′, s′, S′, t′, T′, u′, U′, v′, V′, w′, W′, x′, X′, y′, Y′, z′, Z′, a″, A″, b″, B″c″, C″, d″, D″, e″, E″, f″, F″, g″, G″, h″, H″, i″, I″, j″, J″, k″, K″, l″, L″, m″, M″, n″, N″, o″, O″, p″, P″, q″, Q″, r″, R″, s″, S″, t″, T″, u″, U″, v″, V″, w″, W″, x″, X″, y″, Y″, z″, Z″, a′″, A′″, b′″, B′″, c′″, C′″, d′″, D′″, e′″, E′″, f′″, F′″, g′″, G′″, h′″, H′″, i′″, I′″, j′″, J′″, k′″, K′″, l′″, L′″, m′″, M′″, n′″, N′″, o′″, O′″, p′″, P′″, q′″, Q′″, r′″, R′″, s′″, S′″, t′″, T′″, u′″, U′″, V′″, v′″, w′″, W′″, x′″, X′″, y′″, Y′″, z′″, Z′″, a″″, A″″, b″″, B″″, c″″, C″″, d″″, D″″, e″″, and E″″;   2) P4 is selected from the group consisting of a, A, b, B, C, C, d, D, e, E, f, F, g, G, h, H, i, I, j, J, k, K, l, L, m, M, n, N, o, O, p, q, Q, r, R, s, S, t, T, u, U, v, V, w, W, x, X, y, Y, z, Z, a′, A′, b′, B′, c′, C′, d′, D′, e′, E′, f′, F′, g′, G′, h′, H′, i′, I′, j′, J′, k′, K′, l′, L′, m′, M′, n′, N′, o′, O′, p′, P′, q′, Q′, r′, R′, s′, S′, t′, T′, u′, U′, v′, V′, w′, W′, x′, X′, y′, Y′, z′, Z′, a″, A″, b″, B″c″, C″, d″, D″, e″, E″, f″, F″, g″, G″, h″, H″, i″, I″, j″, J″, k″, K″, l″, L″, m″, M″, n″, N″, o″, O″, p″, P″, q″, Q″, r″, R″, s″, S″, t″, T″, u″, U″, v″, V″, w″, W″, x″, X″, y″, Y″, z″, Z″, a′″, A′″, b′″, B′″, c′″, C′″, d′″, D′″, e′″, E′″, f′″, F′″, g′″, G′″, h′″, H′″, i′″, I′″, j′″, J′″, k′″, K′″, l′″, L′″, m′″, M′″, n′″, N′″, o′″, O′″, p′″, P′″, q′″, Q′″, r′″, R′″, s′″, S′″, t′″, T′″, u′″, U′″, V′″, v′″, w′″, W′″, x′″, X′″, y′″, Y′″, z′″, Z′″, a″″, A″″, b″″, B″″, c″″, C″″, d″″, D″″, e″″, and E″″;   3) T1 is selected from the group consisting of 1, 2, 3, and 4; and wherein all possible combinations of P3, P4 and T1 comprise the library.   
   
   
       32 . A method of producing a library of compounds comprising:
 1) providing   
     
       
         
         
             
             
         
       
        wherein T1 comprises a labeling tag; 
       2) reacting a first equivalent of any of the compounds of  claims 20  or  22  or morpholine in the presence of a base and a solvent; 
       3) removing the solvent; and 
       4) reacting a second equivalent of any of the compounds of  claims 20  or  22  or morpholine in the presence of a base and a solvent, with the proviso that said first equivalent and said second equivalent are not both morpholine. 
     
   
   
       33 . The method of  claim 32 , wherein T1 is selected from the group consisting of: 
     
       
         
         
             
             
         
       
     
   
   
       34 . The method of  claim 32 , wherein said base comprises potassium carbonate. 
   
   
       35 . A compound selected from  claims 1  or  28  comprising demonstration of protein-protein interactions. 
   
   
       36 . A compound selected from  claims 1  or  28  comprising a pharmaceutical lead. 
   
   
       37 . A compound selected from  claim 28  comprising a pharmacological probe. 
   
   
       38 . A compound selected from any one of  claims 1 ,  21 ,  23 ,  25 , or  26  comprising a pharmaceutical.