Compounds for use in synthesis of peptidomimetics

1. A compound of Formula (IA):

wherein A is N-phthalimidyl or NR 1 R 2 ,

R 1 is H,

R 2 is tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, 2-(3,5-dimethoxyphenyl)propan-2-yloxycarbonyl, or

R and R 1 or R 2 are connected and together form a side chain radical of proline;

X is imidazolyl or benzotriazolyl; and

R is selected from the group consisting of H, methyl, isopropyl, isobutyl, benzyl, and side chain radicals of aspartic acid, histidine, glutamic acid, tryptophan, lysine, methionine, tyrosine, threonine, R-isoleucine, S-isoleucine, RS-isoleucine, arginine, glycine, asparagine, serine, and glutamine;

with the proviso that if A is NR 1 R 2 and R 2 is 9-fluorenylmethoxycarbonyl, R is selected from the group consisting of H, isopropyl, isobutyl, and side chain radicals of aspartic acid, histidine, glutamic acid, tryptophan, lysine, methionine, tyrosine, threonine, R-isoleucine, S-isoleucine, RS-isoleucine, arginine, glycine, asparagine, serine, and glutamine.

2. The compound of claim 1 , which is a compound of Formula (III):

wherein R is selected from the group consisting H, methyl, isopropyl, isobutyl, benzyl, and side chain radicals of aspartic acid, histidine, glutamic acid, tryptophan, lysine, methionine, tyrosine, threonine, R-isoleucine, S-isoleucine, RS-isoleucine, arginine, glycine, asparagine, serine, and glutamine.

3. The compound of claim 1 , which is a compound of Formula (II):

wherein R is selected from the group consisting of H, methyl, isopropyl, isobutyl, benzyl, and side chain radicals of aspartic acid, histidine, glutamic acid, tryptophan, lysine, methionine, tyrosine, threonine, R-isoleucine, S-isoleucine, RS-isoleucine, arginine, glycine, asparagine, serine, and glutamine; and M is a substituent selected from the group consisting of a halogen, a C 1 -C 6 alkyl, hydroxyl, —COOH, —COH, methoxyl, ethoxyl, propoxyl, and a C 1 -C 6 haloalkyl.

4. The compound of claim 1 , wherein R is selected from the group consisting of methyl, isopropyl, isobutyl, benzyl, and side chain radicals of aspartic acid, histidine, glutamic acid, tryptophan, threonine, lysine, methionine, tyrosine, R-isoleucine, S-isoleucine, RS-isoleucine, arginine, glycine, asparagine, serine, and glutamine is unsubstituted.

5. The compound of claim 1 , wherein R is substituted with one or more of the following: a halogen, a C 1 -C 6 alkyl, hydroxyl, —COOH, —COH, methoxyl, ethoxyl, propoxyl, a C 1 -C 6 haloalkyl, or a protecting group.

6. The compound of claim 1 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof, wherein PG is selected from the group consisting of H, N-phthalimidyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, and 2-(3,5-dimethoxyphenyl)propan-2-yloxycarbonyl.

7. The compound of claim 6 , wherein the PG is N-phthalimidyl.

8. The compound of claim 6 , wherein the compound is selected from the group consisting of N-(((1H-benzo[d][1,2,3]triazol-1-yl)oxy)carbonyl)-N-(1,3-dioxoisoindolin-2-yl)glycine, 1H-benzo[d][1,2,3]triazol-1-yl benzyl(1,3-dioxoisoindolin-2-yl)carbamate, 1H-benzo[d][1,2,3]triazol-1-yl (1,3-dioxoisoindolin-2-yl)(methyl)carbamate, 1H-benzo[d][1,2,3]triazol-1-yl ((1H-pyrrol-2-yl)methyl)(1,3-dioxoisoindolin-2-yl)carbamate, 3-((((1H-benzo[d][1,2,3]triazol-1-yl)oxy)carbonyl)(1,3-dioxoisoindolin-2-yl)amino)propanoic acid, 1H-benzo[d][1,2,3]triazol-1-yl ((1H-indol-3-yl)methyl)(1,3-dioxoisoindolin-2-yl)carbamate, 1H-benzo[d][1,2,3]triazol-1-yl (1,3-dioxoisoindolin-2-yl)(isopropyl)carbamate (Phth-aza-valine-carbamoyl-O-benzotriazole), 1H-benzo[d][1,2,3]triazol-1-yl (1,3-dioxoisoindolin-2-yl)(isobutyl)carbamate, 1H-benzo[d][1,2,3]triazol-1-yl (4-aminobutyl)(1,3-dioxoisoindolin-2-yl)carbamate, 1H-benzo[d][1,2,3]triazol-1-yl (1,3-dioxoisoindolin-2-yl)(2-(methylthio)ethyl)carbamate, 1H-benzo[d][1,2,3]triazol-1-yl (1,3-dioxoisoindolin-2-yl)(4-hydroxybenzyl)carbamate, 1H-benzo[d][1,2,3]triazol-1-yl sec-butyl(1,3-dioxoisoindolin-2-yl)carbamate, 1H-benzo[d][1,2,3]triazol-1-yl (1,3-dioxoisoindolin-2-yl)(3-guanidinopropyl)carbamate, 1H-benzo[d][1,2,3]triazol-1-yl (1,3-dioxoisoindolin-2-yl)carbamate, 1H-benzo[d][1,2,3]triazol-1-yl (2-amino-2-oxoethyl)(1,3-dioxoisoindolin-2-yl)carbamate, 1H-benzo[d][1,2,3]triazol-1-yl (3-amino-3-oxopropyl)(1,3-dioxoisoindolin-2-yl)carbamate, and pharmaceutically acceptable salts thereof.

9. The compound of claim 1 , wherein the compound is selected from the group consisting of:

and pharmaceutically acceptable salts thereof, wherein PG is selected from the group consisting of H, N-phthalimidyl, tert-butoxycarbonyl, 9-fluorenylmethoxycarbonyl, 2-(3,5-dimethoxyphenyl)propan-2-yloxycarbonyl.

10. The compound of claim 9 , wherein the PG is N-phthalimidyl.

11. The compound of claim 9 , which is selected from the group consisting of N-(((1H-imidazol-1-yl)oxy)carbonyl)-N-(1,3-dioxoisoindolin-2-yl)glycine, 1H-imidazol-1-yl benzyl(1,3-dioxoisoindolin-2-yl)carbamate, 1H-imidazol-1-yl (1,3-dioxoisoindolin-2-yl)(methyl)carbamate, 1H-imidazol-1-yl ((1H-pyrrol-2-yl)methyl)(1,3-dioxoisoindolin-2-yl)carbamate, 3-((((1H-imidazol-1-yl)oxy)carbonyl)(1,3-dioxoisoindolin-2-yl)amino)propanoic acid, 1H-imidazol-1-yl ((1H-indol-3-yl)methyl)(1,3-dioxoisoindolin-2-yl)carbamate, 1H-imidazol-1-yl (1,3-dioxoisoindolin-2-yl)(isopropyl)carbamate, 1H-imidazol-1-yl (1,3-dioxoisoindolin-2-yl)(isobutyl)carbamate, 1H-imidazol-1-yl (4-aminobutyl)(1,3-dioxoisoindolin-2-yl)carbamate, 1H-imidazol-1-yl (1,3-dioxoisoindolin-2-yl)(2-(methylthio)ethyl)carbamate, 1H-imidazol-1-yl (1,3-dioxoisoindolin-2-yl)(4-hydroxybenzyl)carbamate, 1H-imidazol-1-yl sec-butyl(1,3-dioxoisoindolin-2-yl)carbamate, 1H-imidazol-1-yl (1,3-dioxoisoindolin-2-yl)(3-guanidinopropyl)carbamate, 1H-imidazol-1-yl (1,3-dioxoisoindolin-2-yl)carbamate, 1H-imidazol-1-yl (2-amino-2-oxoethyl)(1,3-dioxoisoindolin-2-yl)carbamate, 1H-imidazol-1-yl (3-amino-3-oxopropyl)(1,3-dioxoisoindolin-2-yl)carbamate, and pharmaceutically acceptable salts thereof.

12. A method of preparing an azapeptide comprising

a step of activating a compound according to claim 1 ; and

a step of coupling the activated compound with N-terminal of an amino acid, N-terminal of an aza-mino acid;

wherein the azapeptide is a compound of Formula (V):

wherein

is at the N-terminus and/or the C-terminus of the compound of Formula (V), is adjacent to the N-terminus and/or the C-terminus of the compound of Formula (V) or hydrolysis site of the compound of Formula (V);

B is selected from the group consisting of hydrogen, —NH 2 , —NNH 2 , —CONH 2 , —COOR 3 , —COOH, —COH, —COC 1 -C 4 alkyl, —COC 1 -C 4 haloalkyl, —OH, an amino acid, an aza amino acid, a 2 to 60-mer peptide, a 2 to 60-mer aza peptide, a 2 to 60-mer azatide,

D is selected from the group consisting of —OR 4 , —OH, —NH 2 , —NNH 2 , —NHCOCH 3 , —NHCH 3 , —N(CH 3 ) 2 , —CONH 2 , —COOH, —COH, —COC 1 -C 4 alkyl, —COC 1 -C 4 haloalkyl, an amino acid, an aza amino acid, a 2 to 60-mer peptide, a 2 to 60-mer aza peptide, a 2 to 60-mer azatide,

R 3 and R 4 is each independently selected from the group consisting of C 1 -C 6 alkyl, methoxyl, ethoxyl, propoxyl, a C 1 -C 6 haloalkyl and protecting groups,

R is selected from the group consisting of side chain radicals of aspartic acid, phenylalanine, alanine, histidine, glutamic acid, tryptophan, valine, leucine, lysine, methionine, tyrosine, isoleucine, arginine, glycine, asparagine, serine, threonine, cysteine, and glutamine.

13. The method of claim 12 , wherein the compound of claim 1 is substituted with one or more of the following: a halogen, a C 1 -C 6 alkyl, hydroxyl, —COOH, —COH, methoxyl, ethoxyl, propoxyl, or a C 1 -C 6 haloalkyl.

14. The method of claim 12 , wherein the compound according to claim 1 is activated by iodomethane.

15. The method of claim 12 , wherein said coupling is in acetonitrile.

16. The method of claim 9 , wherein DIPEA is added to the acetonitrile.

17. The method of claim 16 , wherein said coupling is during solid phase azapeptide synthesis.

18. The method of claim 12 , wherein said coupling is during liquid phase azapeptide synthesis.

19. The method of claim 12 , wherein the azapeptide is produced in a yield of at least about 50%.

20. The compound of claim 1 , wherein

A is N-phthalimidyl,

X is imidazolyl or benzotriazolyl, and

R is selected from the group consisting of H, methyl, isopropyl, isobutyl, benzyl, and side chain radicals of aspartic acid, histidine, glutamic acid, tryptophan, lysine, methionine, tyrosine, threonine, R-isoleucine, S-isoleucine, RS-isoleucine, arginine, glycine, asparagine, serine, and glutamine.

21. The compound of claim 1 , wherein A is NR 1 R 2 ,

R 1 is H,

R 2 is 9-fluorenylmethoxycarbonyl,

X is imidazolyl or benzotriazolyl, and

R is selected from the group consisting of H, isopropyl, isobutyl, and side chain radicals of aspartic acid, histidine, glutamic acid, tryptophan, lysine, methionine, tyrosine, threonine, R-isoleucine, S-isoleucine, RS-isoleucine, arginine, glycine, asparagine, serine, and glutamine.